tBHQ mitigates fatty liver ischemia-reperfusion injury by activating Nrf2 to attenuate hepatocyte mitochondrial damage and macrophage STING activation.

BACKGROUND: Liver ischemia-reperfusion (IR) injury is an inevitable pathophysiological process in various liver surgeries. Previous studies have found that IR injury is exacerbated in fatty liver due to significant hepatocellular damage and macrophage inflammatory activation, though the underlying mechanisms are not fully understood. In this study, we aim to explore the role and mechanism of Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling in regulating hepatocellular damage and macrophage immune response in fatty liver IR injury. METHODS: The study used high-fat diet-induced fatty liver mice to establish an IR model, alongside an in vitro co-culture system of primary hepatocytes and macrophages. This approach was used to examine mitochondrial dysfunction, oxidative stress, mitochondrial DNA (mtDNA) release, and activation of macrophage STING (Stimulator of interferon genes) signaling. We also conducted recovery verification using H-151 (a STING inhibitor) and tBHQ (an Nrf2 activator). RESULTS: Compared to the control group, mice on a high-fat diet demonstrated more severe liver IR injury, as evidenced by increased histological damage, elevated liver enzyme levels, and heightened inflammatory markers. The HFD group showed significant oxidative stress and mitochondrial dysfunction and damage post-IR, as indicated by elevated levels of ROS and lipid peroxidation markers, and decreased antioxidant enzyme activity. Elevated mtDNA release from hepatocytes post-IR activated macrophage STING signaling, worsening inflammation and liver damage. However, STING signaling inhibition with H-151 in vivo or employing STING knockout macrophages significantly reduced these injuries. In-depth mechanism studies have found that the transfer of Nrf2 protein into the nucleus of liver cells after IR in fatty liver is reduced. Pre-treatment with tBHQ ameliorated liver oxidative stress, mitochondrial damage and suppressed the macrophage STING signaling activation. CONCLUSIONS: Our study reveals a novel mechanism where the interaction between hepatocellular damage and macrophage inflammation intensifies liver IR injury in fatty liver. Enhancing Nrf2 activation to protect mitochondrial from oxidative stress damage and inhibiting macrophage STING signaling activation emerge as promising strategies for clinical intervention in fatty liver IR injury.

A Resonance-Sensitive Ultralow-Frequency Raman Mode in Twisted Bilayer Graphene.

Twisted bilayer graphene (tBLG) possesses intriguing physical properties including unconventional superconductivity, enhanced light-matter interaction due to the formation of van Hove singularities (vHS), and a divergence of density of states in the electronic band structures. The vHS energy band gap provides optical resonant transition channels that can be tuned by the twist angle and interlayer coupling. Raman spectroscopy provides rich information on the vHS structure of tBLG. Here, we report the discovery of an ultralow-frequency Raman mode at ∼49 cm-1 in tBLG. This mode is assigned to the combination of ZA (an out-of-plane acoustic phonon) and TA (a transverse acoustic phonon) phonons, and the Raman scattering is proposed to occur at the so-called mini-valley. This mode is found to be particularly sensitive to the change in vHS in tBLG. Our findings may deepen the understanding of Raman scattering in tBLG and help to reveal vHS-related electron-phonon interactions in tBLG.

Waveguide-integrated twisted bilayer graphene photodetectors.

Graphene photodetectors have exhibited high bandwidth and capability of being integrated with silicon photonics (SiPh), holding promise for future optical communication devices. However, they usually suffer from a low photoresponsivity due to weak optical absorption. In this work, we have implemented SiPh-integrated twisted bilayer graphene (tBLG) detectors and reported a responsivity of 0.65 A W-1 for telecom wavelength 1,550 nm. The high responsivity enables a 3-dB bandwidth of >65 GHz and a high data stream rate of 50 Gbit s-1. Such high responsivity is attributed to the enhanced optical absorption, which is facilitated by van Hove singularities in the band structure of high-mobility tBLG with 4.1o twist angle. The uniform performance of the fabricated photodetector arrays demonstrates a fascinating prospect of large-area tBLG as a material candidate for heterogeneous integration with SiPh.

A Novel Lysosome Targeting Chimera for Targeted Protein Degradation via Split-and-Mix Strategy.

Targeted protein degradation is becoming more and more important in the field of drug development. Compared with proteasomal-based degraders, lysosomal-based degraders have a broader target spectrum of targets, which have been demonstrated to have great potential, especially in degrading undruggable proteins. Recently, we developed a programmable and facile screening PROTAC development platform based on peptide self-assembly termed split-and-mix PROTAC (SM-PROTAC). In this study, we applied this technology for the development of lysosome-based degraders, named a split-and-mix chaperone-mediated autophagy-based degrader (SM-CMAD). We successfully demonstrated SM-CMAD as a universal platform by degrading several targets, including ERα, AR, MEK1/2, and BCR-ABL. Different from other lysosomal-based degraders, SM-CMAD was capable of facile screening with programmable ligand ratios. We believe that our work will promote the development of other multifunctional molecules and clinical translation for lysosomal-based degraders.

Mitochondrial dynamics as a novel treatment strategy for triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis. METHODS: The Wst-8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA-MB-231 (TNBC), and MCF-7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin-related protein-1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC). RESULTS: MDA-MB-231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)-based metabolism. HCC38, a doxorubicin-sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor-negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence-free survival. CONCLUSION: Our findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.

Selective Protein of Interest Degradation through the Split-and-Mix Liposome Proteolysis Targeting Chimera Approach.

Proteolysis Targeting Chimera (PROTAC) technology represents a promising new approach for target protein degradation using a cellular ubiquitin-proteasome system. Recently, we developed a split-and-mix nanoplatform based on peptide self-assembly, which could serve as a self-adjustable platform for multifunctional applications. However, the lower drug efficacy limits further biomedical applications of peptide-based SM-PROTAC. In this study, we develop a novel split-and-mix PROTAC system based on liposome self-assembly (LipoSM-PROTAC), concurrent with modification of FA (folate) to enhance its tumor-targeting capabilities. Estrogen receptors (ERα) were chosen as the protein of interest (POI) to validate the efficacy of Lipo degraders. Results demonstrate that this PROTAC can be efficiently and selectively taken up into the cells by FA receptor-positive cells (FR+) and degrade the POI with significantly reduced concentration. Compared to the peptide-based SM-PROTACs, our designed LipoSM-PROTAC system could achieve therapeutic efficacy with a lower concentration and provide opportunities for clinical translational potential. Overall, the LipoSM-based platform shows a higher drug efficacy, which offers promising potential applications for PROTAC and other biomolecule regulations.

Enhanced Layer-Breathing Modes in van der Waals Heterostructures Based on Twisted Bilayer Graphene.

The characterization of interlayer coupling in two-dimensional van der Waals heterostructures (vdWHs) is essential to understand their quantum behaviors and structural functionalities. Interlayer shear and layer-breathing (LB) phonons carry rich information on interlayer interaction, but they are usually too weak to be detected via standard Raman spectroscopy due to the weak electron-phonon coupling (EPC). Here, we report a universal strategy to enhance LB modes of vdWHs based on twisted bilayer graphene (tBLG). In both tBLG/hBN and tBLG/MoS2 vdWHs, the resonantly excited electrons in tBLG can strongly couple to LB phonons extended over the entire layers in the vdWHs, whose resonance condition is tunable by the twist angle of tBLG. In vdWHs containing twisted graphene layers with multiple twisted interfaces, the EPC of LB phonons coming from the collective LB vibrations of entire heterostructure layers can be tuned by resonant excitation of programmable van Hove singularities according to each twisted interface. The universality and tunability of enhanced LB phonons by tBLG make it a promising method to investigate EPC and interlayer interaction in related vdWHs.

Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach.

The development of bifunction al molecules, which can enable targeted RNA degradation, targeted protein acetylation, or targeted protein degradation, remains a time-consuming process that requires tedious optimization. We propose a split-and-mix nanoplatform that serves as a self-adjustable platform capable of facile screening, programmable ligand ratios, self-optimized biomolecule spatial recognition, and multifunctional applications. Herein, we demonstrate the potential of our proposed nanoplatform by showcasing proteolysis-targeting chimeras (PROTACs), namely, split-and-mix PROTAC (SM-PROTAC). We highlight the scope of our platform through the targeted disruption of intracellular therapeutic targets involving ERα, CDK4/6, AR, MEK1/2, BRD2/4, BCR-ABL, etc. These studies confirm the effectiveness and universality of the SM-PROTAC platform for proximity-induced applications. This platform is programmable, with significant potential applications to biomolecule regulation, including the fields of epigenetics, gene editing, and biomolecule modification regulation.

Online-Dynamic-Clustering-Based Soft Sensor for Industrial Semi-Supervised Data Streams.

In the era of big data, industrial process data are often generated rapidly in the form of streams. Thus, how to process such sequential and high-speed stream data in real time and provide critical quality variable predictions has become a critical issue for facilitating efficient process control and monitoring in the process industry. Traditionally, soft sensor models are usually built through offline batch learning, which remain unchanged during the online implementation phase. Once the process state changes, soft sensors built from historical data cannot provide accurate predictions. In practice, industrial process data streams often exhibit characteristics such as nonlinearity, time-varying behavior, and label scarcity, which pose great challenges for building high-performance soft sensor models. To address this issue, an online-dynamic-clustering-based soft sensor (ODCSS) is proposed for industrial semi-supervised data streams. The method achieves automatic generation and update of clusters and samples deletion through online dynamic clustering, thus enabling online dynamic identification of process states. Meanwhile, selective ensemble learning and just-in-time learning (JITL) are employed through an adaptive switching prediction strategy, which enables dealing with gradual and abrupt changes in process characteristics and thus alleviates model performance degradation caused by concept drift. In addition, semi-supervised learning is introduced to exploit the information of unlabeled samples and obtain high-confidence pseudo-labeled samples to expand the labeled training set. The proposed method can effectively deal with nonlinearity, time-variability, and label scarcity issues in the process data stream environment and thus enable reliable target variable predictions. The application results from two case studies show that the proposed ODCSS soft sensor approach is superior to conventional soft sensors in a semi-supervised data stream environment.

Mitochondrial DNA polymorphisms in COX1 affect the lifespan of Caenorhabditis elegans through nuclear gene dct-15.

Mutations in the mitochondrial DNA (mtDNA) are closely related to age and age-related complex diseases, but the exact regulatory mechanism of mtDNA natural variation or polymorphism and ageing remains unclear. Recently, nuclear genes that regulate mitochondrial functions and thereby influence ageing have been widely studied. In this study, the relationship between the retrograde communication from the mitochondria to the nucleus and its ultimate effect on ageing has been elucidated. This study found that the natural variations in COX1 of the mitochondria in the Caenorhabditis elegans population do not correlate with multiple phenotypes, except for a mild correlation with lifespan. After excluding the differences in the nuclear genome, the correlation between natural mitochondrial variation and lifespan increased significantly. Moreover, mtDNA variation downregulated the nuclear dct-15 gene expression, which consequently reduced the lifespan, development rate and motility of C. elegans. dct-15 mutations decreased mitochondria copy number but increased ATP content and mitochondrial ultrastructure. Thus, the results indicated that dct-15 interacted with the mitochondrial DNA polymorphisms in COX1 and is associated with ageing. Finally, bioinformatic analyses revealed that mtDNA variation regulated the structural constituent of the cuticle via dct-15 and suggested that the structural constituent of the cuticle could have an important role in the development and ageing processes. These results provide insights into the mtDNA mechanism that can alter the nuclear gene and thereby regulate ageing and ageing-related diseases.

DNA N6-Methyladenine Modification in Eukaryotic Genome.

DNA methylation is treated as an important epigenetic mark in various biological activities. In the past, a large number of articles focused on 5 mC while lacking attention to N6-methyladenine (6 mA). The presence of 6 mA modification was previously discovered only in prokaryotes. Recently, with the development of detection technologies, 6 mA has been found in several eukaryotes, including protozoans, metazoans, plants, and fungi. The importance of 6 mA in prokaryotes and single-celled eukaryotes has been widely accepted. However, due to the incredibly low density of 6 mA and restrictions on detection technologies, the prevalence of 6 mA and its role in biological processes in eukaryotic organisms are highly debated. In this review, we first summarize the advantages and disadvantages of 6 mA detection methods. Then, we conclude existing reports on the prevalence of 6 mA in eukaryotic organisms. Next, we highlight possible methyltransferases, demethylases, and the recognition proteins of 6 mA. In addition, we summarize the functions of 6 mA in eukaryotes. Last but not least, we summarize our point of view and put forward the problems that need further research.

Progress of CRISPR-Cas13 Mediated Live-Cell RNA Imaging and Detection of RNA-Protein Interactions.

Ribonucleic acid (RNA) and proteins play critical roles in gene expression and regulation. The relevant study increases the understanding of various life processes and contributes to the diagnosis and treatment of different diseases. RNA imaging and mapping RNA-protein interactions expand the understanding of RNA biology. However, the existing methods have some limitations. Recently, precise RNA targeting of CRISPR-Cas13 in cells has been reported, which is considered a new promising platform for RNA imaging in living cells and recognition of RNA-protein interactions. In this review, we first described the current findings on Cas13. Furthermore, we introduced current tools of RNA real-time imaging and mapping RNA-protein interactions and highlighted the latest advances in Cas13-mediated tools. Finally, we discussed the advantages and disadvantages of Cas13-based methods, providing a set of new ideas for the optimization of Cas13-mediated methods.

Toward Epitaxial Growth of Misorientation-Free Graphene on Cu(111) Foils.

The epitaxial growth of single-crystal thin films relies on the availability of a single-crystal substrate and a strong interaction between epilayer and substrate. Previous studies have reported the roles of the substrate (e.g., symmetry and lattice constant) in determining the orientations of chemical vapor deposition (CVD)-grown graphene, and Cu(111) is considered as the most promising substrate for epitaxial growth of graphene single crystals. However, the roles of gas-phase reactants and graphene-substrate interaction in determining the graphene orientation are still unclear. Here, we find that trace amounts of oxygen is capable of enhancing the interaction between graphene edges and Cu(111) substrate and, therefore, eliminating the misoriented graphene domains in the nucleation stage. A modified anomalous grain growth method is developed to improve the size of the as-obtained Cu(111) single crystal, relying on strongly textured polycrystalline Cu foils. The batch-to-batch production of A3-size (∼0.42 × 0.3 m2) single-crystal graphene films is achieved on Cu(111) foils relying on a self-designed pilot-scale CVD system. The as-grown graphene exhibits ultrahigh carrier mobilities of 68 000 cm2 V-1 s-1 at room temperature and 210 000 cm2 V-1 s-1 at 2.2 K. The findings and strategies provided in our work would accelerate the mass production of high-quality misorientation-free graphene films.

Positivity, creativity, and reappraisal's emotion regulation efficacy.

The relationship between cognitive reappraisal's creativity (both novelty and appropriateness), positivity (the positive or negative attitudes), and emotion regulation efficacy was analyzed. Positivity was found to play a full mediating role between creativity and regulation effectiveness.

Hetero-site nucleation for growing twisted bilayer graphene with a wide range of twist angles.

Twisted bilayer graphene (tBLG) has recently attracted growing interest due to its unique twist-angle-dependent electronic properties. The preparation of high-quality large-area bilayer graphene with rich rotation angles would be important for the investigation of angle-dependent physics and applications, which, however, is still challenging. Here, we demonstrate a chemical vapor deposition (CVD) approach for growing high-quality tBLG using a hetero-site nucleation strategy, which enables the nucleation of the second layer at a different site from that of the first layer. The fraction of tBLGs in bilayer graphene domains with twist angles ranging from 0° to 30° was found to be improved to 88%, which is significantly higher than those reported previously. The hetero-site nucleation behavior was carefully investigated using an isotope-labeling technique. Furthermore, the clear Moiré patterns and ultrahigh room-temperature carrier mobility of 68,000 cm2 V-1 s-1 confirmed the high crystalline quality of our tBLG. Our study opens an avenue for the controllable growth of tBLGs for both fundamental research and practical applications.

Invasive Micropapillary Carcinoma with CEP17 Monosomy of the Bilateral Breast: A Rare Case Report and Review of the Literature.

Invasive micropapillary carcinoma (IMPC) is a novel type of breast cancer which is potentially very aggressive and may show early lymphatic infiltration. Monosomy of chromosome 17 (m17) is rare in breast cancer, and according to the 2018 guidelines of the American Society of Clinical Oncology/College of American Pathologists, the decision to administer trastuzumab treatment should be made based on positive human epidermal growth factor receptor 2 results by immunohistochemistry. Here, we report a rare case of bilateral local advanced IMPC involving m17. A 33-year-old woman found a mass measuring 30 mm on the left breast that increased to 100 mm over 3 months. A diagnosis of IMPC was made based on the findings of core needle biopsies of bilateral breast masses and left axillary lymph node, and m17 was detected by fluorescence in situ hybridization (FISH). The patient underwent 6 cycles of neoadjuvant chemotherapy (docetaxel, epirubicin, and cyclophosphamide) and left-side modified radical mastectomy, left axillary lymph node dissection, right breast-conserving surgery, and right sentinel lymph node biopsy. Postoperative pathologic analysis of both breasts revealed IMPC, and m17 was confirmed by FISH. The patient received radiotherapy and endocrine therapy but rejected trastuzumab treatment. The patient was still alive at the 30-month follow-up, without recurrence or metastasis. Our findings suggest that loss of chromosome 17 may influence prognosis or therapeutic response, which needs to be further confirmed.

Large Single-Crystal Cu Foils with High-Index Facets by Strain-Engineered Anomalous Grain Growth.

The rich and complex arrangements of metal atoms in high-index metal facets afford appealing physical and chemical properties, which attracts extensive research interest in material science for the applications in catalysis and surface chemistry. However, it is still a challenge to prepare large-area high-index single crystals in a controllable and cost-efficient manner. Herein, entire commercially available decimeter-sized polycrystalline Cu foils are successfully transformed into single crystals with a series of high-index facets, relying on a strain-engineered anomalous grain growth technique. The introduction of a moderate thermal-contact stress upon the Cu foil during the annealing leads to the formation of high-index grains dominated by the thermal strain of the Cu foils, rather than the (111) surface driven by the surface energy. Besides, the designed static gradient of the temperature enables the as-formed high-index grain seed to expand throughout the entire Cu foil. The as-received high-index Cu foils can serve as the templates for producing high-index single-crystal Cu-based alloys. This work provides an appealing material basis for the epitaxial growth of 2D materials, and the applications that require the unique surface structures of high-index metal foils and their alloys.

Correction: Spatial distribution of heavy metals in the West Dongting Lake floodplain, China.

Correction for 'Spatial distribution of heavy metals in the West Dongting Lake floodplain, China' by Dong Peng et al., Environ. Sci.: Processes Impacts, 2020, DOI: .

Characterization of glycogen molecular structure in the worm Caenorhabditis elegans.

Glycogen, a glucose homopolymer with many glucose chains, is the primary blood-sugar reservoir in many organisms. It comprises ß particles (∼20 nm) which can bind together to form large α particles with a rosette morphology. When dimethyl sulfoxide (DMSO) is added to glycogen from diabetic livers, α particles break apart to ß particles ('fragility'), possibly due to H-bond disruption; this is not seen in healthy livers. Glycogen α and ß particles, and α-particle fragility, are observed in mammals and bacteria, and are examined here in the worm Caenorhabditis elegans, with glycogen from two C. elegans strains, cultured in normal and high-glucose conditions. There were mainly ß particles, with some large α particles. Most particles were fragile in DMSO. Growing in a high-glucose medium results in more long chains and more fragility, consistent with previous observations in diabetic animal models. Why high glucose levels facilitate fragility is worthy of further investigation.