TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons.

Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

Precise arrangement of metal atoms at the interface by a thermal printing strategy.

The kinetics and pathway of most catalyzed reactions depend on the existence of interface, which makes the precise construction of highly active single-atom sites at the reaction interface a desirable goal. Herein, we propose a thermal printing strategy that not only arranges metal atoms at the silica and carbon layer interface but also stabilizes them by strong coordination. Just like the typesetting of Chinese characters on paper, this method relies on the controlled migration of movable nanoparticles between two contact substrates and the simultaneous emission of atoms from the nanoparticle surface at high temperatures. Observed by in situ transmission electron microscopy, a single Fe3O4 nanoparticle migrates from the core of a SiO2 sphere to the surface like a droplet at high temperatures, moves along the interface of SiO2 and the coated carbon layer, and releases metal atoms until it disappears completely. These detached atoms are then in situ trapped by nitrogen and sulfur defects in the carbon layer to generate Fe single-atom sites, exhibiting excellent activity for oxygen reduction reaction. Also, sites' densities can be regulated by controlling the size of Fe3O4 nanoparticle between the two surfaces. More importantly, this strategy is applicable to synthesize Mn, Co, Pt, Pd, Au single-atom sites, which provide a general route to arrange single-atom sites at the interface of different supports for various applications.

SET7 methylates the deubiquitinase OTUB1 at Lys 122 to impair its binding to E2 enzyme UBC13 and relieve its suppressive role on ferroptosis.

The deubiquitinating enzyme OTUB1 possesses canonical deubiquitinase (DUB) activity and noncanonical, catalytic-independent activity, which has been identified as an essential regulator of diverse physiological processes. Posttranslational modifications of OTUB1 affect both its DUB activity and its noncanonical activity of binding to the E2 ubiquitin-conjugation enzyme UBC13, but further investigation is needed to characterize the full inventory of modifications to OTUB1. Here, we demonstrate that SET7, a lysine monomethylase, directly interacts with OTUB1 to catalyze OTUB1 methylation at lysine 122. This modification does not affect DUB activity of OTUB1 but impairs its noncanonical activity, binding to UBC13. Moreover, we found using cell viability analysis and intracellular reactive oxygen species assay that SET7-mediated methylation of OTUB1 relieves its suppressive role on ferroptosis. Notably, the methylation-mimic mutant of OTUB1 not only loses the ability to bind to UBC13 but also relieves its suppressive role on Tert-Butyl hydroperoxide-induced cell death and Cystine starvation/Erastin-induced cellular reactive oxygen species. Collectively, our data identify a novel modification of OTUB1 that is critical for inhibiting its noncanonical activity.

SIRT5 impairs aggregation and activation of the signaling adaptor MAVS through catalyzing lysine desuccinylation.

RLR-mediated type I IFN production plays a pivotal role in innate antiviral immune responses, where the signaling adaptor MAVS is a critical determinant. Here, we show that MAVS is a physiological substrate of SIRT5. Moreover, MAVS is succinylated upon viral challenge, and SIRT5 catalyzes desuccinylation of MAVS. Mass spectrometric analysis indicated that Lysine 7 of MAVS is succinylated. SIRT5-catalyzed desuccinylation of MAVS at Lysine 7 diminishes the formation of MAVS aggregation after viral infection, resulting in the inhibition of MAVS activation and leading to the impairment of type I IFN production and antiviral gene expression. However, the enzyme-deficient mutant of SIRT5 (SIRT5-H158Y) loses its suppressive role on MAVS activation. Furthermore, we show that Sirt5-deficient mice are resistant to viral infection. Our study reveals the critical role of SIRT5 in limiting RLR signaling through desuccinylating MAVS.

Ionic Liquids Modulating Local Microenvironment of Ni-Fe Binary Single Atom Catalyst for Efficient Electrochemical CO2 Reduction.

The Ni and Fe dual-atom catalysts still undergo strikingly attenuation under high current density and high overpotential. To ameliorate the issue, the ionic liquids with different cations or anions are used in this work to regulate the micro-surface of nitrogen-doped carbon supported Ni and Fe dual-atom sites catalyst (NiFe-N-C) by an impregnation method. The experimental data reveals the dual function of ionic liquids, which enhances CO2 adsorption ability and modulates electronic structure, facilitating CO2 anion radical (CO2 •¯) stabilization and decreasing onset potential. The theoretical calculation results prove that the attachment of ionic liquids modulates electronic structure, reduces energy barrier of CO2 •¯ formation, and enhances overall ECR performance. Based on these merits, BMImPF6 modified NiFe-N-C (NiFe-N-C/BMImPF6) achieves the high CO faradaic efficiency of 91.9% with a CO partial current density of -120 mA cm-2 at -1.0 V. When the NiFe-N-C/BMImPF6 is assembled as cathode of Zn-CO2 battery, it delivers the highest power density of 2.61 mW cm-2 at 2.57 mA cm-2 and superior cycling stability. This work will afford a direction to modify the microenvironment of other dual-atom catalysts for high-performance CO2 electroreduction.

ZIFs-Derived Hollow Nanostructures via a Strong/Weak Coetching Strategy for Long-Life Rechargeable Zn-Air Batteries.

Recently, zeolitic imidazolate frameworks (ZIFs) composites have emerged as promising precursors for synthesizing hollow-structured N-doped carbon-based noble-metal materials with diverse structures and compositions. Here, a strong/weak competitive coordination strategy is presented for synthesizing high-performance electrocatalysts with hollow features. During the competitive coordination process, the cubic zeolitic-imidazole framework-8 (Cube-8)@ZIF-67 with core-shell structures are transformed into Cube-8@ZIF-67@PF/POM with yolk-shell nanostructures employing phosphomolybdic acid (POM) and potassium ferricyanide (PF) as the strong chelator and the weak chelator, respectively. After calcination, the hollow Mo/Fe/Co@NC catalyst exhibits superior performance in both oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). Interestingly, the Mo/Fe/Co@NC catalyst exhibits efficient electrocatalytic performance for Zn-air batteries (ZABs), with a high power density (≈150 mW cm-2) and superior cycling life (≈500 h) compared to commercial platinum/carbon (Pt/C) and ruthenium dioxide (RuO2) mixture benchmarks catalysts. In addition, the density functional theory further proves that after the introduction of Mo and Fe atoms, the adsorption energy with the adsorption intermediates is weakened by adjusting the d-band center, thus weakening the reaction barrier and promoting the reaction kinetics of OER. Undoubtedly, this study presents novel insights into the fabrication of ZIFs-derived hollow structure bifunctional oxygen electrocatalysts for clean-energy diverse applications.

Enhanced growth resistance but no decline in growth resilience under long-term extreme droughts.

The frequency, intensity, and duration of extreme droughts, with devastating impacts on tree growth and survival, have increased with climate change over the past decades. Assessing growth resistance and resilience to drought is a crucial prerequisite for understanding the responses of forest functioning to drought events. However, the responses of growth resistance and resilience to extreme droughts with different durations across different climatic zones remain unclear. Here, we investigated the spatiotemporal patterns in growth resistance and resilience in response to extreme droughts with different durations during 1901-2015, relying on tree-ring chronologies from 2389 forest stands over the mid- and high-latitudinal Northern Hemisphere, species-specific plant functional traits, and diverse climatic factors. The findings revealed that growth resistance and resilience under 1-year droughts were higher in humid regions than in arid regions. Significant higher growth resistance was observed under 2-year droughts than under 1-year droughts in both arid and humid regions, while growth resilience did not show a significant difference. Temporally, tree growth became less resistant and resilient to 1-year droughts in 1980-2015 than in 1901-1979 in both arid and humid regions. As drought duration lengthened, the predominant impacts of climatic factors on growth resistance and resilience weakened and instead foliar economic traits, plant hydraulic traits, and soil properties became much more important in both climatic regions; in addition, such trends were also observed temporally. Finally, we found that most of the Earth system models (ESMs) used in this study overestimated growth resistance and underestimated growth resilience under both 1-year and 2-year droughts. A comprehensive ecophysiological understanding of tree growth responses to longer and intensified drought events is urgently needed, and a specific emphasis should be placed on improving the performance of ESMs.

A network meta-analysis of psychological interventions for children and adolescents after natural and man-made disasters.

INTRODUCTION: Children and adolescents, after natural and man-made disasters, often exhibit various psychological, emotional, and behavioral issues, showing a range of clinical symptoms related to post-traumatic stress disorder (PTSD) and depression. This review used a network meta-analysis (NMA) approach to compare and rank psychological interventions for PTSD and depression in children and adolescents after exposure to natural and man-made disasters. METHODS: Randomized studies of psychosocial interventions for PTSD and depression in children and adolescents exposed to natural and man-made disasters were identified. PTSD and depression symptoms at postintervention and 1-12 month follow-up are the outcomes. The standardized mean differences (SMDs) between pairs of interventions at postintervention and follow-up were pooled. Mean effect sizes with 95% credible intervals (CI) were calculated, and the ranking probabilities for all interventions were estimated using the surface under the cumulative ranking curve. Study quality was assessed with version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). RESULTS: In total, 26 studies with 4331 participants were included in this NMA. Eye movement desensitization and reprocessing therapy (EMDR) (SMD = - 0.67; 95% CI - 1.17 to - 0.17), exposure therapy (ET) (SMD = - 0.66; 95% CI - 1.11 to - 0.22), and cognitive behavioral therapy (CBT) (SMD = - 0.62; 95% CI - 0.90 to - 0.34) were significantly more effective for PTSD at postintervention than inactive intervention. EMDR (SMD = - 0.72; 95% CI - 1.11 to - 0.33) and ET (SMD = - 0.62; 95% CI - 0.97 to - 0.27) were associated with a higher reduction in PTSD symptoms at follow-up than inactive intervention. EMDR (SMD = - 0.40; 95% CI - 0.78 to - 0.03) and play therapy (PT) (SMD = - 0.37; 95% CI - 0.62 to - 0.12) were significantly more effective for depression at postintervention than inactive intervention. For all psychological interventions in reducing depression symptoms at follow-up compared with inactive intervention, the differences were not significant. CONCLUSION: EMDR appears to be most effective in reducing PTSD and depression in children and adolescents exposed to natural and man-made disasters. In addition, ET and CBT are potentially effective in reducing PTSD symptoms at postintervention, while PT is beneficial in managing depression symptoms at the treatment endpoint.

Characterization of Fusarium species causing soybean root rot in Heilongjiang, China, and mechanism underlying the differences in sensitivity to DMI fungicides.

Soybean root rot is a worldwide soil-borne disease threatening soybean production, causing large losses in soybean yield and quality. Fusarium species are the most detrimental pathogens of soybean root rot worldwide, causing large production losses. Fusarium root rot has been frequently reported in Heilongjiang Province of China, but the predominant Fusarium species and the sensitivity of these pathogens to different fungicides remain unclear. In this study, diseased soybean roots were collected from 14 regions of Heilongjiang province in 2021 and 2022. A total of 144 isolates of Fusarium spp. were isolated and identified as seven distinct species: F. scirpi, F. oxysporum, F. graminearum, F. clavum, F. acuminatum, F. avenaceum, and F. sporotrichioide. F. scirpi and F. oxysporum had high separation frequency and strong pathogenicity. The sensitivity of Fusarium spp. to five different fungicides was determined. Mefentrifluconazole and fludioxonil showed good inhibitory effects, and the sensitivity to pydiflumetofen and phenamacril varied between Fusarium species. In particular, the activity of DMI fungicide prothioconazole was lower than that of mefentrifluconazole. Molecular docking showed that mefentrifluconazole mainly bound to CYP51C, but prothioconazole mainly bound to CYP51B. Furthermore, the sensitivity to prothioconazole only significantly decreased in ΔFgCYP51B mutant, and the sensitivity to mefentrifluconazole changed in ΔFgCYP51C and ΔFgCYP51A mutants. The results demonstrated that the predominant Fusarium species causing soybean root rot in Heilongjiang province were F. scirpi and F. oxysporum and DMI fungicides had differences in binding cavity due to the diversity of CYP51 proteins in Fusarium.

Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2.

Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity of NSD2 reported in numerous cancers, efforts to selectively inhibit the catalytic activity of this protein with small molecules have been unsuccessful to date. Here, we report the development of UNC8153, a novel NSD2-targeted degrader that potently and selectively reduces the cellular levels of both NSD2 protein and the H3K36me2 chromatin mark. UNC8153 contains a simple warhead that confers proteasome-dependent degradation of NSD2 through a novel mechanism. Importantly, UNC8153-mediated reduction of H3K36me2 through the degradation of NSD2 results in the downregulation of pathological phenotypes in multiple myeloma cells including mild antiproliferative effects in MM1.S cells containing an activating point mutation and antiadhesive effects in KMS11 cells harboring the t(4;14) translocation that upregulates NSD2 expression.

Epigenetic (De)regulation in Prostate Cancer.

Prostate cancer (PCa) is a heterogeneous disease exhibiting both genetic and epigenetic deregulations. Epigenetic alterations are defined as changes not based on DNA sequence, which include those of DNA methylation, histone modification, and chromatin remodeling. Androgen receptor (AR) is the main driver for PCa and androgen deprivation therapy (ADT) remains a backbone treatment for patients with PCa; however, ADT resistance almost inevitably occurs and advanced diseases develop termed castration-resistant PCa (CRPC), due to both genetic and epigenetic changes. Due to the reversible nature of epigenetic modifications, inhibitors targeting epigenetic factors have become promising anti-cancer agents. In this chapter, we focus on recent studies about the dysregulation of epigenetic regulators crucially involved in the initiation, development, and progression of PCa and discuss the potential use of inhibitors targeting epigenetic modifiers for treatment of advanced PCa.

Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer.

Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.

Experimental Study on Monitoring Damage Progression of Basalt-FRP Reinforced Concrete Slabs Using Acoustic Emission and Machine Learning.

Basalt fiber-reinforced polymer (BFRP) reinforced concrete is a new alternative to conventional steel-reinforced concrete due to its high tensile strength and corrosion resistance characteristics. However, as BFRP is a brittle material, unexpected failure of concrete structures reinforced with BFRP may occur. In this study, the damage initiation and progression of BFRP-reinforced concrete slabs were monitored using the acoustic emission (AE) method as a structural health monitoring (SHM) solution. Two simply supported slabs were instrumented with an array of AE sensors in addition to a high-resolution camera, strain, and displacement sensors and then loaded until failure. The dominant damage mechanism was concrete cracking due to the over-reinforced design and adequate BFRP bar-concrete bonding. The AE method was evaluated in terms of identifying the damage initiation, progression from tensile to shear cracks, and the evolution of crack width. Unsupervised machine learning was applied to the AE data obtained from the first slab testing to develop the clusters of the damage mechanisms. The cluster results were validated using the k-means supervised learning model applied to the data obtained from the second slab. The accuracy of the K-NN model trained on the first slab was 99.2% in predicting three clusters (tensile crack, shear crack, and noise). Due to the limitation of a single indicator to characterize complex damage properties, a Statistical SHapley Additive exPlanation (SHAP) analysis was conducted to quantify the contribution of each AE feature to crack width. Based on the SHAP analysis, the AE duration had the highest correlation with the crack width. The cumulative duration of the AE sensor near the crack had close to 100% accuracy to track the crack width. It was concluded that the AE sensors positioned at the mid-span of slabs can be used as an effective SHM solution to monitor the initiation of tensile cracks, sudden changes in structural response due to major damage, damage evolution from tensile to shear cracks, and the progression of crack width.

Zebrafish prmt5 arginine methyltransferase is essential for germ cell development.

Protein arginine methyltransferase 5 (Prmt5), a type II arginine methyltransferase, symmetrically dimethylates arginine in nuclear and cytoplasmic proteins. Prmt5 is involved in a variety of cellular processes, including ribosome biogenesis, cellular differentiation, germ cell development and tumorigenesis. However, the mechanisms by which prmt5 influences cellular processes have remained unclear. Here, prmt5 loss in zebrafish led to the expression of an infertile male phenotype due to a reduction in germ cell number, an increase in germ cell apoptosis and the failure of gonads to differentiate into normal testes or ovaries. Moreover, arginine methylation of the germ cell-specific proteins Zili and Vasa, as well as histones H3 (H3R8me2s) and H4 (H4R3me2s), was reduced in the gonads of prmt5-null zebrafish. This resulted in the downregulation of several Piwi pathway proteins, including Zili, and Vasa. In addition, various genes related to meiosis, gonad development and sexual differentiation were dysregulated in the gonads of prmt5-null zebrafish. Our results revealed a novel mechanism associated with prmt5, i.e. prmt5 apparently controls germ cell development in vertebrates by catalyzing arginine methylation of the germline-specific proteins Zili and Vasa.

Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.

Depression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

Local resection versus radical resection for early-stage rectal cancer: a systematic review and meta-analysis.

PURPOSE: The optimal surgical approach for early-stage rectal cancer remains controversial. Radical resection is considered to be the gold standard for rectal cancer treatment. More and more studies show that local resection can replace traditional radical resection in the treatment of early rectal cancer. This research aimed to compare the efficacy of local excision and radical surgery for early-stage rectal cancer and report the evidence-based clinical advantages of both techniques. METHODS: The clinical trials comparing oncological and perioperative local and radical resection outcomes for early-stage rectal cancer were searched from 7 national and international databases. RESULTS: Finally, 3 randomized controlled trials and 14 cohort studies were included. In terms of oncology and perioperative outcomes, there were no statistically significant differences between the radical resection group and the local resection group in terms of OS (HR = 1.05, 95% CI (0.98, 1.13), DFS [HR = 1.18, 95% CI (0.93, 1.48), p = 0.168), distant metastasis rate (RR = 1.04, 95% CI (0.49, 2.20), p = 0.928), and mortality rate (RR = 1.52, 95% CI (0.80, 2.91), p = 0.200). However, there were significant differences in the outcomes of complications (RR = 2.85, 95% CI (2.07, 3.92), p < 0.001), length of hospital stays (WMD = 5.41, 95% CI (3.94, 6.87), p < 0.001), stoma rate (RR = 7.69, 95% CI (2.39, 24.77), p = 0.001), local recurrence rate (RR = 0.48, 95% CI (0.27, 0.86), p = 0.013), operative time (WMD = 74.68, 95% CI (68.00, 81.36), p < 0.001), blood loss (WMD = 156.36, 95% CI (95.48, 217.21, p < 0.001), and adverse events (RR = 1.59, 95% CI (1.05, 2.41), p = 0.027). CONCLUSION: Local excision may be a viable alternative to radical resection for early-stage rectal cancer, but higher quality clinical studies are needed to confirm this.

A triple-classification for differentiating renal oncocytoma from renal cell carcinoma subtypes and CK7 expression evaluation: a radiomics analysis.

BACKGROUND: To investigate the value of computed tomography (CT)-based radiomics model analysis in differentiating renal oncocytoma (RO) from renal cell carcinoma subtypes (chromophobe renal cell carcinoma, clear cell carcinoma) and predicting the expression of Cytokeratin 7 (CK7). METHODS: In this retrospective study, radiomics was applied for patients with RO, chRCC and ccRCC who underwent surgery between January 2013 and December 2019 comprised the training cohort, and the testing cohort was collected between January and October 2020. The corticomedullary (CMP) and nephrographic phases (NP) were manually segmented, and radiomics texture parameters were extracted. Support vector machine was generated from CMP and NP after feature selection. Shapley additive explanations were applied to interpret the radiomics features. A radiomics signature was built using the selected features from the two phases, and the radiomics nomogram was constructed by incorporating the radiomics features and clinical factors. Receiver operating characteristic curve was calculated to evaluate the above models in the two sets. Furthermore, Rad-score was used for correlation analysis with CK7. RESULTS: A total of 123 patients with RO, chRCC and ccRCC were analyzed in the training cohort and 57 patients in the testing cohort. Subsequently, 396 radiomics features were selected from each phase. The radiomics features combining two phases yielded the highest area under the curve values of 0.941 and 0.935 in the training and testing sets, respectively. The Pearson's correlation coefficient was statistically significant between Rad-score and CK7. CONCLUSION: We proposed a non-invasive and individualized CT-based radiomics nomogram to differentiation among RO, chRCC and ccRCC preoperatively and predict the immunohistochemical protein expression for accurate clinical diagnosis and treatment decision.

A triple-classification for the evaluation of lung nodules manifesting as pure ground-glass sign: a CT-based radiomic analysis.

OBJECTIVES: To construct a noninvasive radiomics model for evaluating the pathological degree and an individualized treatment strategy for patients with the manifestation of ground glass nodules (GGNs) on CT images. METHODS: The retrospective primary cohort investigation included patients with GGNs on CT images who underwent resection between June 2015 and June 2020. The intratumoral regions of interest were segmented semiautomatically, and radiomics features were extracted from the intratumoral and peritumoral regions. After feature selection by ANOVA, Max-Relevance and Min-Redundancy (mRMR) and Least Absolute Shrinkage and Selection Operator (Lasso) regression, a random forest (RF) model was generated. Receiver operating characteristic (ROC) analysis was calculated to evaluate each classification. Shapley additive explanations (SHAP) was applied to interpret the radiomics features. RESULTS: In this study, 241 patients including atypical adenomatous hyperplasia (AAH) or adenocarcinoma in situ (AIS) (n = 72), minimally invasive adenocarcinoma (MIA) (n = 83) and invasive adenocarcinoma (IAC) (n = 86) were selected for radiomics analysis. Three intratumoral radiomics features and one peritumoral feature were finally identified by the triple RF classifier with an average area under the curve (AUC) of 0.960 (0.963 for AAH/AIS, 0.940 for MIA, 0.978 for IAC) in the training set and 0.944 (0.955 for AAH/AIS, 0.952 for MIA, 0.926 for IAC) in the testing set for evaluation of the GGNs. CONCLUSION: The triple classification based on intra- and peritumoral radiomics features derived from the noncontrast CT images had satisfactory performance and may be used as a noninvasive tool for preoperative evaluation of the pure ground-glass nodules and developing of individualized treatment strategies.

Time-series gene expression patterns and their characteristics of Beauveria bassiana in the process of infecting pest insects.

Beauveria bassiana has been widely used as an important biological control fungus for agricultural and forest pests, and clarifying the interaction mechanism between B. bassiana and its host will help to better exert the efficacy of the mycoinsecticide. Here, we proposed a novel pattern analysis (PA) method for analyzing time-series data and applied it to a transcriptomic data set of B. bassiana infecting Galleria mellonella. We screened out 14 patterns including 868 genes, which had some characteristics that were not inferior to differentially expressed genes (DEGs). Compared with the previous analysis of this data set, we had three novel discoveries during B. bassiana infection, including overall downregulation of gene expression, the more critical first 24 h, and enrichment of regulatory functions of downregulated genes. Our new PA method promises to be an important complement to DEGs analysis for time-series transcriptomic data, and our findings enrich our knowledge of molecular mechanisms of fungal-host interactions.

TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation.

Hypoxia-inducible factors are heterodimeric transcription factors that play a crucial role in a cell's ability to adapt to low oxygen. The von Hippel-Lindau tumor suppressor (pVHL) acts as a master regulator of HIF activity, and its targeting of prolyl hydroxylated HIF-α for proteasomal degradation under normoxia is thought to be a major mechanism for pVHL tumor suppression and cellular response to oxygen. Whether pVHL regulates other targets through a similar mechanism is largely unknown. Here, we identify TET2/3 as novel targets of pVHL. pVHL induces proteasomal degradation of TET2/3, resulting in reduced global 5-hydroxymethylcytosine levels. Conserved proline residues within the LAP/LAP-like motifs of these two proteins are hydroxylated by the prolyl hydroxylase enzymes (PHD2/EGLN1 and PHD3/EGLN3), which is prerequisite for pVHL-mediated degradation. Using zebrafish as a model, we determined that global 5-hydroxymethylcytosine levels are enhanced in vhl-null, egln1a/b-double-null, and egln3-null embryos. Therefore, we reveal a novel function for the PHD-pVHL pathway in regulating TET protein stability and activity. These data extend our understanding of how TET proteins are regulated and provide new insight into the mechanisms of pVHL in tumor suppression.