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The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 ( SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1. Despite being a promising treatment for hepatocellular carcinoma (HCC), resistance to tyrosine kinase inhibitors (TKI) present a major obstacle. Here, the authors demonstrate that lipid metabolism reprogramming via URI mediated stearoyl-CoA desaturase 1 upregulation present a targetable driver of sorafenib resistance in HCC.

Objective To investigate the important active sites within the NTFs to affect the in vitro interaction of oxidized low-density lipoprotein (ox-LDL) with its receptor, OLR1. Methods Simulation analysis online was performed to generate various OLR1 chimeras, truncation mutants, and site-specific mutations. They were transfected in COS-7 cells and subjected to ox-LDL stimulations to observe the different reactions. Immunoprecipitation-mass spectrometry (IP-MS) was performed to show what proteins combined with OLR1 mutants in reaction to ox-LDL. Lipid uptake in human monocytes (THP-1) originated foam cells overexpressing somatic mutant of OLR1 were also determined. Further studies focusing on these regions were conducted using truncation mutants and site-specific mutants such as G43A, V44A, L45A, C46A, and L47A. Results Amino acids within the TM were highly conserved, spanning amino acids 35 to 57. The induction of intracellular p-ERK1/2 in response to ox-LDL stimulation was highly promoted in Chimera 3 possessing the TM from OLR1 like OLR1/WT (p < 0.05). Sequence alignment revealed two conserved regions within the TM of OLR1, Leu45-Cys46-Leu47 and Val55-Leu56-Gly57. Western blot showed that most of the TM changes ablated ERK1/2 activation in response to ox-LDL stimulation (p < 0.05). One human somatic mutation at L45F revealed significantly lower p-ERK1/2 levels with enhanced intake of ox-LDL in THP-1-derived foam cells than the control cells (p < 0.05). L45A and C46A molecular complexes were identified. After ox-LDL stimulation, these underlined interactions with keratins, namely KRT2 and KRT6A. Conclusion These findings emphasize the vital role of the TM in the interactions between OLR1 and ox-LDL and point to an exciting possibility that signal transduction induced by ox-LDL through its receptor OLR1 may involve complex interactions with cytoskeletal proteins.

The Baihetan Hydropower Station, the second largest in the world, is currently impounded, posing significant challenges to reservoir slope stability and nearby community’s safety. Thus, continuous monitoring as well as updation of landslide inventory is pressing requirements. InSAR technology, with its mm-scale precision and round-the-year usability, will be highly effective in this region. However, single-source SAR data are limited for long-term detection, and traditional atmospheric models in InSAR grapple with attenuating the external atmospheric disturbances caused by impoundment, affecting InSAR accuracy. Therefore, we used multi-source SAR data (ALOS PALSAR and Sentinel-1A/B), and used time-series InSAR with the GACOS atmospheric correction model to accurately detect and update landslide inventory before and during impoundment. The results show that a total of 52 landslides were detected, including 31 newly detected during impoundment. Among them, 22 landslides have toe slopes in direct contact with water. Comparing landslides before and during impoundment, deformations exhibit three behaviors: new deformation emergence, weakening of existing deformation, and continuous increase. These landslides mainly develop in landforms with an inclination angle of 30° to 40°, trending northeast and northwest, and an altitude of 800 to 1200 m. Most landslides reside in non-massive rock strata and are modulated by fault zones, and their frequency diminishes with increasing distance from the reservoir boundary. Moreover, the deformation time series results show that intense summer rainfall and rapid reservoir water level rise are key factors accelerating deformation in active landslides and reactivating unstable slopes. Thus, this research can be directly used for landslide prevention and mitigation in the Baihetan reservoir area, providing an important reference for detecting similar reservoir landslides in atmospherically influenced areas.

Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA. We investigated the prognostic value and clinical relevance of TLS in CCA using a surgery cohort containing 471 CCA patients (cohort 1) and an immunotherapy cohort containing 100 CCA patients (cohort 2). Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were used to evaluate the maturity of TLS. Multiplex IHC (mIHC) was employed to characterize the composition of TLS. Different maturity of TLS were observed in CCA tissue sections. Strong staining of the four-gene signature including PAX5, TCL1A, TNFRSF13C, and CD79A were found in TLS regions. A high density of intra-tumoral TLS (T-score high) were significantly correlated with longer overall survival (OS) both in CCA cohort 1 (p = 0.002) and cohort 2 (p = 0.01), whereas a high density of peri-tumoral TLS (P-score high) were associated with shorter OS in these two cohorts (p = 0.003 and p = 0.03, respectively). The established four-gene signature efficiently identified the TLS in CCA tissues. The abundance and spatial distribution of TLS were significantly correlated with the prognosis and immune checkpoint inhibitors (ICIs) immunotherapy response of CCA patients. The presence of intra-tumoral TLS are positive prognostic factors for CCA, which provide a theoretical basis for the future diagnosis and treatment of CCA.

In technology and industrial production, many applications require wide-bandwidth current measurements. In this paper, a signal fusion scheme for a current sensor comprising tunneling magnetoresistance and a current transformer is proposed, achieving a flat frequency response in the DC to MHz range. The measurement principles in different cases of the scheme are introduced, and the total transfer function of the entire scheme is derived by analyzing each section separately. Furthermore, the feasibility and selected parameters of the scheme are verified through a systematic simulation utilizing the MATLAB software. Based on the proposed scheme, a group of principal prototypes are built to experimentally evaluate the bandwidth, amplitude and phase flatness, accuracy, sensitivity, and impulse response. The relative amplitude variation in the passband of the fusion sensor is less than 4%, and the estimated bandwidth of the fusion sensor is close to 17 MHz. The accuracy is better than 0.6%, even when measuring the current at 1 MHz, and the relative standard deviation is 5% when measuring the impulse signal. The sensors developed using this scheme, with a low financial cost, have advantages in many wide-bandwidth current measuring scenarios.

WUSCHEL-related homeobox (WOX) is a large group of transcription factors specifically found in plants. WOX members contain the conserved homeodomain essential for plant development by regulating cell division and differentiation. However, the evolutionary relationship of WOX members in plant kingdom remains to be elucidated. In this study, we searched 350 WOX members from 50 species in plant kingdom. Linkage analysis of WOX protein sequences demonstrated that amino acid residues 141–145 and 153–160 located in the homeodomain are possibly associated with the function of WOXs during the evolution. These 350 members were grouped into 3 clades: the first clade represents the conservative WOXs from the lower plant algae to higher plants; the second clade has the members from vascular plant species; the third clade has the members only from spermatophyte species. Furthermore, among the members of Arabidopsis thaliana and Oryza sativa, we observed ubiquitous expression of genes in the first clade and the diversified expression pattern of WOX genes in distinct organs in the second clade and the third clade. This work provides insight into the origin and evolutionary process of WOXs, facilitating their functional investigations in the future.

NRF2 is the master transcriptional activator of cytoprotective genes and Kelch-like ECH-associated protein 1 (Keap1), a biosensor for electrophiles and oxidation, promotes NRF2 degradation in unstressed conditions. SQSTM1/p62, an oncogenic protein aberrantly accumulated in hepatocellular carcinoma (HCC), binds and sequestrates Keap1, leading to the prevention of NRF2 degradation. Here, we show that p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A) is highly expressed in HCC tumors and correlated with aggressive clinicopathological features. RPRD1A competitively interacts with TRIM21, an E3 ubiquitin ligase of p62, resulting in the decrease of p62 ubiquitination and the increased sequestration for Keap1. Therefore, RPRD1A enhances the nuclear translocation of NRF2, which induces gene expression for counteracting oxidative stress, maintaining cancer cells survival, and promoting HCC development. Moreover, disturbing the redox homeostasis of cancer cells by genetic knockdown of RPRD1A sensitizes cancer cells to platinum-induced cell death. Our study reveals RPRD1A is involved in the oxidative stress defense program and highlights the therapeutic benefits of targeting pathways that support antioxidation.

The Arabidopsis thaliana ABORTED MICROSPORES (AMS) gene encodes a basic helix-loop-helix (bHLH) transcription factor that is required for tapetal cell development and postmeiotic microspore formation. However, the regulatory role of AMS in anther and pollen development has not been fully defined. Here, we show by microarray analysis that the expression of 549 anther-expressed genes was altered in ams buds and that these genes are associated with tapetal function and pollen wall formation. We demonstrate that AMS has the ability to bind in vitro to DNA containing a 6-bp consensus motif, CANNTG. Moreover, 13 genes involved in transportation of lipids, oligopeptides, and ions, fatty acid synthesis and metabolism, flavonol accumulation, substrate oxidation, methyl-modification, and pectin dynamics were identified as direct targets of AMS by chromatin immunoprecipitation. The functional importance of the AMS regulatory pathway was further demonstrated by analysis of an insertional mutant of one of these downstream AMS targets, an ABC transporter, White-Brown Complex homolog, which fails to undergo pollen development and is male sterile. Yeast two-hybrid screens and pull-down assays revealed that AMS has the ability to interact with two bHLH proteins (AtbHLH089 and AtbHLH091) and the ATA20 protein. These results provide insight into the regulatory role of the AMS network during anther development.

Leather dyeing is a critical step in leather manufacturing, as it is responsible for providing leather products with an eye-catching visual aspect and adequate quality properties to meet customers' expectations. This step is becoming more and more challenging as the leather industry advances hand in hand with new environmentally friendly policies and regulations to achieve a safer and healthier planet by replacing the highly polluting Cr-based leather tanning technology with greener alternatives. As a result, achieving high-performance dyeing of organic chrome-free leather is one of the bottlenecks for the sustainable development of the leather industry. Herein, we propose a novel strategy to fabricate an isocyanate-based oligomeric dye (IBD) with high coloring capabilities (component content higher than 62.8%) based on toluene 2,4-diisocyanate and reactive red dye 180. This material has been tested for the dyeing of biomass-derived aldehyde (BDA)-tanned leather with excellent outcomes. The experimental results showed that the crust leather dyed with our novel IBD dyeing agent had higher color fastness and better fullness than the leather dyed with conventional anionic (CAD) or reactive red 180 (RRD-180) dyes. These excellent and promising results open new avenues in manufacturing high-performance organic Cr-free leather products and help to ensure the sustainable transition of the leather industry from Cr-based leather tanning to more sustainable alternatives, maintaining the final quality of the leather products.

The relative risk and benefits of Laparoscopic liver resection (LLR) are still controversial. This study aimed to evaluate perioperative and survival outcomes for three primary malignant liver tumors related outcomes following LLR. Data from three Homogeneous-High-Volume-Expert-Centers were collected. Multivariable logistic regression analysis was performed for the association between LLR, and major complications defined as Clavien-Dindo Classification grade ≥ II. Multivariable Cox proportional hazards regression was used to explore the impact of LLR on primary malignant liver tumor survival. Overall, 5886 patients underwent liver resection, of which 1991 underwent LLR. After adjusting for covariables, LLR had significantly lower rate of CDC grade ≥ II (OR = 0.56, 95% CI: 0.48–0.67, P  < 0.001). Interaction analysis showed that LLR had significant association with sex, drinking status, history of abdominal surgery, and platelet count (all P  < 0.05). The overall survival for each primary malignant liver tumor shown potential risk but without significantly different between LLR and OLR (all P  > 0.05). LLR was associated with lower rate of major complications, especially in women, non-drinkers, those without a history of abdominal surgery, and those with normal platelet. For primary malignant liver tumors, the survival outcomes did not differ significantly between LLR and OLR.