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Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) constitute a mammalian STE20-like serine/threonine kinase subfamily. Recent studies provide substantial evidence for MAP4K family kinases in the Hippo pathway regulation, suggesting a broad role of MAP4Ks in human physiology and diseases. However, a comprehensive analysis of the regulators and effectors for this key kinase family has not been fully achieved. Using a proteomic approach, we define the protein-protein interaction network for human MAP4K family kinases and reveal diverse cellular signaling events involving this important kinase family. Through it, we identify a STRIPAK complex component, STRN4, as a generic binding partner for MAP4Ks and a key regulator of the Hippo pathway in endometrial cancer development. Taken together, the results of our study not only generate a rich resource for further characterizing human MAP4K family kinases in numerous biological processes but also dissect the STRIPAK-mediated regulation of MAP4Ks in the Hippo pathway.

The Hippo pathway, which plays a critical role in organ size control and cancer, features numerous WW domain-based protein-protein interactions. However, ~100 WW domains and 2,000 PY motif-containing peptide ligands are found in the human proteome, raising a "WW-PY" binding specificity issue in the Hippo pathway. In this study, we have established the WW domain binding specificity for Hippo pathway components and uncovered a unique amino acid sequence required for it. By using this criterion, we have identified a WW domain-containing protein, STXBP4, as a negative regulator of YAP. Mechanistically, STXBP4 assembles a protein complex comprising α-catenin and a group of Hippo PY motif-containing components/regulators to inhibit YAP, a process that is regulated by actin cytoskeleton tension. Interestingly, STXBP4 is a potential tumor suppressor for human kidney cancer, whose downregulation is correlated with YAP activation in clear cell renal cell carcinoma. Taken together, our study not only elucidates the WW domain binding specificity for the Hippo pathway, but also reveals STXBP4 as a player in actin cytoskeleton tension-mediated Hippo pathway regulation.

Single-molecule cytoplasmic dynein function is well understood, but there are major gaps in mechanistic understanding of cellular dynein regulation. We reported a mode of dynein regulation, force adaptation, where lipid droplets adapt to opposition to motion by increasing the duration and magnitude of force production, and found LIS1 and NudEL to be essential. Adaptation reflects increasing NudEL-LIS1 utilization; here, we hypothesize that such increasing utilization reflects CDK5-mediated NudEL phosphorylation, which increases the dynein-NudEL interaction, and makes force adaptation possible. We report that CDK5, 14-3-3ε, and CDK5 cofactor KIAA0528 together promote NudEL phosphorylation and are essential for force adaptation. By studying the process in COS-1 cells lacking Tau, we avoid confounding neuronal effects of CDK5 on microtubules. Finally, we extend this in vivo regulatory pathway to lysosomes and mitochondria. Ultimately, we show that dynein force adaptation can control the severity of lysosomal tug-of-wars among other intracellular transport functions involving high force.

The Hippo pathway, a signaling pathway highly conserved across species, plays a crucial role in organ size control and cancer suppression. Our recent study shows that phosphatidic acid can regulate the Hippo pathway through a physical lipid-protein interaction, providing additional insights into the Hippo-related tissue homeostasis and cancer development.

Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal cancer. Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/β-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by β-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer. Genetic ablation of TMEM9 inhibits colorectal cancer cell proliferation in vitro, ex vivo and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/β-catenin signalling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for colorectal cancer treatment.

Over the past decades, the Hippo has been established as a crucial pathway involved in organ size control and cancer suppression. Dysregulation of Hippo signaling and hyperactivation of its downstream effector YAP are frequently associated with various human cancers. However, the underlying significance of such YAP activation in cancer development and therapy has not been fully characterized. In this study, we reported that the Hippo signaling deficiency can lead to a YAP-dependent oncogene addiction for cancer cells. Through a clinical compound library screen, we identified histone deacetylase (HDAC) inhibitors as putative inhibitors to suppress YAP expression. Importantly, HDAC inhibitors specifically targeted the viability and xenograft tumor growth for the cancer cells in which YAP is constitutively active. Taken together, our results not only establish an active YAP-induced oncogene addiction in cancer cells, but also lay the foundation to develop targeted therapies for the cancers with Hippo dysfunction and YAP activation.

Solid–liquid triboelectric nanogenerators (S–L TENGs) are extensively researched for their capability to harvest mechanical energy from natural sources. Nevertheless, some TENGs based on friction electrification and electrostatic induction are partially limited, and liquids exhibit slow separation speeds upon contact with solid interfaces, resulting in lower output currents and voltages. This limitation hinders their ability to satisfy real-world electricity demands. This study introduces a wave-driven closed polytetrafluoroethylene tube TENG (PT-TENG) and enhances the conventional tank car model by applying the principle of interface charge transfer. The improvements enable the output current and voltage to reach 900 μA and 150 V, respectively, with a power output of 17.74 mW. This represents a thirteen-fold increase over the traditional model's performance, effectively capturing the kinetic energy of water flow. The mechanism and influencing factors of the PT-TENG are analysed, including the effect of external conditions on the movement state of water flow within the device, to enhance PT-TENG's output. This novel S–L TENG efficiently gathers low-frequency energy, offering a straightforward manufacturing process and elevated output. It enhances charge transfer at the solid–liquid interface and offers a new strategy for harvesting ocean wave energy. [ABSTRACT FROM AUTHOR]

Automatic ship detection is a crucial task within the domain of maritime transportation management. With the progressive success of convolutional neural networks (CNNs), a number of advanced CNN models have been presented in order to detect ships. Although these detection models have achieved marked performance, several undesired results may occur under complex maritime conditions, such as missed detections, false positives, and low detection accuracy. Moreover, the existing detection models endure large number of parameters and heavy computation cost. To deal with these problems, we suggest a lightweight ship model of detection called DSSM–LightNet based upon the improved YOLOv8n. First, we introduce a lightweight Dual Convolutional (DualConv) into the model to lower both the number of parameters and the computational complexity. The principle is that DualConv combines two types of convolution kernels, 3x3 and 1x1, and utilizes group convolution techniques to effectively reduce computational costs while processing the same input feature map channels. Second, we propose a Slim-neck structure in the neck network, which introduces GSConv and VoVGSCSP modules to construct an efficient feature-fusion layer. This fusion strategy helps the model better capture the features of targets of different sizes. Meanwhile, a spatially enhanced attention module (SEAM) is leveraged to integrate with a Feature Pyramid Network (FPN) and the Slim-neck to achieve simple yet effective feature extraction, minimizing information loss during feature fusion. CIoU may not accurately reflect the relative positional relationship between bounding boxes in some complex scenarios. In contrast, MPDIoU can provide more accurate positional information in bounding-box regression by directly minimizing point distance and considering comprehensive loss. Therefore, we utilize the minimum point distance IoU (MPDIoU) rather than the Complete Intersection over Union (CIoU) Loss to further enhance the detection precision of the suggested model. Comprehensive tests carried out on the publicly accessible SeaShips dataset have demonstrated that our model greatly exceeds other algorithms in relation to their detection accuracy and efficiency, while reserving its lightweight nature. [ABSTRACT FROM AUTHOR]

Because low-impact development (LID) infrastructures are effective in capturing and utilizing urban stormwater runoff, real-time control (RTC) strategies can be viewed as soft infrastructures, offering an additional suite of opportunities to improve the stormwater drainage system performance. However, there is a paucity of analyses that disentangle the contributing sources of performance enhancement in these joint hard–soft stormwater infrastructures. This study evaluated the stormwater system performance with integrated LID infrastructures, in-sewer storage capacity, and RTC strategies. Our results showed that LID infrastructures play a major role in mitigating the flow peaks and high volumes, whereas adding RTC to the storage unit and in-sewer flow control mostly improves the performance under relatively small rainfall events, e.g., those with a 3-year return period. The critical contribution of RTC is realized by utilizing storage units as much as possible during the rainfall event. A downstream storage unit that is too close to the outfall may not be suitable for RTC application together with in-sewer capacity utilization. In the present case, the combination of a midstream storage unit and upstream control site at branch pipes worked better than those at other locations. The results suggest that the integration of LID and RTC on a simulation-system level can enhance the reduction of the peak runoff and total discharged volume only if the storage site and control locations are selected carefully. [ABSTRACT FROM AUTHOR]

AbstractElectrochromic devices (ECDs) have broad application prospects in smart windows, low-power displays, anti-glare rearview mirrors, and so on. The electrolyte layer is one of the crucial components of ECDs acting as an interface layer between two electrodes to provide ions transport. Conventional liquid electrolytes have disadvantages of easy leakage, low safety and complex encapsulation, while inorganic solid electrolytes (ISEs) have very poor room temperature conductivity. Polymer electrolytes are composites consisting of polymeric matrices, solvents, conductive salts and curing agents, including solid polymer electrolytes (SPEs), gel polymer electrolytes (GPEs) and composite polymer electrolytes (CPEs). They are widely used in ECDs because of their excellent ionic conductivity, superior electrochemical stability, high transparency and simplicity of processing. This review provides a detailed discussion of the types, mechanisms, characteristics and preparation methods of polymer electrolytes for ECDs. The latest research progresses in the design and application of CPEs based on poly(ethylene oxide) (PEO), poly(methyl methacrylate) (PMMA), poly(vinylidene fluoride) (PVDF) and poly(vinyl alcohol) (PVA) are highlighted, and the potential applications of polymer electrolytes in the field of electrochromism are reviewed. Furthermore, the future development of polymer electrolytes in ECDs with stability, significant coloration efficiency and high ionic conductivity is discussed. [ABSTRACT FROM AUTHOR]

Epithelial integrity is maintained by the cytoskeleton and through cell adhesion. However, it is not yet known how a deregulated cytoskeleton is associated with cancer. We identified cancer-related regulator of actin dynamics (CRAD) as frequently mutated or transcriptionally downregulated in colorectal cancer. We found that CRAD stabilizes the cadherin-catenin-actin complex via capping protein inhibition. The loss of CRAD inhibits F-actin polymerization and subsequently disrupts the cadherin-catenin-actin complex, which leads to β-catenin release and Wnt signalling hyperactivation. In mice, CRAD knockout induces epithelial cell integrity loss and Wnt signalling activation, resulting in the development of intestinal mucinous adenoma. With APC mutation, CRAD knockout initiates and accelerates mucinous and invasive adenoma development in the colorectum. These results define CRAD as a tumour suppressor, the inactivation of which deregulates the cytoskeleton and hyperactivates Wnt signalling thus initiating mucinous colorectal cancer. Our study reveals the unexpected roles of an actin cytoskeletal regulator in maintaining epithelial cell integrity and suppressing tumorigenesis.

The Hippo pathway plays a crucial role in organ size control and tumor suppression, but its precise regulation is not fully understood. In this study, we discovered that phosphatidic acid (PA)-related lipid signaling is a key regulator of the Hippo pathway. Supplementing PA in various Hippo-activating conditions activates YAP. This PA-related lipid signaling is involved in Rho-mediated YAP activation. Mechanistically, PA directly interacts with Hippo components LATS and NF2 to disrupt LATS-MOB1 complex formation and NF2-mediated LATS membrane translocation and activation, respectively. Inhibition of phospholipase D (PLD)-dependent PA production suppresses YAP oncogenic activities. PLD1 is highly expressed in breast cancer and positively correlates with YAP activation, suggesting their pathological relevance in breast cancer development. Taken together, our study not only reveals a role of PLD-PA lipid signaling in regulating the Hippo pathway but also indicates that the PLD-PA-YAP axis is a potential therapeutic target for cancer treatment.

Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCFSKP2 E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function. Independently of Hippo signaling, mutation of YAP's K63-linkage specific ubiquitination sites K321 and K497, depletion of SKP2, or overexpression of OTUD1 retains YAP in the cytoplasm and inhibits its activity. Conversely, overexpression of SKP2 or loss of OTUD1 leads to nuclear localization and activation of YAP. Altogether, our study sheds light on the ubiquitination-mediated, Hippo-independent regulation of YAP.