Dysregulation of tRNA methylation in cancer: Mechanisms and targeting therapeutic strategies.

tRNA is the RNA type that undergoes the most modifications among known RNA, and in recent years, tRNA methylation has emerged as a crucial process in regulating gene translation. Dysregulation of tRNA abundance occurs in cancer cells, along with increased expression and activity of tRNA methyltransferases to raise the level of tRNA modification and stability. This leads to hijacking of translation and synthesis of multiple proteins associated with tumor proliferation, metastasis, invasion, autophagy, chemotherapy resistance, and metabolic reprogramming. In this review, we provide an overview of current research on tRNA methylation in cancer to clarify its involvement in human malignancies and establish a theoretical framework for future therapeutic interventions targeting tRNA methylation processes.

Screening and identification of miRNAs negatively regulating FAM83A/Wnt/ß-catenin signaling pathway in non-small cell lung cancer.

The prevalence of non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers, with the Wnt/ß-catenin signaling pathway exhibiting robust activation in this particular subtype. The expression of FAM83A (family with sequence similarity 83, member A) has been found to be significantly upregulated in lung cancer, leading to the stabilization of ß-catenin and activation of the Wnt signaling pathway. In this study, we conducted a screening of down-regulated miRNAs in lung cancer with FAM83A as the target. Ultimately, we identified miR-1 as a negative regulator of FAM83A and confirmed that FAM83A is a direct target gene of miR-1 through dual luciferase reporter assays. The overexpression of miR-1 significantly attenuated the expression level of FAM83A and suppressed the Wnt signaling pathway, leading to a reduction in the expression levels of downstream target genes AXIN2, CyclinD1, and C-MYC. Additionally, it decreased the nuclear translocation of ß-catenin. In addition, overexpression of miR-1 accelerated the degradation of ß-catenin by inhibiting FAM83A, promoted the assembly of ß-catenin degradation complex, and inhibited the proliferation, migration and invasion of NSCLC cells. In summary, miR-1 may be a potential candidate miRNA for the treatment of NSCLC.

Bayesian hybrid gamma-GPD model for extreme traffic conflict threshold determination in the peak over threshold approach.

Extreme value theory (EVT) models have been frequently utilized to estimate crash risk from traffic conflicts with the peak over threshold commonly used to identify conflict extremes. However, a common problem for the peak over threshold method is the selection of a suitable threshold to distinguish general and extreme conflicts. Subjective and arbitrary selection of the threshold in peak over threshold method can result in bias and unstable estimation results. The primary objective of the study is to propose a hybrid modelling approach for the threshold determination in peak over threshold method. The hybrid model consists of a joint gamma distribution and generalized Pareto distribution (GPD). The gamma distribution is used to fit general conflicts while the GPD is used to fit extreme conflicts. Specially, discontinued, continued and differentiable gamma-GPD models are developed with the threshold being treated as a model parameter. Traffic conflict data collected from three signalized intersections in the city of Surrey, British Columbia were used for the study. The modified time to collision (MTTC) was employed as conflict indicator. The Bayesian approach was employed to estimate the threshold as well as other hybrid gamma-GPD model parameters. The results show that the discontinued gamma-GPD model is superior to the continued and differentiable gamma-GPD models for determining the threshold in terms of crash estimation accuracy and model fit. The crash estimates using the threshold determined by the hybrid gamma-GPD model outperform those estimated based on the traditional quantile plots method, indicating that the superiority of the proposed threshold determination approach based on gamma-GPD hybrid model. The proposed hybrid gamma-GPD model could determine the threshold parameter in peak over threshold method for traffic conflicts extremes automatically in an objective and quantitative way. It contributes to existing peak over threshold method for producing reliable crash estimation.

LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance.

Pancreatic cancer is a malignancy with high mortality. In addition to the few symptoms until the disease reaches an advanced stage, the high fatality rate is attributed to its rapid development, drug resistance and lack of appropriate treatment. In the selection and research of therapeutic drugs, gemcitabine is the first-line drug for pancreatic cancer. Solving the problem of gemcitabine resistance in pancreatic cancer will contribute to the progress of pancreatic cancer treatment. Long non coding RNAs (lncRNAs), which are RNA transcripts longer than 200 nucleotides, play vital roles in cellular physiological metabolic activities. Currently, our group and others have found that some lncRNAs are aberrantly expressed in pancreatic cancer cells, which can regulate the process of cancer through autophagy and Wnt/ß-catenin pathways simultaneously and affect the sensitivity of cancer cells to therapeutic drugs. This review presents an overview of the recent evidence concerning the node of lncRNA for the cross-talk between autophagy and Wnt/ß-catenin signaling in pancreatic cancer, together with the practicability of lncRNAs and the core regulatory factors as targets in therapeutic resistance.

Bioinspired Flexible Hydrogelation with Programmable Properties for Tactile Sensing.

Tactile sensing requires integrated detection platforms with distributed and highly sensitive haptic sensing capabilities along with biocompatibility, aiming to replicate the physiological functions of the human skin and empower industrial robotic and prosthetic wearers to detect tactile information. In this regard, short peptide-based self-assembled hydrogels show promising potential to act as bioinspired supramolecular substrates for developing tactile sensors showing biocompatibility and biodegradability. However, the intrinsic difficulty to modulate the mechanical properties severely restricts their extensive employment. Herein, by controlling the self-assembly of 9-fluorenylmethoxycarbonyl-modifid diphenylalanine (Fmoc-FF) through introduction of polyethylene glycol diacrylate (PEGDA), wider nanoribbons are achieved by untwisting from well-established thinner nanofibers, and the mechanical properties of the supramolecular hydrogels can be enhanced 10-fold, supplying bioinspired supramolecular encapsulating substrate for tactile sensing. Furthermore, by doping with poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) and 9-fluorenylmethoxycarbonyl-modifid 3,4-dihydroxy-l-phenylalanine (Fmoc-DOPA), the Fmoc-FF self-assembled hydrogels can be engineered to be conductive and adhesive, providing bioinspired sensing units and adhesive layer for tactile sensing applications. Therefore, the integration of these modules results in peptide hydrogelation-based tactile sensors, showing high sensitivity and sustainable responses with intrinsic biocompatibility and biodegradability. The findings establish the feasibility of developing programmable peptide self-assembly with adjustable features for tactile sensing applications.

Sense and anti-sense: Role of FAM83A and FAM83A-AS1 in Wnt, EGFR, PI3K, EMT pathways and tumor progression.

An increasing number of studies have shown that FAM83A, a member of the family with sequence similarity 83 (FAM83), which consists of eight members, is a key tumor therapeutic target involved in multiple signaling pathways. It has been reported that FAM83A plays essential roles in the regulation of Wnt/ß-catenin, EGFR, MAPK, EMT, and other signaling pathways and physiological processes in models of pancreatic cancer, lung cancer, breast cancer, and other malignant tumors. Moreover, the expression of FAM83A could be significantly affected by multiple noncoding RNAs that are dysregulated in malignant tumors, the dysregulation of which is essential for the malignant process. Among these noncoding RNAs, the most noteworthy is the antisense long noncoding (Lnc) RNA of FAM83A itself (FAM83A-AS1), indicating an outstanding synergistic carcinogenic effect between FAM83A and FAM83A-AS1. In the present study, the specific mechanisms by which FAM83A and FAM83A-AS1 cofunction in the Wnt/ß-catenin and EGFR signaling pathways were reviewed in detail, which will guide subsequent research. We also described the applications of FAM83A and FAM83A-AS1 in tumor therapy and provided a certain theoretical basis for subsequent drug target development and combination therapy strategies.

The TRPV6 Calcium Channel and Its Relationship with Cancer.

Transient receptor potential vanilloid-6 (TRPV6) is a cation channel belonging to the TRP superfamily, specifically the vanilloid subfamily, and is the sixth member of this subfamily. Its presence in the body is primarily limited to the skin, ovaries, kidney, testes, and digestive tract epithelium. The body maintains calcium homeostasis using the TRPV6 channel, which has a greater calcium selectivity than the other TRP channels. Several pieces of evidence suggest that it is upregulated in the advanced stages of thyroid, ovarian, breast, colon, and prostate cancers. The function of TRPV6 in regulating calcium signaling in cancer will be covered in this review, along with its potential applications as a cancer treatment target.

ILKAP Promotes the Metastasis of Hepatocellular Carcinoma Cells by Inhibiting ß-Catenin Degradation and Enhancing the WNT Signaling Pathway.

The incidence of Hepatocellular carcinoma (HCC) and HCC-related deaths have remarkably increased over the recent decades. It has been reported that ß-catenin activation can be frequently observed in HCC cases. This study identified the integrin-linked kinase-associated phosphatase (ILKAP) as a novel ß-catenin-interacting protein. ILKAP is localized both in the nucleus and cytoplasm and regulates the WNT pathway in different ways. First, it is demonstrated that ILKAP activates the WNT pathway in HCC cells by increasing the protein level of ß-catenin and other proteins associated with the WNT signaling, such as c-Myc and CyclinD1. Next, it is shown that ILKAP promotes the metastasis of HCC both in vitro and in vivo in a zebrafish xenograft model. It is also found that ILKAP dephosphorylates the GSK3ß and CK1, contributing to the reduced ubiquitination of ß-catenin. Furthermore, it is identified that ILKAP functions by mediating binding between TCF4 and ß-catenin to enhance expression of WNT target genes. Taken together, the study demonstrates a critical function of ILKAP in metastasis of HCC, since ILKAP is crucial for the activation of the WNT pathway via stabilization of ß-catenin and increased binding between TCF4 and ß-catenin.

Insights into the Roles of Epigenetic Modifications in Ferroptosis.

Ferroptosis is a non-apoptotic mode of cell death driven by membrane lipid peroxidation and is characterized by elevated intracellular levels of Fe2+, ROS, and lipid peroxidation. Studies have shown that ferroptosis is related to the development of multiple diseases, such as cancer, neurodegenerative diseases, and acute myeloid leukemia. Ferroptosis plays a dual role in the occurrence and development of these diseases. Ferroptosis mainly involves iron metabolism, ROS, and lipid metabolism. Various mechanisms, including epigenetic regulation, have been reported to be deeply involved in ferroptosis. Abnormal epigenetic modifications have been reported to promote tumor onset or other diseases and resistance to chemotherapy drugs. In recent years, diversified studies have shown that epigenetic modification is involved in ferroptosis. In this review, we reviewed the current resistance system of ferroptosis and the research progress of epigenetic modification, such as DNA methylation, RNA methylation, non-coding RNAs, and histone modification in cancer and other diseases by regulating ferroptosis.

Deep neural networks for crack detection inside structures.

Crack detection is a long-standing topic in structural health monitoring. Conventional damage detection techniques rely on intensive, time-consuming, resource-intensive intervention. The current trend of crack detection emphasizes using deep neural networks to build an automated pipeline from measured signals to damaged areas. This work focuses on the seismic-wave-based technique of crack detection for plate structures. Previous work proposed an encoder-decoder network to extract crack-related wave patterns from measured wave signals and predict crack existence on the plate. We extend previous work with extensive experiments on different network components and a data preprocessing strategy. The proposed methods are tested on an expanded crack detection dataset. We found that a robust backbone network, such as Densely Connected Convolutional Network (DenseNet) can effectively extract the features characterizing cracks of wave signals, and by using the reference wave field for normalization, the accuracy of detecting small cracks can be further improved.

RUNDC1 negatively mediates the fusion of autophagosomes with lysosomes via regulating SNARE complex assembly.

Macroautophagy/autophagy is an essential pro-survival mechanism activated in response to nutrient deficiency. The proper fusion between autophagosomes and lysosomes is a critical step for autophagic degradation. We recently reported that RUNDC1 (RUN domain containing 1) inhibits autolysosome formation via clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding. We showed that RUNDC1 colocalizes with LC3 and associates with mature autophagosomes in cell lines and the zebrafish model. We utilized liposome fusion and in vitro autophagosome-lysosome fusion assays to demonstrate that RUNDC1 inhibits autolysosome formation. Moreover, we found that RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation, which in turn prevents VAMP8 from binding to STX17-SNAP29. Our results demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes and is crucial for zebrafish survival in nutrient-deficient conditions. Here, we summarize our findings and discuss their implications for our understanding of autophagy regulation.

Injectable cell-laden silk acid hydrogel.

This study presents an injectable cell-laden hydrogel system based on silk acid, a carboxylated derivative of natural silk fibroin, which exhibits promising applications in biomedicine. The hydrogel is produced under physiological conditions (37 °C and pH 7.4) via physical crosslinking. Notably, the hydrogel demonstrates remarkable cytocompatibility, enabling efficient cell encapsulation, and exhibits good injectability. These promising results strongly indicate the potential of silk acid hydrogel for transformative applications, including 3D cell culture, targeted cell delivery, and tissue engineering.

Energy Applications of Ionic Liquids: Recent Developments and Future Prospects.

Ionic liquids (ILs) consisting entirely of ions exhibit many fascinating and tunable properties, making them promising functional materials for a large number of energy-related applications. For example, ILs have been employed as electrolytes for electrochemical energy storage and conversion, as heat transfer fluids and phase-change materials for thermal energy transfer and storage, as solvents and/or catalysts for CO2 capture, CO2 conversion, biomass treatment and biofuel extraction, and as high-energy propellants for aerospace applications. This paper provides an extensive overview on the various energy applications of ILs and offers some thinking and viewpoints on the current challenges and emerging opportunities in each area. The basic fundamentals (structures and properties) of ILs are first introduced. Then, motivations and successful applications of ILs in the energy field are concisely outlined. Later, a detailed review of recent representative works in each area is provided. For each application, the role of ILs and their associated benefits are elaborated. Research trends and insights into the selection of ILs to achieve improved performance are analyzed as well. Challenges and future opportunities are pointed out before the paper is concluded.

Cellular senescence: a double-edged sword in cancer therapy.

Over the past few decades, cellular senescence has been identified in cancer patients undergoing chemotherapy and radiotherapy. Senescent cells are generally characterized by permanent cell cycle arrest as a response to endogenous and exogenous stresses. In addition to exiting the cell cycle process, cellular senescence also triggers profound phenotypic changes such as senescence-associated secretory phenotype (SASP), autophagy modulation, or metabolic reprograming. Consequently, cellular senescence is often considered as a tumor-suppressive mechanism that permanently arrests cells at risk of malignant transformation. However, accumulating evidence shows that therapy-induced senescence can promote epithelial-mesenchymal transition and tumorigenesis in neighboring cells, as well as re-entry into the cell cycle and activation of cancer stem cells, thereby promoting cancer cell survival. Therefore, it is particularly important to rapidly eliminate therapy-induced senescent cells in patients with cancer. Here we review the hallmarks of cellular senescence and the relationship between cellular senescence and cancer. We also discuss several pathways to induce senescence in tumor therapy, as well as strategies to eliminate senescent cells after cancer treatment. We believe that exploiting the intersection between cellular senescence and tumor cells is an important means to defeat tumors.

RUNDC1 inhibits autolysosome formation and survival of zebrafish via clasping ATG14-STX17-SNAP29 complex.

Autophagy serves as a pro-survival mechanism for a cell or a whole organism to cope with nutrient stress. Our understanding of the molecular regulation of this fusion event remains incomplete. Here, we identified RUNDC1 as a novel ATG14-interacting protein, which is highly conserved across vertebrates, including zebrafish and humans. By gain and loss of function studies, we demonstrate that RUNDC1 negatively modulates autophagy by blocking fusion between autophagosomes and lysosomes via inhibiting the assembly of the STX17-SNAP29-VAMP8 complex both in human cells and the zebrafish model. Moreover, RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation. This also prevents VAMP8 from binding to STX17-SNAP29. We further identified that phosphorylation of RUNDC1 Ser379 is crucial to inhibit the assembly of the STX17-SNAP29-VAMP8 complex via promoting ATG14 homo-oligomerization. In line with our findings, RunDC1 is crucial for zebrafish in their response to nutrient-deficient conditions. Taken together, our findings demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes by clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding.

Tunable 1D and 2D Polyacrylonitrile Nanosheet Superstructures.

Carbon superstructures are widely applied in energy and environment-related areas. Among them, the flower-like polyacrylonitrile (PAN)-derived carbon materials have shown great promise due to their high surface area, large pore volume, and improved mass transport. In this work, we report a versatile and straightforward method for synthesizing one-dimensional (1D) nanostructured fibers and two-dimensional (2D) nanostructured thin films based on flower-like PAN chemistry by taking advantage of the nucleation and growth behavior of PAN. The resulting nanofibers and thin films exhibited distinct morphologies with intersecting PAN nanosheets, which formed through rapid nucleation on existing PAN. We further constructed a variety of hierarchical PAN superstructures based on different templates, solvents, and concentrations. These PAN nanosheet superstructures can be readily converted to carbon superstructures. As a demonstration, the nanostructured thin film exhibited a contact angle of ∼180° after surface modification with fluoroalkyl monolayers, which is attributed to high surface roughness enabled by the nanosheet assemblies. This study offers a strategy for the synthesis of nanostructured carbon materials for various applications.

The Effect of Rolling Texture on the Plastic Deformation of Nano-Gradient Aluminum.

Creating alloys with a gradient microstructure in grain size has been shown to be a potential method to resolve the trade-off dilemma between strength and ductility. However, different textures developed with various processing methods cannot be fully eliminated, which can significantly affect the mechanical behavior of alloys. In this study, we use a multiscale framework based on dislocation theory to investigate how the combination of rolling texture and gradient in grain size affects the plastic deformation of nano-gradient aluminum during a tensile test. We found that specific rolling textures, such as {110} texture, can significantly enhance the strength and ductility of nano-gradient aluminum. This improvement is the result of the grain being reoriented and the redistribution of stress and strain, which are caused by the combined influence of texture and variation in grain size. These results provide new insights into developing high-performance aluminum by mediating texture and grain size gradient.

Silk Acid as an Implantable Biomaterial for Tissue Regeneration.

Silk fibroin derived from the domesticated silkworm Bombyx mori is a protein-based biopolymer with low immunogenicity, intrinsic biodegradability, and tunable mechanical properties, showing great potential in biomedical applications. Using chemical modification to alter the primary structure of silk fibroin enables the expanded generation of new silk-based biomaterials. Inspired by the molecular structure of hyaluronic acid, which is enriched in carboxyl groups, an efficient method with scaling-up potential to achieve controlled carboxylation of silk fibroin to prepare silk acid (SA) is reported, and the biological properties of SA are further studied. The SA materials show tunable hydrophilicity and enzymatic degradation properties at different carboxylation degrees (CDs). Subcutaneous implantation in mice for up to 1 month reveals that the SA materials with a high CD present enhanced degradation while causing a mild foreign-body response, including a low inflammatory response and reduced fibrotic encapsulation. Immunofluorescence analysis further indicates that the SA materials show pro-angiogenesis properties and promote M2-type macrophage polarization to facilitate tissue regeneration. This implies great promise for SA materials as a new implantable biomaterial for tissue regeneration.

Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells.

Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.