Regulation of pluripotency and self- renewal of ESCs through epigenetic-threshold modulation and mRNA pruning.

Embryonic stem cell (ESC) pluripotency requires bivalent epigenetic modifications of key developmental genes regulated by various transcription factors and chromatin-modifying enzymes. How these factors coordinate with one another to maintain the bivalent chromatin state so that ESCs can undergo rapid self-renewal while retaining pluripotency is poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of messenger RNAs (mRNAs) transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA decapping. These opposing functions of Utf1 promote coordinated differentiation. The mRNA degradation function also ensures rapid cell proliferation by blocking the Myc-Arf feedback control. Thus, Utf1 couples the core pluripotency factors with Myc and PRC2 networks to promote the pluripotency and proliferation of ESCs.

Phosphorylation and ubiquitination of OsWRKY31 are integral to OsMKK10-2-mediated defense responses in rice.

Mitogen-activated protein kinase (MPK) cascades play vital roles in plant innate immunity, growth, and development. Here, we report that the rice (Oryza sativa) transcription factor gene OsWRKY31 is a key component in a MPK signaling pathway involved in plant disease resistance in rice. We found that the activation of OsMKK10-2 enhances resistance against the rice blast pathogen Magnaporthe oryzae and suppresses growth through an increase in jasmonic acid and salicylic acid accumulation and a decrease of indole-3-acetic acid levels. Knockout of OsWRKY31 compromises the defense responses mediated by OsMKK10-2. OsMKK10-2 and OsWRKY31 physically interact, and OsWRKY31 is phosphorylated by OsMPK3, OsMPK4, and OsMPK6. Phosphomimetic OsWRKY31 has elevated DNA-binding activity and confers enhanced resistance to M. oryzae. In addition, OsWRKY31 stability is regulated by phosphorylation and ubiquitination via RING-finger E3 ubiquitin ligases interacting with WRKY 1 (OsREIW1). Taken together, our findings indicate that modification of OsWRKY31 by phosphorylation and ubiquitination functions in the OsMKK10-2-mediated defense signaling pathway.

Compression drives diverse transcriptomic and phenotypic adaptations in melanoma.

Physical forces are prominent during tumor progression. However, it is still unclear how they impact and drive the diverse phenotypes found in cancer. Here, we apply an integrative approach to investigate the impact of compression on melanoma cells. We apply bioinformatics to screen for the most significant compression-induced transcriptomic changes and investigate phenotypic responses. We show that compression-induced transcriptomic changes are associated with both improvement and worsening of patient prognoses. Phenotypically, volumetric compression inhibits cell proliferation and cell migration. It also induces organelle stress and intracellular oxidative stress and increases pigmentation in malignant melanoma cells and normal human melanocytes. Finally, cells that have undergone compression become more resistant to cisplatin treatment. Our findings indicate that volumetric compression is a double-edged sword for melanoma progression and drives tumor evolution.

A Spike-destructing human antibody effectively neutralizes Omicron-included SARS-CoV-2 variants with therapeutic efficacy.

Neutralizing antibodies (nAbs) are important assets to fight COVID-19, but most existing nAbs lose the activities against Omicron subvariants. Here, we report a human monoclonal antibody (Ab08) isolated from a convalescent patient infected with the prototype strain (Wuhan-Hu-1). Ab08 binds to the receptor-binding domain (RBD) with pico-molar affinity (230 pM), effectively neutralizes SARS-CoV-2 and variants of concern (VOCs) including Alpha, Beta, Gamma, Mu, Omicron BA.1 and BA.2, and to a lesser extent for Delta and Omicron BA.4/BA.5 which bear the L452R mutation. Of medical importance, Ab08 shows therapeutic efficacy in SARS-CoV-2-infected hACE2 mice. X-ray crystallography of the Ab08-RBD complex reveals an antibody footprint largely in the ß-strand core and away from the ACE2-binding motif. Negative staining electron-microscopy suggests a neutralizing mechanism through which Ab08 destructs the Spike trimer. Together, our work identifies a nAb with therapeutic potential for COVID-19.

Engineering extracellular electron transfer pathways of electroactive microorganisms by synthetic biology for energy and chemicals production.

The excessive consumption of fossil fuels causes massive emission of CO2, leading to climate deterioration and environmental pollution. The development of substitutes and sustainable energy sources to replace fossil fuels has become a worldwide priority. Bio-electrochemical systems (BESs), employing redox reactions of electroactive microorganisms (EAMs) on electrodes to achieve a meritorious combination of biocatalysis and electrocatalysis, provide a green and sustainable alternative approach for bioremediation, CO2 fixation, and energy and chemicals production. EAMs, including exoelectrogens and electrotrophs, perform extracellular electron transfer (EET) (i.e., outward and inward EET), respectively, to exchange energy with the environment, whose rate determines the efficiency and performance of BESs. Therefore, we review the synthetic biology strategies developed in the last decade for engineering EAMs to enhance the EET rate in cell-electrode interfaces for facilitating the production of electricity energy and value-added chemicals, which include (1) progress in genetic manipulation and editing tools to achieve the efficient regulation of gene expression, knockout, and knockdown of EAMs; (2) synthetic biological engineering strategies to enhance the outward EET of exoelectrogens to anodes for electricity power production and anodic electro-fermentation (AEF) for chemicals production, including (i) broadening and strengthening substrate utilization, (ii) increasing the intracellular releasable reducing equivalents, (iii) optimizing c-type cytochrome (c-Cyts) expression and maturation, (iv) enhancing conductive nanowire biosynthesis and modification, (v) promoting electron shuttle biosynthesis, secretion, and immobilization, (vi) engineering global regulators to promote EET rate, (vii) facilitating biofilm formation, and (viii) constructing cell-material hybrids; (3) the mechanisms of inward EET, CO2 fixation pathway, and engineering strategies for improving the inward EET of electrotrophic cells for CO2 reduction and chemical production, including (i) programming metabolic pathways of electrotrophs, (ii) rewiring bioelectrical circuits for enhancing inward EET, and (iii) constructing microbial (photo)electrosynthesis by cell-material hybridization; (4) perspectives on future challenges and opportunities for engineering EET to develop highly efficient BESs for sustainable energy and chemical production. We expect that this review will provide a theoretical basis for the future development of BESs in energy harvesting, CO2 fixation, and chemical synthesis.

Light-Driven Access to Selenium-Substituted Thiazole-2-imine Derivatives.

The thiazole-2-imine derivatives with interesting pharmacological activities have attracted significant attention. However, previously reported synthesis strategies usually suffered from some drawbacks, such as the use of metals/additive and harsh reaction conditions. Herein, we developed a metal- and photoinitiator-free photocatalytic strategy for the synthesis of various selenium-substituted thiazole-2-imine derivatives for the first time. The reaction displayed mild reaction conditions, simple operation, a broad substrate scope (37 examples), and good to excellent yields.

Complete long-term monitoring of greenhouse gas emissions from a full-scale industrial wastewater treatment plant with different cover configurations.

The greenhouse gas (GHG) emissions from wastewater treatment plants (WWTPs), consisting mainly of methane (CH4) and nitrous oxide (N2O), have been constantly increasing and become a non-negligible contributor towards carbon neutrality. The precise evaluation of plant-specific GHG emissions, however, remains challenging. The current assessment approach is based on the product of influent load and emission factor (EF), of which the latter is quite often a single value with huge uncertainty. In particular, the latest default Tier 1 value of N2O EF, 0.016 ± 0.012 kgN2O-N kgTN-1, is estimated based on the measurement of 30 municipal WWTPs only, without involving any industrial wastewater. Therefore, to resolve the pattern of GHG emissions from industrial WWTPs, this work conducted a 14-month monitoring campaign covering all the process units at a full-scale industrial WWTP in Shanghai, China. The total CH4 and N2O emissions from the whole plant were, on average, 447.7 ± 224.5 kgCO2-eq d-1 and 1605.3 ± 2491.0 kgCO2-eq d-1, respectively, exhibiting a 5.2- or 3.9-times more significant deviation than the influent loads of chemical oxygen demand (COD) or total nitrogen (TN). The resulting EFs, 0.00072 kgCH4 kgCOD-1 and 0.00211 kgN2O-N kgTN-1, were just 0.36% of the IPCC recommended value for CH4, and 13.2% for N2O. Besides, the parallel anoxic-oxic (A/O) lines of this industrial WWTP were covered in two configurations, allowing the comparison of GHG emissions from different odor control setup. Unit-specific analysis showed that the replacement of enclosed A/open O with enclosed A/O reduced the CH4 EF by three times, from 0.00159 to 0.00051 kgCH4 kgCOD-1, and dramatically decreased the N2O EF by an order of magnitude, from 0.00376 to 0.00032 kgN2O-N kgTN-1, which was among the lowest of all full-scale WWTPs.

[Correlations between tanshinones and soil factors of Salviae Miltiorrhizae Radix et Rhizoma from different producing areas].

Soil nutrients and inorganic elements affect not only the growth and development of medicinal plants but also the formation and accumulation of active ingredients in traditional Chinese medicines. The content of tanshinones and 28 inorganic elements in Salviae Miltiorrhizae Radix et Rhizoma samples from 18 producing areas in 6 provinces was determined, and 35 physical and chemical properties of the corresponding soil samples were determined. The enrichment characteristics of inorganic elements in Salviae Miltiorrhizae Radix et Rhizoma were analyzed. The correlation analysis and stepwise regression analysis were performed to screen out the main soil factors affecting the content of tanshinones in Salviae Miltiorrhizae Radix et Rhizoma. The results showed that the content of tanshinones in the samples from different areas varied significantly, being the highest in the samples from Shandong, the second in the samples from Henan, and low in the samples from Shanxi and Sichuan. K, Mg, Ca, and Na were rich in Salviae Miltiorrhizae Radix et Rhizoma samples, among which Na and K had the highest enrichment coefficients. The results of correlation and regression analyses showed that soil K, Na, Ti, and total nitrogen were the main soil factors affecting the tanshinones in Salviae Miltiorrhizae Radix et Rhizoma. Specifically, the content of tanshinones was positively correlated with Ti and negatively correlated with Na, K, and total nitrogen in the soil. Therefore, during the planting of Salvia miltiorrhiza, the land should be selected with full consideration to the salinity and saline land should be avoided. Secondly, the application of nitrogen and potassium fertilizers can be appropriately reduced, and water-soluble elemental fertilizers for S. miltiorrhiza should be developed.

Genome Sequence Resource of a Colletotrichum graminicola Field Strain from China.

The maize anthracnose stalk rot and leaf blight diseases caused by the fungal pathogen Colletotrichum graminicola is emerging as an important threat to corn production worldwide. In this work, we provide an improved genome assembly of a C. graminicola strain (TZ-3) by using the PacBio Sequel II and Illumina high-throughput sequencing technologies. The genome of TZ-3 consists of 36 contigs with a length of 59.3 Mb. After correction and evaluation with the Illumina sequencing data and BUSCO, this genome showed a high assembly quality and integrity. Gene annotation of this genome predicted 11,911 protein-coding genes, among which 983 secreted protein-coding genes and 332 effector genes were predicted. Compared with previous genomes of C. graminicola strains, TZ-3 genome is superior in nearly all parameters. The genome assembly and annotation will enhance our knowledge of the genetic makeup of the pathogen and molecular mechanisms underlying its pathogenicity and will provide valuable insights into genome variation across different regions. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Transition-Metal-Free Synthesis of Polyfluoro-Polyarylmethanes via Direct Cross-Coupling of Polyfluoroarenes and Benzyl Chlorides.

The transition-metal-free direct cross-coupling between polyfluoroarenes and benzyl chlorides is reported. In this strategy, a variety of polyfluoro di-, tri- and tetra-arylmethanes was efficiently prepared with good to excellent yields in the presence of Mg turnings via a one-pot procedure. Significantly, this method provides a general approach for the synthesis of polyfluorinated polyarylmethanes.

Electrochemical Difunctionalization of Alkenes: Simultaneous Construction of C-Se and C-S Bonds.

Electrochemical oxidation of alkene difunctionalization with simultaneous construction of C-Se and C-S bonds is reported. The products of ß-selenylethyl dithiocarbamates are obtained with CS2, amines, alkenes, and diphenyl diselenides in the absence of any oxidant or metal. Furthermore, the transformation is compatible with various groups. In the preliminary mechanism studies, we propose three possible pathways.

Photoinduced Metal- and Photosensitizer-Free Decarbonylative C-H Alkylation of Cyclic Sulfamidate Imines.

Photoinduced decarbonylative C-C bond formation with readily accessible aldehydes as alkyl sources is described. This protocol provides a sustainable alternative for the effective construction of diverse valuable 4-alkylated sulfonyl ketimines under metal- and photosensitizer-free conditions. Significantly, in this reaction, air serves as the green oxidant, and cyclic sulfamidate imines play a dual role of substrate and photocatalyst, thus affording a concise reaction system for C-H alkylation of cyclic sulfamidate imines.

Reactivities of α-Oxo BMIDA Gold Carbenes Generated by Gold-Catalyzed Oxidation of BMIDA-Terminated Alkynes.

An oxidative strategy is reported to access α-oxo BMIDA gold carbenes directly from BMIDA-terminated alkynes. Besides offering expedient access to seldom studied boryl metal carbenes, these BMIDA gold carbene species undergo facile insertions into methyl, methylene, methine, and benzylic C-H bonds in the absence of the Thorpe-Ingold effect. They also undergo efficient OH insertion, cyclopropanation, and F-C alkylations. This chemistry provides rapid access to structurally diverse α-BMIDA ketones, which are scarcely documented. In combination with DFT studies, the role of BMIDA is established to be an electron-donating group that attenuates the high electrophilicity of the gold carbene center.

A Comprehensive Comparison of Different Nodal Subclassification Methods in Surgically Resected Non-Small-Cell Lung Cancer Patients.

INTRODUCTION: The revision of the N descriptor in non-small-cell lung cancer has been widely discussed in the past few years. Many different subclassification methods based on number or location of lymph nodes have been proposed for better distinguishing different N patients. This study aimed to systematically collect them and provide a comprehensive comparison among different subclassification methods in a large cohort. METHOD: Pathological N1 or N2 non-small-cell lung cancer patients undergoing surgical resection between 2005 and 2016 in the Western China Lung Cancer Database were retrospectively reviewed. A literature review was conducted to collect previous subclassification methods. Kaplan-Meier and multivariable Cox analyses were used to examine the prognostic performance of subclassification methods. Decision curve analysis, Akaike's information criterion, and area under the receiver operating curve concordance were also performed to evaluate the standardized net benefit of the subclassification methods. RESULTS: A total of 1625 patients were identified in our cohort. Eight subclassification methods were collected from previous articles and further grouped into subclassification based on number categories (node number or station number), location categories (lymph node zone or chain) or combination of number and location categories. Subclassification based on combination of lymph node location and number tended to have better discrimination ability in multivariable Cox analysis. No significant superiority among the different subclassification methods was observed in the three statistical models. CONCLUSION: Subclassification based on the combination of location and number could be used to provide a more accurate prognostic stratification in surgically resected NSCLC and is worth further validation.

Ring-Opening Selenation of Cyclopropanol for the Selective Synthesis of ß-Hydroxy-Substituted Selenylated Ketones.

Ring opening of cycloalkanols has been employed as a commonly used strategy to prepare diverse distal functionalized ketones. However, most of these ketones obtained by this strategy belong to monofunctional ketones, while difunctional ketones with more potential application value have been rarely reported. Herein, we first reported a mild I2-promoted ring-opening selenation of cyclopropanol to synthesize various distal difunctional ketones. In the reaction, hydroxyl (-OH) derived from water and RSe+ from diselenide can be introduced into the α- and ß-positions, respectively, delivering ß-hydroxy selenylated ketones in good to excellent yields.

Traffic-Data Recovery Using Geometric-Algebra-Based Generative Adversarial Network.

Traffic-data recovery plays an important role in traffic prediction, congestion judgment, road network planning and other fields. Complete and accurate traffic data help to find the laws contained in the data more efficiently and effectively. However, existing methods still have problems to cope with the case when large amounts of traffic data are missed. As a generalization of vector algebra, geometric algebra has more powerful representation and processing capability for high-dimensional data. In this article, we are thus inspired to propose the geometric-algebra-based generative adversarial network to repair the missing traffic data by learning the correlation of multidimensional traffic parameters. The generator of the proposed model consists of a geometric algebra convolution module, an attention module and a deconvolution module. Global and local data mean squared errors are simultaneously applied to form the loss function of the generator. The discriminator is composed of a multichannel convolutional neural network which can continuously optimize the adversarial training process. Real traffic data from two elevated highways are used for experimental verification. Experimental results demonstrate that our method can effectively repair missing traffic data in a robust way and has better performance when compared with the state-of-the-art methods.

Exposure levels of mycophenolic acid are associated with comorbidities in children with systemic lupus erythematosus.

INTRODUCTION: Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. METHODS: Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. RESULTS: This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. CONCLUSIONS: Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.

[3 + 2]-Annulation of gem-Difluoroalkenes and Pyridinium Ylides: Access to Functionalized 2-Fluoroindolizines.

A [3 + 2]-annulation of gem-difluoroalkenes and pyridinium ylides was developed employing ambient air as the sole oxidant in an open-vessel manner, affording a series of multifunctionalized 2-fluoroindolizines in moderate to good yields. In this reaction, gem-difluoroalkene acts as a C2 synthon and entirely avoids the competitive addition-elimination process, which provides facile access to 2-fluoroindolizines.

Selective divergent radical cyclization of 1,6-dienes with alkyl nitriles.

An efficient, selective, and step economical radical cyclization of 1,6-dienes with alkyl nitriles initiated by α-C(sp3)-H functionalization under the Sc(OTf)3 and Ag2CO3 system is described here. The selective divergent cyclization relies on the substitution effect at the α-position of the acrylamide moiety and nitriles, which is terminated by hydrogen abstraction, direct cyclization with the aryl ring, or further cyclization with the CN bond and hydrolysis, respectively.

CRISPR/Cas9-mediated metabolic pathway reprogramming in a novel humanized rat model ameliorates primary hyperoxaluria type 1.

Primary hyperoxaluria type I is caused by mutations in the alanine glyoxylate aminotransferase gene (AGXT), leading to accumulation of glyoxylate and subsequent production of oxalate and urolithiasis. Here, we generated a novel rat model of primary hyperoxaluria type I that carries a D205N mutation in the partially humanized Agxt gene through the CRISPR/Cas9 system. The AgxtD205N mutant rats showed undetectable alanine glyoxylate aminotransferase protein expression, developed hyperoxaluria at 1 month of age and exhibited severe renal calcium oxalate deposition after ethylene glycol challenge. This suggests our novel model is more relevant to the human disease than existing animal models. To test whether this model could be used for the development of innovative therapeutics, SaCas9 targeting hydroxyacid oxidase 1, responsible for metabolizing glycolate into glyoxylate, was delivered via adeno-associated viral vectors into newborn rats with primary hyperoxaluria type 1. This approach generated nearly 30% indels in the Hao1 gene in the liver, leading to 42% lower urine oxalate levels in the treated group than in the control group and preventing the rats with primary hyperoxaluria type 1 from undergoing severe nephrocalcinosis for at least 12 months. Thus, our results demonstrate that this partially humanized AgxtD205N rat strain is a high-performing model of primary hyperoxaluria type 1 for understanding pathology, and the development of novel therapeutics, such as reprogramming of the metabolic pathway through genome editing.