TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.

Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An ,intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall not only shed insight into cancer progression but also benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. Whether and how TFE3 responds to glucose starvation remain unclear. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.

YTHDF2 protein stabilization by the deubiquitinase OTUB1 promotes prostate cancer cell proliferation via PRSS8 mRNA degradation.

Prostate cancer is a leading cause of cancer-related mortality in males. Dysregulation of RNA adenine N-6 methylation (m6A) contributes to cancer malignancy. m6A on mRNA may affect mRNA splicing, turnover, transportation, and translation. m6A exerts these effects, at least partly, through dedicated m6A reader proteins, including YTH domain-containing family protein 2 (YTHDF2). YTHDF2 is necessary for development while its dysregulation is seen in various cancers, including prostate cancer. However, the mechanism underlying the dysregulation and function of YTHDF2 in cancer remains elusive. Here, we find that the deubiquitinase OUT domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) increases YTHDF2 protein stability by inhibiting its ubiquitination. With in vivo and in vitro ubiquitination assays, OTUB1 is shown to block ubiquitin transfer to YTHDF2 independent of its deubiquitinase activity. Furthermore, analysis of functional transcriptomic data and m6A-sequencing data identifies PRSS8 as a potential tumor suppressor gene. OTUB1 and YTHDF2 decrease mRNA and protein levels of PRSS8, which is a trypsin-like serine protease. Mechanistically, YTHDF2 binds PRSS8 mRNA and promotes its degradation in an m6A-dependent manner. Further functional study on cellular and mouse models reveals PRSS8 is a critical downstream effector of the OTUB1-YTHDF2 axis in prostate cancer. We find in prostate cancer cells, PRSS8 decreases nuclear ß-catenin level through E-cadherin, which is independent of its protease activity. Collectively, our study uncovers a key regulator of YTHDF2 protein stability and establishes a functional OTUB1-YTHDF2-PRSS8 axis in prostate cancer.

Synthesis of Biobased Poly(butylene Furandicarboxylate) Containing Polysulfone with Excellent Thermal Resistance Properties.

A synthetic biopolymer derived from furandicarboxylic acid monomer and hydroxyethyl-terminated poly(ether sulfone) is presented. The synthesis involves 4,4'-dichlorodiphenyl sulfone and 4,4-dihydroxydiphenyl sulfone, resulting in poly(butylene furandicarboxylate)-poly(ether sulfone) copolyesters (PBFES) through melt polycondensation with titanium-catalyzed polymerization. This facile method yields segmented polyesters incorporating polysulfone, creating a versatile group of high-temperature thermoplastics with adjustable thermomechanical properties. The PBFES copolyesters demonstrate an impressive tensile modulus of 2830 MPa and a tensile strength of 84 MPa for PBFES55. Additionally, the poly(ether sulfone) unit imparts a relatively high glass transition temperature (Tg), ranging from 36.6 °C for poly(butylene 2,5-furandicarboxylate) to 112.3 °C for PBFES62. Moreover, the complete amorphous film of PBFES exhibits excellent transparency and solvent resistance, making it suitable for applications, such as food packaging materials.

The P53-P21-RB1 pathway promotes BRD4 degradation in liver cancer through USP1.

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the pro-tumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer.

Vertical Distribution Mapping for Methane Fugitive Emissions Using Laser Path-Integral Sensing in Non-Cooperative Open Paths.

Observing the vertical diffusion distribution of methane fugitive emissions from oil/gas facilities is significant for predicting the pollutant's spatiotemporal transport and quantifying the random emission sources. A method is proposed for methane's vertical distribution mapping by combining the laser path-integral sensing in non-non-cooperative open paths and the computer-assisted tomography (CAT) techniques. It uses a vertical-plume-mapping optical path configuration and adapts the developed dynamic relaxation and simultaneous algebraic reconstruction technique (DR-SART) into methane-emission-distribution reconstruction. A self-made miniaturized TDLAS telemetry sensor provides a reliable path to integral concentration information in non-non-cooperative open paths, with Allan variance analysis yielding a 3.59 ppm·m sensitivity. We employed a six-indexes system for the reconstruction performance analysis of four potential optical path-projection configurations and conducted the corresponding validation experiment. The results have shown that that of multiple fan-beams combined with parallel-beam modes (MFPM) is better than the other optical path-projection configurations, and its reconstruction similarity coefficient (ε) is at least 22.4% higher. For the different methane gas bag-layout schemes, the reconstruction errors of maximum concentration (γm) are consistently around 0.05, with the positional errors of maximum concentration (δ) falling within the range of 0.01 to 0.025. Moreover, considering the trade-off between scanning duration and reconstruction accuracy, it is recommended to appropriately extend the sensor measurement time on a single optical path to mitigate the impact of mechanical vibrations induced by scanning motion.

Strontium-Containing Piezoelectric Biofilm Promotes Dentin Tissue Regeneration.

It remains an obstacle to induce the regeneration of hard dentin tissue in clinical settings. To overcome this, a P(VDF-TrFE) piezoelectric film with 2 wt% SrCl2 addition is designed. The biofilm shows a high flexibility, a harmonious biocompatibility, and a large piezoelectric d33 coefficient of 14 pC N-1 , all contributing to building an electric microenvironment that favor the recruitment of dental pulp stem cells (DPSCs) and their differentiation into odontoblasts during normal chewing, speaking, etc. On the other hand, the strontium ions can be gradually released from the film, thus promoting DPSC odonto-differentiation. In vivo experiments also demonstrate that the film induces the release of dentin minerals and regeneration of dentin tissue. In the large animal dentin defect models, this piezoelectric film induces in situ dentin tissue formation effectively over a period of three months. This study illustrates a therapeutic potential of the piezoelectric film to improve dentin tissue repair in clinical settings.

Characteristics of tunable aluminum-doped Ga2O3thin films and photodetectors.

Aluminum-doped Ga2O3(AGO) thin films were prepared by plasma-enhanced atomic layer deposition (PE-ALD). The growth mechanism, surface morphology, chemical composition, and optical properties of AGO films were systematically investigated. The bandgap of AGO films can be theoretically set between 4.65 and 6.8 eV. Based on typical AGO films, metal-semiconductor-metal photodetectors (PDs) were created, and their photoelectric response was examined. The preliminary results show that PE-ALD grown AGO films have high quality and tunable bandgap, and AGO PDs possess superior characterizations to undoped films. The AGO realized using PE-ALD is expected to be an important route for the development of a new generation of gallium oxide-based photodetectors into the deep-ultraviolet.

Structural organization of the retriever-CCC endosomal recycling complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of vacuolar protein-sorting-associated protein (VPS)35L, VPS26C and VPS29, together with the CCC complex comprising coiled-coil domain-containing (CCDC)22, CCDC93 and copper metabolism domain-containing (COMMD) proteins, plays a crucial role in this process. The precise mechanisms underlying retriever assembly and its interaction with CCC have remained elusive. Here, we present a high-resolution structure of retriever in humans determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog retromer. By combining AlphaFold predictions and biochemical, cellular and proteomic analyses, we further elucidate the structural organization of the entire retriever-CCC complex across evolution and uncover how cancer-associated mutations in humans disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with retriever-CCC-mediated endosomal recycling.

Effectivenes of incentive constraint policies in enhancing green bond credit rating and certification: A theoretical and empirical study.

This paper aims to effectively reduce CO2 emissions by examining the impact of three distinct incentive and constraint policies on the quality of rating and certification information in China's green bond issuance market. To accomplish this, the government has implemented incentives, while regulators have introduced constraints to curb the spread of inflated rating and certification information. We build on the integrated rating and certification regulation mechanism by presenting a two-stage Stackelberg game model that involves four key participants: the China Securities Regulatory Commission, local governments, green evaluation and certification agencies, and credit rating agencies. We incorporate environmental effects indicators into the expected utility of rating and certification agencies to investigate the equilibrium conditions under three policy scenarios: a single financial incentive policy, a single regulatory constraint policy, and a combined incentive and constraint policy. The paper employs Stackelberg game theory to analyze how different policies mitigate the occurrence of "inflated" ratings and "greenwashing" in certifications. Numerical analysis is conducted to validate the theoretical findings. Moreover, we assess the impact of these policies on the quality of rating and evaluation information, using data from China's green bond issuance market between 2016 and 2021. Our research offers valuable management insights and regulatory recommendations for both regulators and local governments.

Study on Efficacy of Non-cutting Traction Seton Technique on Perianal Abscess.

Objective: Investigating the therapeutic effect of the non-cutting traction seton technique on perianal abscess. Methods: The clinical data of 70 patients with perianal abscesses diagnosed and treated by the Department of Anorectal Surgery of University Affiliated Hospital from January 2020 to December 2021 were collected, and conducted a retrospective study on them, of which 40 cases were treated with non-cut traction seton in the study group, and other 30 cases were treated with perianal abscess incision and drainage in the control group. The perioperative indexes (operation time, intraoperative bleeding volume, time of postoperative dressing change, time of postoperative granulation tissue formation, postoperative defecation-control ability, postoperative pain score, postoperative wound cleanliness) and follow-up indexes (wound healing time, incontinence Wexner score, recurrence rate, patient satisfaction) were compared between these two groups. Results: The operation time of the study group was more than that of the control group, and the difference was not statistically significant (P > .05). The intraoperative bleeding volume, time of postoperative dressing change, time of postoperative granulation tissue formation, the scores on postoperative defecation-control ability, the scores on postoperative wound cleanliness, postoperative complication rate, postoperative pain score, time of wound healing, incontinence Wexner score, and recurrence rate all from the study group were better than those in the control group. The patient satisfaction from the study group was higher than that in the control group, and the above differences were statistically significant (P < .05). Conclusion: Non-cutting traction suture technique has obvious advantages in the treatment of perianal abscess, shortening wound healing time and granulation tissue formation time, reducing intraoperative blood loss and postoperative complication rate, etc. It provides a reference for clinical treatment of perianal abscess.

A stretchable hardness sensor for the assessment of skin disease in systemic sclerosis.

OBJECTIVE: To determine the validity of a hardness sensor to objectively assess skin induration in patients with systemic sclerosis, and to compare the hardness sensor with the modified Rodnan skin score (MRSS) and a durometer. METHODS: The skin induration was measured in two assessments: a Latin square experiment to examine the hardness sensor's intraobserver and interobserver reliability; and a longitudinal cohort to evaluate the distribution of hardness sensor measurements, the correlation between hardness sensor, durometer and MRSS, and the sensitivity to change in skin hardness. Other outcome data collected included the health assessment questionnaire (HAQ) disability index and Keitel function test (KTF) score. RESULTS: The reliability of the hardness sensor was excellent, with high intraobserver and interobserver intraclass correlation coefficients (0.97; 0.96), which was higher than MRSS (0.86; 0.74). Interobserver reproducibility of hardness sensor was only poor in abdomen (0.38), yet for durometer it was poor in face (0.11) and abdomen (0.33). The hardness sensor score provided a greater dynamic evaluation range than MRSS. Total hardness sensor score correlated well with MRSS (r=0.90, p<0.001), total durometer score (r=0.95, p<0.001), HAQ disability index (r=0.70, p<0.001) and KTF score (r=0.66, p<0.001). Change in hardness sensor score also correlated with change in MRSS (r=0.78, p<0.001), total durometer score (r=0.85, p<0.001), HAQ disability index (r=0.76, p<0.001) and KTF score (r=0.67, p<0.001). CONCLUSION: The hardness sensor showed greater reproducibility and accuracy than MRSS, and more application sites than durometer; it can also reflect patients' self-assessments and function test outcomes.

Macroscopic Piezoelectricity of Halide Perovskite Single Crystals and Their Highly Sensitive Self-Powered X-ray Detectors.

The FAxMA1-xPbI3 single crystal has excellent semiconductor photoelectric performance and good stability; however, there have been conflicting opinions regarding its macroscopic piezoelectricity. Here, the FAxMA1-xPbI3 (x = 0-0.1) single crystals (FAx SCs) exhibit a high macroscopic piezoelectric d33 coefficient of over 10 pC/N. The single crystal transforms from a tetragonal ferroelectric phase to a cubic paraelectric phase at x = 0.1-0.125. Furthermore, the fully polarized MAPbI3 and FA0.05 SCs were applied to prepare self-powered X-ray detectors with vertical structures. The sensitivity of the detector reaches 5.1 × 104 µC·Gy-1·cm-2 under a 0 V bias voltage, and its detection limit is as low as 50 nGy/s. This work provides an approach to designing self-powered and high-quality detectors with piezoelectric semiconductors.

Neoadjuvant docetaxel, oxaliplatin plus capecitabine versus oxaliplatin plus capecitabine for patients with locally advanced gastric adenocarcinoma: long-term results of a phase III randomized controlled trial.

BACKGROUND: Neoadjuvant chemotherapy with docetaxel, oxaliplatin, and capecitabine (DOX regimen) is rarely used in Eastern countries and its efficacy and safety in advanced gastric cancer have not been reported. In this open-label, randomized, controlled trial, the authors aimed to assess the clinical efficacy of neoadjuvant chemotherapy using the DOX and oxaliplatin plus capecitabine (XELOX) regimens, in comparison to surgery alone. MATERIALS AND METHODS: Three hundred patients younger than 60 years with potentially resectable advanced gastric cancer (cT3-4, Nany, M0) were enrolled in this randomized controlled clinical trial between November 2014 and June 2018. The primary endpoint of the study was the pathological complete response (pCR) rate. Secondary endpoints included 3-year overall survival (OS), 3-year disease-free survival. RESULTS: In total, 280 patients (93 in the DOX group, 92 in the XELOX group, and 95 in the surgery group) were included in the per-protocol analysis. The DOX group demonstrated a significantly higher pCR rate compared to the XELOX group (16.1 vs. 4.3%, P =0.008). For patients with intestinal type, the DOX group exhibited significantly higher rates of both pCR and major pathological response compared to the XELOX group ( P =0.007, P <0.001). The 3-year OS rates of the DOX group, the XELOX group and the surgery group were 56.9, 44.6, and 34.7%, respectively. The 3-year disease-free survival rates were 45.2, 40.2, and 28.4%, respectively. The neoadjuvant DOX regimen demonstrated a significant improvement in the 3-year OS of patients compared to the neoadjuvant XELOX regimen ( P =0.037). CONCLUSION: The neoadjuvant DOX regimen has shown the potential to increase the pCR rate and improve the prognosis of patients with advanced gastric cancer who are under 60 years old.

Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

[Sc©[3]CPP]+: A Viable Metal-Centered [3]Cycloparaphenylene.

[n]Cycloparaphenylenes ([n]CPPs, n denotes the number of phenyl groups) are difficult to synthesize because of the strain related to their bent phenyl rings. In particular, the strain in [3]CPP is high enough to destroy the π electron delocalization, leading to the spontaneous structural transition to an energetically more stable "bond-shift" (BS) isomer ([3]BS). In this contribution, we propose to achieve [3]CPP by enhancing the π electron delocalization through hosting a guest metal atom. Our computations revealed that Sc could stabilize [3]CPP by forming the [Sc©[3]CPP]+ complex through the favorable π-Sc donation-backdonation interactions. Thermodynamically, the binding energy between the Sc atom and [3]CPP was -205.7 kcal/mol, which could well compensate not only the energy difference of 44.2 kcal/mol between [3]CPP and [3]BS but also the extremely high strain energy of 170.3 kcal/mol in [3]CPP. Simultaneously, the [Sc©[3]CPP]+ complex is stable up to 1500 K in dynamic simulations, suggesting its high viability in the synthesis.

Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

Schottky Barrier Control of Self-Polarization for a Colossal Ferroelectric Resistive Switching.

Controlling the domain evolution is critical both for optimizing ferroelectric properties and for designing functional electronic devices. Here we report an approach of using the Schottky barrier formed at the metal/ferroelectric interface to tailor the self-polarization states of a model ferroelectric thin film heterostructure system SrRuO3/(Bi,Sm)FeO3. Upon complementary investigations of the piezoresponse force microscopy, electric transport measurements, X-ray photoelectron/absorption spectra, and theoretical studies, we demonstrate that Sm doping changes the concentration and spatial distribution of oxygen vacancies with the tunable host Fermi level which modulates the SrRuO3/(Bi,Sm)FeO3 Schottky barrier and the depolarization field, leading to the evolution of the system from a single domain of downward polarization to polydomain states. Accompanied by such modulation on self-polarization, we further tailor the symmetry of the resistive switching behaviors and achieve a colossal on/off ratio of ∼1.1 × 106 in the corresponding SrRuO3/BiFeO3/Pt ferroelectric diodes (FDs). In addition, the present FD also exhibits a fast operation speed of ∼30 ns with a potential for sub-nanosecond and an ultralow writing current density of ∼132 A/cm2. Our studies provide a way for engineering self-polarization and reveal its strong link to the device performance, facilitating FDs as a competitive memristor candidate used for neuromorphic computing.

Study of an Ultrasensitive Label-Free Electrochemiluminescent Immunosensor Fabricated with a Composite Electrode for Detecting the Glutamate Decarboxylase Antibody.

Antibody testing for the glutamic acid decarboxylase 65 antibody (GADA) is widely used as a golden standard for autoimmune diabetes diagnosis, while current methods for antibody testing are not sensitive enough for clinical usage. Here, a label-free electrochemiluminescent (ECL) immunosensor for detecting GADA in autoimmune diabetes is fabricated and investigated. In the designed immunosensor, a composite film including the multiwalled carbon nanotubes (MWCNTs), zinc oxide (ZnO), and Au nanoparticles (AuNPs) was prepared through nanofabrication processes to improve the performance of sensor. The MWCNTs, which can provide a larger specific surface area, ZnO as a good photocatalytic material, and AuNPs that can enhance the ECL signal of luminol and immobilize the GAD65 antigen were applied to prefunctionalize indium tin oxide (ITO) glass based on a nanofabrication process. The GADA concentration was detected using the ECL immunosensor after incubating with GAD65 antigen-coated prefunctionalized ITO glass. After a direct immunoreaction, it is found that the degree of decreased ECL intensity has a good linear regression toward the logarithm of the GADA concentration in the range of 0.01 to 50 ng mL-1 with a detection limit down to 10 pg mL-1. Human serum samples positive or negative for GADA all nicely fell in the expected area. The fabricated immunosensor with excellent sensitivity, specificity, and stability has potential capability for clinical usage in GADA detection.

Effect of Curing Conditions on the Hydration of MgO in Cement Paste Mixed with MgO Expansive Agent.

Using the volume expansion generated by the hydration of the MgO expansive agent to compensate for the shrinkage deformation of concrete is considered to be an effective measure to prevent concrete shrinkage and cracking. Existing studies have mainly focused on the effect of the MgO expansive agent on the deformation of concrete under constant temperature conditions, but mass concrete in practical engineering experiences a temperature change process. Obviously, the experience obtained under constant temperature conditions makes it difficult to accurately guide the selection of the MgO expansive agent under actual engineering conditions. Based on the C50 concrete project, this paper mainly investigates the effect of curing conditions on the hydration of MgO in cement paste under actual variable temperature conditions by simulating the actual temperature change course of C50 concrete so as to provide a reference for the selection of the MgO expansive agent in engineering practice. The results show that temperature was the main factor affecting the hydration of MgO under variable temperature curing conditions, and the increase in the temperature could obviously promote the hydration of MgO in cement paste, while the change in the curing methods and cementitious system had an effect on the hydration of MgO, though this effect was not obvious.