NUMA1 modulates apoptosis of esophageal squamous cell carcinoma cells through regulating ASK1-JNK signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide with a low survival rate due to a lack of therapeutic targets. Here, our results showed that nuclear mitotic apparatus protein 1 (NUMA1) transcript and protein levels are significantly upregulated in ESCC patient samples and its high expression predicated poor prognosis. Knock-down of NUMA1 promoted cell apoptosis and suppressed cell proliferation and colony formation. By using cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice models, we found silencing the NUMA1 expression suppressed tumor progression. In addition, conditional knocking-out of NUMA1 reduced 4NQO-induced carcinogenesis in mice esophagus, which further confirmed the oncogenic role of NUMA1 in ESCC. Mechanistically, from the immunoprecipitation assay we revealed that NUMA1 interacted with GSTP1 and TRAF2, promoted the association of TRAF2 with GSTP1 while inhibited the interaction of TRAF2 and ASK1, thus to regulate sustained activation of JNK. In summary, our findings suggest that NUMA1 plays an important role during ESCC progression and it functions through regulating ASK1-MKK4-SAPK/JNK signaling pathway.

Diaphragms simulation, fabrication, and testing of a high temperature fiber optic F-P accelerometer based on MEMS.

High-sensitivity detection of vibrations under high temperatures is a topic of great interest in modern engineering such as thermal engine deep-sea aquaculture factory ship, aerospace, high temperature casting, energy, etc. As traditional accelerometers and some fiber optic F-P accelerometers have shown their sensing limits at about 400 °C and 650 °C, respectively, a high temperature fiber optic F-P accelerometer based on MEMS technology is proposed. To obtain a high-performance chip for the sensor, an examination of the theoretical performance of an L and Г-shaped cantilever beam diaphragm shows a sensitivity of 15.05 nm/g and 53.7 nm/g, respectively, and a wide working frequency range. Thanks to the designed sensor's various protections, frequency measurements with a high-temperature performance of 850 °C are recorded. The L-shaped cantilever beams diaphragm allows the sensor measurements at 850 °C with a repeatability of 5.46%, a working frequency range of 100-1000 Hz, an experimental sensitivity of 389 mV/g, an overall stability of 8 jumps at its adjacent frequency resolution range over 150 measurements, a linearity of 0.9856 and a maximum relative error maintained below 1.72%. In the field of application, it also exhibits a good relative error of measurement respecting the technical specification of 5 Hz.

A retrospective case-control study of facial emotion recognition in male veterans with chronic schizophrenia and its correlation with interpersonal communication.

OBJECTIVE: To understand the facial emotion recognition of male veterans with chronic schizophrenia and the relationship between facial emotion recognition and interpersonal communication to provide a reference for designing social skills training programmes. METHOD: Fifty-six eligible male patients with chronic schizophrenia who were admitted to our hospital from October 2020 to April 2021 were selected, and 24 healthy people were selected as controls. Facial emotion recognition, social communication skills and self-perceived interpersonal disturbance were assessed using a facial emotion recognition stimulus manual, the Social Skills Checklist (SSC) and the Interpersonal Relationship Integrative Diagnostic Scale (IRIDS). Disease status was assessed using the Positive and Negative Syndrome Scale. RESULTS: Both the control group and the patient group had the highest recognition accuracy for neutral faces. The recognition rate for neutral expression was higher in the control group than in the patient group (p = 0.008). The rate of neutral expressions identified as happiness was higher in the patient group than in the control group (p = 0.001). The identification of anger as happiness was higher in the control group than in the patient group (p = 0.026), and the pattern of misidentification was similar between the control group and the patient group. The accuracy of facial emotion recognition was negatively associated with the age of onset (p < 0.05). The recognition accuracy for happiness was negatively associated with negative symptoms, general pathological symptoms and total scale scores (p < 0.05). The total score for expression recognition was negatively associated with the negative symptom subscale scores (p < 0.05), and there was no correlation between expression recognition and positive symptoms (p > 0.05). The recognition accuracy for happiness was negatively correlated with the IRIDS conversation factor (p < 0.05). The recognition accuracy for happiness and anger and the total scores for facial emotion recognition were negatively correlated with the SSC subscale score and the total score (p < 0.05 and p < 0.01, respectively). The main influencing factors on facial emotion recognition were the SSC total score (p < 0.001) and the positive factor score (p = 0.039). CONCLUSION: Veterans with chronic schizophrenia have facial emotion recognition impairments affected by negative symptoms. There is a correlation between facial emotion recognition and interpersonal communication. HIGHLIGHTS: 1. There are extensive facial expression recognition disorders in schizophrenia. 2. The pattern of misidentification was similar in both the control group and the patient group, with the tendency for happiness to be identified as a neutral emotion, anger as happiness, and fear as neutral emotion and anger. 3. Based on the comprehensive assessment of social cognitive impairment in patients with schizophrenia, prospective studies of standardised interventions are designed to provide support for clinical practice.

Structural basis for multifunctional roles of human Ints3 C-terminal domain.

Proper repair of damaged DNA is critical for the maintenance of genome stability. A complex composed of Integrator subunit 3 (Ints3), single-stranded DNA-binding protein 1 (SSB1), and SSB-interacting protein 1 (SSBIP1) is required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs) and ataxia-telangiectasia mutated (ATM)-dependent signaling pathways. It is known that in this complex the Ints3 N-terminal domain scaffolds SSB1 and SSBIP1. However, the molecular basis for the function of the Ints3 C-terminal domain remains unclear. Here, we present the crystal structure of the Ints3 C-terminal domain, uncovering a HEAT-repeat superhelical fold. Using structure and mutation analysis, we show that the C-terminal domain exists as a stable dimer. A basic groove and a cluster of conserved residues on two opposite sides of the dimer bind single-stranded RNA/DNA (ssRNA/ssDNA) and Integrator complex subunit 6 (Ints6), respectively. Dimerization is required for nucleic acid binding, but not for Ints6 binding. Additionally, in vitro experiments using HEK 293T cells demonstrate that Ints6 interaction is critical for maintaining SSB1 protein level. Taken together, our findings establish the structural basis of a multifunctional Ints3 C-terminal module, allowing us to propose a novel mode of nucleic acid recognition by helical repeat protein and paving the way for future mechanistic studies.

F-box only protein 9 and its role in cancer.

The F-box proteins (FBP), substrate recognition subunit of the SCF (Skp1-Cullin1-F-box protein complex) E3 ligase, play important roles in the ubiquitylation and subsequent degradation of the target proteins from several cellular processes. Disorders of F-box protein-mediated proteolysis lead to human malignancies. FBP plays an important role in many cellular processes, including cell proliferation, cell cycle, apoptosis, migration, invasion, and metastasis, suggesting that it can be associated with tumorigenesis, cancer development and progression. However, the expression and function of FBXO9 (F-box only protein 9) differ in various types of human cancer. Due to the ability to regulate the stability and activity of oncogenes and tumor-suppressor genes, and the physiological functions of many of the F-box proteins remain subtle, further genetic and mechanistic studies will elaborate and help define FBXO9's role. Targeting F-box protein or F-box protein signaling pathways could be an effective strategy for preventing or treating human cancer. This review is presented to summarize the part of FBXO9 in different types of human cancer and its regulation mechanism, and to pave the way to design FBXO9-targeting anticancer therapies.

Systematic Review and Meta-Analysis of Lysine-Specific Demethylase 1 Expression as a Prognostic Biomarker of Cancer Survival and Disease Progression.

BACKGROUND: Numerous studies on the prognostic significance of lysine-specific demethylase 1 (LSD1) up-regulation in tumors have different outcomes. The inconsistency originated from various studies looking into the association between LSD1 and tumor cells has prompted the decision of this quantitative systematic review to decipher how up-regulated LSD1 and overall survival (OS) or recurrence-free survival (RFS) or disease-free survival (DFS) are linked in tumor patients. METHODS: Articles were searched from online databases such as Embase, Web of Science Core, PubMed, Google Scholar, and Scopus. The extraction of the hazard ratios (HR) with their 95% confidence intervals (CIs) was attained and survival data of 3151 tumor patients from 17 pieces of related research were used for this meta-analysis. RESULTS: To shed light on the link between LSD1 up-regulation and the prognosis of diverse tumors, the pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were determined. In this meta-analysis, it was observed that LSD1 up-regulation is linked with poor OS (HR = 2.08, 95% CI: 1.66-2.61, P < .01) and RFS (HR = 3.09, 95% CI: 1.81-5.26, P < .01) in tumor patients. However, LSD1 up-regulation was not linked to DFS (HR = 1.49, 95% CI: .83-2.69, P = .18) in tumor patients. The subcategory examination grouped by tumor type and ethnicity showed that LSD1 up-regulation was linked with a poor outcome in the esophageal tumor and hepatocellular carcinoma and Asian patients, respectively. For clinical-pathological factors, up-regulated LSD1 was significantly linked with Lymph node status. CONCLUSION: Despite the shortfall of the present work, this meta-analysis proposes that LSD1 up-regulation may be a prognostic biomarker for patients with tumors including esophageal tumors and hepatocellular carcinoma. We propose that large-scale studies are vital to substantiate these outcomes.

Visible to near-infrared photodetector based on SnSe2/WSe2heterojunction with potential application in artificial visual neuron.

Two-dimensional (2d) transition-metal dichalcogenides (TMDCs) are promising candidate materials for developing next generation nano optoelectronic devices, due to their strong interaction with light. In addition, the free of surface dangling bonds makes it possible to stacking any different types of 2D TMDCs together to form heterojunctions with desirable band structures for various applications. However, most of the 2D TMDCs are bipolar or strong unipolar n-type doped, while very few of them show weak p-type doping, which severely affects the performance of the formed heterojunctions. In this work, we fabricated a SnSe2/WSe2heterojunction of type II band alignment with a small bandgap of ∼0.1 eV, which is ideally for developing optoelectronic devices responsible to a broad light spectrum. N2O plasma treatment is applied to enhance the p-type doping of both WSe2and SnSe2, which results in the increased on-off ratio of n-type SnSe2by 50 times and the hole mobility of WSe2by 527 times. The WSe2/SnSe2heterostructure also achieves a decent performance as a p-n junction, which exhibits photo responsivity of 450 mA W-1and 133 mA W-1for 700 nm visible light and 1600 nm infrared light, respectively, without any gate or source-drain bias, showing great photovoltaic effect. Moreover, the heterojunction shows great promise as an artificial visual neuron, which can differentiate the dark, visible and infrared light illumination conditions by applying a series of electrical pulses through the back-gate electrode.

UV light modulated synaptic behavior of MoTe2/BN heterostructure.

Electrical synaptic devices are the basic components for the hardware based neuromorphic computational systems, which are expected to break the bottleneck of current von Neumann architecture. So far, synaptic devices based on three-terminal transistors are considered to provide the most stable performance, which usually use gate pulses to modulate the channel conductance through a floating gate and/or charge trapping layer. Herein, we report a three-terminal synaptic device based on a two-dimensional molybdenum ditelluride (MoTe2)/hexagonal boron nitride (hBN) heterostructure. This structure enables stable and prominent conductance modulation of the MoTe2channel by the photo-induced doping method through electron migration between the MoTe2channel and ultraviolet (UV) light excited mid-gap defect states in hBN. Therefore, it is free of the floating gate and charge trapping layer to reduce the thickness and simplify the fabrication/design of the device. Moreover, since UV illumination is indispensable for stable doping in MoTe2channel, the device can realize both short- (without UV illumination) and long- (with UV illumination) term plasticity. Meanwhile, the introduction of UV light allows additional tunability on the MoTe2channel conductance through the wavelength and power intensity of incident UV, which may be important to mimic advanced synaptic functions. In addition, the photo-induced doping method can bidirectionally dope MoTe2channel, which not only leads to large high/low resistance ratio for potential multi-level storage, but also implement both potentiation (n-doping) and depression (p-doping) of synaptic weight. This work explores alternative three-terminal synaptic configuration without floating gate and charge trapping layer, which may inspire researches on novel electrical synapse mechanisms.

A non-canonical GTPase interaction enables ORP1L-Rab7-RILP complex formation and late endosome positioning.

Endosomal transport represents the primary mode for intracellular trafficking and signaling transduction and thus has to be tightly controlled. The molecular processes controlling the endosomal positioning utilize several large protein complexes, one of which contains the small GTPase Rab7, Rab-interacting lysosomal protein (RILP), and oxysterol-binding protein-related protein 1 (ORP1L). Rab7 is known to interact with RILP through a canonical binding site termed the effector-interacting switch region, but it is not clear how Rab7 interacts with ORP1L, limiting our understanding of the overall process. Here, we report structural and biochemical investigation of the Rab7-ORP1L interaction. We found that, contrary to prior studies, the interaction between Rab7 and the N-terminal ankyrin repeat domain (ARDN) of ORP1L is independent of Rab7's GTP- or GDP-binding state. Moreover, we show that Rab7 interacts with ORP1L ARDN via a unique region consisting of helix3 (α3) and 310-helix 2 (η2). This architecture leaves the canonical effector-interacting switch regions available for RILP binding and thus allows formation of the ORP1L-Rab7-RILP tripartite complex. Mutational disruption of the interacting interface between ORP1L and Rab7 compromised the ability of ORP1L-Rab7-RILP to regulate the late endosome positioning. Collectively, our results again manifested the versatility in the interaction between GTPase and its effector.

Mutations found in cancer patients compromise DNA binding of the winged helix protein STK19.

Serine/threonine protein kinase 19 (STK19) has been reported to phosphorylate and activate oncogenic NRAS to promote melanomagenesis. However, concerns have been raised about whether STK19 is a kinase. STK19 has also been identified as a putative factor involved in the transcription-coupled nucleotide excision repair (TC-NER) pathway. In this study, we determined the 1.32 Å crystal structure of human STK19. The structure reveals that STK19 is a winged helix (WH) protein consisting of three tandem WH domains. STK19 binds more strongly to double-stranded DNA and RNA (dsDNA/dsRNA) than to ssDNA. A positively charged patch centered on helix WH3-H1 contributes to dsDNA binding, which is unusual because the WH domain typically uses helix H3 as the recognition helix. Importantly, mutations of the conserved residues in the basic patch, K186N, R200W, and R215W, are found in cancer patients, and these mutations compromise STK19 DNA binding. Other mutations have been predicted to produce a similar effect, including two mutations that disrupt the nuclear localization signal (NLS) motif. These mutations may indirectly impact the DNA binding capacity of STK19 by interfering with its nuclear localization.

Exploring the regulatory role of non-coding RNAs in fiber development and direct regulation of GhKCR2 in the fatty acid metabolic pathway in upland cotton.

Cotton fiber holds immense importance as the primary raw material for the textile industry. Consequently, comprehending the regulatory mechanisms governing fiber development is pivotal for enhancing fiber quality. Our study aimed to construct a regulatory network of competing endogenous RNAs (ceRNAs) and assess the impact of non-coding RNAs on gene expression throughout fiber development. Through whole transcriptome data analysis, we identified differentially expressed genes (DEGs) regulated by non-coding RNA (ncRNA) that were predominantly enriched in phenylpropanoid biosynthesis and the fatty acid elongation pathway. This analysis involved two contrasting phenotypic materials (J02-508 and ZRI015) at five stages of fiber development. Additionally, we conducted a detailed analysis of genes involved in fatty acid elongation, including KCS, KCR, HACD, ECR, and ACOT, to unveil the factors contributing to the variation in fatty acid elongation between J02-508 and ZRI015. Through the integration of histochemical GUS staining, dual luciferase assay experiments, and correlation analysis of expression levels during fiber development stages for lncRNA MSTRG.44818.23 (MST23) and GhKCR2, we elucidated that MST23 positively regulates GhKCR2 expression in the fatty acid elongation pathway. This identification provides valuable insights into the molecular mechanisms underlying fiber development, emphasizing the intricate interplay between non-coding RNAs and protein-coding genes.

Exogenous melatonin improves Malus resistance to Marssonina apple blotch.

We examined whether exogenously applied melatonin could improve resistance to Marssonina apple blotch (Diplocarpon mali) by apple [Malus prunifolia (Willd.) Borkh. cv. Donghongguo]. This serious disease leads to premature defoliation in the main regions of apple production. When plants were pretreated with melatonin, resistance was increased in the leaves. We investigated the potential roles for melatonin in modulating levels of hydrogen peroxide (H2O2), as well the activities of antioxidant enzymes and pathogenesis-related proteins during these plant-pathogen interactions. Pretreatment enabled plants to maintain intracellular H2O2 concentrations at steady-state levels and enhance the activities of plant defence-related enzymes, possibly improving disease resistance. Because melatonin is safe and beneficial to animals and humans, exogenous pretreatment might represent a promising cultivation strategy to protect plants against this pathogen infection.

Effect of Academic Self-Efficacy on Test Anxiety of Higher Vocational College Students: The Chain Mediating Effect.

Objective: This study aimed to investigate the impact of academic self-efficacy on test anxiety among higher vocational students, as well as the role of sense of life meaning, fear of failure, and gender difference in mediating this relationship. Methods: A total of 2231 higher vocational students from Shandong Province were surveyed by means of Academic Self-efficacy Questionnaire, Meaning in Life Questionnaire, and Test Anxiety Scale. Results: There were significant negative correlations among academic self-efficacy, sense of life meaning, and test anxiety. Fear of failure was positively correlated with test anxiety. Sense of life meaning and fear of failure played a mediating role in the relationship between academic self-efficacy and test anxiety. The chain mediating effect was significant only in the female group, not in the male group. In contrast, academic self-efficacy indirectly predicted test anxiety by the independent mediating effect of sense of life meaning or fear of failure in the male group. Conclusion: Academic self-efficacy may influence test anxiety through the independent mediating effect of sense of life meaning, fear of failure, and the chain mediating effect, and there is a gender difference in these effects.

Overexpressed transferrin receptor implied poor prognosis and relapse in gastrointestinal stromal tumors.

Ferroptosis, as a novel-induced programmed cell death, plays critical roles in the pathogenesis of cancers. However, the promising biomarkers of ferroptosis in gastrointestinal stromal tumor (GIST) remain to be elucidated. Herein, the expression of ferroptosis-related genes was analyzed in GIST. Among the 64 ferroptosis-related genes, transferrin receptor (TFRC) expression presented a remarkable upregulation in high-risk patients through Gene Expression Omnibus (GEO) dataset analysis, as well as its significant change after imatinib was treated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TFRC-relevant genes revealed that TFRC expression was closely associated with cell growth pathways and metabolism-related pathways. Furthermore, patients at high risk of recurrence were more likely to exhibit high TFRC expression by immunohistochemistry. Additionally, high TFRC expression indicated an undesirable state of patient relapse, which could serve as a powerful significant independent predictor of recurrence-free survival (RFS). In summary, we systematically summarize the expression characteristics and clinical relevance of TFRC and show that TFRC can be used as a prognostic factor, which can be considered a potential therapeutic target in GIST.

Phenotypic and histological analyses on the resistance of melon to Phelipanche aegyptiaca.

Melon (Cucumis melo L.) is an economically important crop in Xinjiang, China, but its production is constrained by the parasitic plant Phelipanche aegyptiaca that attaches to the roots of many crops and causes severe stunting and loss of yield. Rhizotron, pot, and field experiments were employed to evaluate the resistance of 27 melon cultivars to P. aegyptiaca. Then, the resistant and susceptible cultivars were inoculated with P. aegyptiaca from six populations to assess their resistance stability and broad spectrum. Further microscopic and histological analyses were used to clarify the resistance phenotypes and histological structure. The results showed that Huangpi 9818 and KR1326 were more resistant to P. aegyptiaca compared to other cultivars in the rhizotron, pot, and field experiments. In addition, compared to the susceptible cultivar K1076, Huangpi 9818 and KR1326 showed broad-spectrum resistance to six P. aegyptiaca populations. These two resistant cultivars had lower P. aegyptiaca biomass and fewer and smaller P. aegyptiaca attachments on their roots compared to susceptible cultivar K1076. KR1326 (resistant) and K1076 (susceptible) were selected to further study resistance phenotypes and mechanisms. Germination-inducing activity of root exudates and microscopic analysis showed that the resistance in KR1326 was not related to low induction of P. aegyptiaca germination. The tubercles of parasite on KR1326 were observed slightly brown at 14 days after inoculation (DAI), the necrosis and arrest of parasite development occurred at 23 DAI. Histological analysis of necrosis tubercles showed that the endophyte of parasite had reached host central cylinder, connected with host xylem, and accumulation of secretions and callose were detected in neighbouring cells. We concluded that KR1326 is an important melon cultivar for P. aegyptiaca resistance that could be used to expand the genetic basis of cultivated muskmelon for resistance to the parasite.

Orobol, 3'-hydroxy-genistein, suppresses the development and regrowth of cutaneous SCC.

Chronic solar ultraviolet exposure is a major risk factor for cutaneous squamous cell carcinoma (cSCC), which is the second most common type of skin cancer. Our previous data showed that total protein and phosphorylation levels of T-LAK cell-originated protein kinase (TOPK) were enhanced in solar-simulated light (SSL)-induced skin carcinogenesis and overexpressed in actinic keratosis (AK) and cSCC human skin tissues compared to those in matched normal skin. Thus, targeting TOPK activity could be a helpful approach for treating cSCC. Our data showed that orobol directly binds to TOPK in an ATP-independent manner and inhibits TOPK kinase activity. Furthermore, orobol inhibited anchorage-independent colony formation by SCC12 cells in a dose-dependent manner. After discontinuing the treatment, patients commonly return to tumor-bearing conditions; therefore, therapy or intermittent dosing of drugs must be continued indefinitely. Thus, to examine the efficacy of orobol against the development and regrowth of cSCC, we established mouse models including prevention, and therapeutic models on the chronic SSL-irradiated SKH-1 hairless mice. Early treatment with orobol attenuates chronic SSL-induced cSCC development. Furthermore, orobol showed therapeutic efficacy after the formation of chronic SSL irradiation-induced tumor. In the mouse model with intermittent dosing of orobol, our data showed that re-application of orobol is effective for reducing tumor regrowth after discontinuation of treatment. Moreover, oncogenic protein levels were significantly attenuated by orobol treatment in the SSL-stimulated human skin. Thus, we suggest that orobol, as a promising TOPK inhibitor, could have an effective clinical approach to prevent and treat the development and regrowth of cSCC.

Epigenetic compounds targeting pharmacological target lysine specific demethylase 1 and its impact on immunotherapy, chemotherapy and radiotherapy for treatment of tumor recurrence and resistance.

It has been proven that metastatic recurrence and therapeutic resistance are linked. Due to the variability of individuals and tumors, as well as the tumor's versatility in avoiding therapies, therapy resistance is more difficult to treat. Therapy resistance has significantly restricted the clinical feasibility and efficacy of tumor therapy, despite the discovery of novel compounds and therapy combinations with increasing efficacy. In several tumors, lysine specific demethylase 1 (LSD1) has been associated to metastatic recurrence and therapeutic resistance. For researchers to better comprehend how LSD1-mediated tumor therapy resistance occurs and how to overcome it in various tumors, this study focused on the role of LSD1 in tumor recurrence and therapeutic resistance. The importance of therapeutically targeted LSD1 was also discussed. Most gene pathway signatures are related to LSD1 inhibitor sensitivity. However, some gene pathway signatures, especially in AML, negatively correlate with LSD1 inhibitor sensitivity, but targeting LSD1 makes the therapy-resistant tumor sensitive to physiological doses of conventional therapy. We propose that combining LSD1 inhibitor with traditional tumor therapy can help patients attain a complete response and prevent cancer relapse.

Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2.

Constitutive activation of RAS-RAF-MEK-ERK signaling pathway (MAPK pathway) frequently occurs in many cancers harboring RAS or RAF oncogenic mutations. Because of the paradoxical activation induced by a single use of BRAF or MEK inhibitors, dual-target RAF and MEK treatment is thought to be a promising strategy. In this work, we evaluated erianin is a novel inhibitor of CRAF and MEK1/2 kinases, thus suppressing constitutive activation of the MAPK signaling pathway induced by BRAF V600E or RAS mutations. KinaseProfiler enzyme profiling, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), cellular thermal shift assay, computational docking, and molecular dynamics simulations were utilized to screen and identify erianin binding to CRAF and MEK1/2. Kinase assay, luminescent ADP detection assay, and enzyme kinetics assay were investigated to identify the efficiency of erianin in CRAF and MEK1/2 kinase activity. Notably, erianin suppressed BRAF V600E or RAS mutant melanoma and colorectal cancer cell by inhibiting MEK1/2 and CRAF but not BRAF kinase activity. Moreover, erianin attenuated melanoma and colorectal cancer in vivo. Overall, we provide a promising leading compound for BRAF V600E or RAS mutant melanoma and colorectal cancer through dual targeting of CRAF and MEK1/2.

Emergence of an ancient and pathogenic mammarenavirus.

Emerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents a unique ecological niche with diverse wildlife that harbours several human pathogens and numerous previously uncharacterized pathogens. In this study, we identified and characterized a novel arenavirus (namely, plateau pika virus, PPV) from plateau pikas (Ochotona curzoniae) on the Qinghai-Tibet Plateau by virome analysis. Isolated PPV strains could replicate in several mammalian cells. We further investigated PPV pathogenesis using animal models. PPV administered via an intraventricular route caused trembling and sudden death in IFNαßR-/- mice, and pathological inflammatory lesions in brain tissue were observed. According to a retrospective serological survey in the geographical region where PPV was isolated, PPV-specific IgG antibodies were detected in 8 (2.4%) of 335 outpatients with available sera. Phylogenetic analyses revealed that this virus was clearly separated from previously reported New and Old World mammarenaviruses. Under the co-speciation framework, the estimated divergence time of PPV was 77-88 million years ago (MYA), earlier than that of OW and NW mammarenaviruses (26-34 MYA).

Engineering of Oxidized Line Defects on CVD-Grown MoS2 Flakes.

Defect engineering is a promising means to create patterns on two-dimensional (2D) materials to enable unconventional properties. However, defects usually exist abundantly and randomly on 2D materials, which makes it difficult to tune the properties in a controllable manner. Therefore, it is highly desirable to find out the formation mechanism and controllable fabrication method of defects on 2D materials. In this report, we systematically investigated the line defects on monolayer MoS2 formed by introducing oxygen during the CVD growth. The line defects were formed due to the overoxidation of the MoS2 flake along crystal boundaries, which bulged out of the surface and had the same surface potential as the basal plane. Therefore, the MoS2 flake with line defects maintained the optical and electrical integrity but exhibited distinct properties as compared to the pristine one. By controlling the oxygen concentration during CVD growth, the density of the line defects can be precisely controlled to implement controllable property tuning. Moreover, during the transfer process, the MoS2 flake was easily broken along the line defects, which increased the active sites to achieve enhanced hydrogen evolution reaction performance. This work is expected to inspire the development of patterned functional 2D materials by defect engineering.