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Aromatic nitrification with mixed acid is an important industrial reaction with fast, strong-exothermic, and high-risk reaction characteristics. To investigate the promotion for the preparation of nitrotoluene (MNT) and nitrochlorobenzene (NCB), three microreactors with different structural features, namely, heart-shaped, diamond-shaped, and zigzag-shaped microreactors, are designed and fabricated. Firstly, the effects of temperature, residence time, and molar ratio on toluene (TOL) and chlorobenzene (CB) nitrification are investigated, and orthogonal experiments are further conducted to determine the optimum reaction conditions. Results showed that channel structures and the residence time τ have negligible effects on the isomers selectivity of the three microreactors, and higher reaction temperatures and mole ratios would lead to the substantial occurrence of side reactions and byproducts in the zigzag microreactor. The heart-shaped microreactor has the highest value of 91.49 % for the MNT's optimal yield, followed by the diamond-shaped and zigzag-shaped microreactors (89.91 % and 89.81 %, respectively). The heart-shaped microreactor provides the maximum amount of NCB preparation (93.95 %), while the yields of the diamond-shaped and zigzag-shaped microreactors are 91.51 % and 88.25 %, respectively. This work provides the experimental basis for the efficient preparation and industrial scale-up of aromatic nitrification in microreactors.

Fossils of Ginkgophyta are widely recognized as a suitable proxy to estimate Mesozoic and Cenozoic atmospheric CO2levels. In this study, the fossil Ginkgoitesspecies, Ginkgoites huttonii(Sternberg) Black is described based on a collection from the Middle Jurassic (Bajocian) deposits in Northeast Iran. The palaeoatmospheric CO2level during Middle Jurassic in Iran is estimated for the first time based on the stomatal ratio (SR) method using this plant fossil. We show that the palaeoatmospheric CO2concentration was about 1123 ppmv as calculated from stomatal parameters measured in this study. A comparison of our results with previously reported geochemical models indicates close accordance with the GEOCARB II model for Middle Jurassic.

Iodinated aromatic disinfection byproducts have attracted much attention owing to their high toxicity. However, little has been known about the iodination mechanism to date. In this study, the iodination of model aromatic precursors, tyrosine (Tyr) and its model dipeptides, by HOI and other iodinating agents was explored using a quantum chemical computational method, and the halogenation of Tyr by HOX (X = Cl, Br, and I) was compared. The results indicate that the phenolate salt plays a key role in the iodination of the phenol ring in Tyr compounds by HOI viathe classic SEAr mechanism and the second deprotonation becomes the rate-limiting step, which explains why the kinetic isotope effect (KIE) was observed in the iodination of aromatic compounds. Among the seven possible iodinating agents present in chloramination, HOI is the predominant one, and I2is the second in the iodination of the phenol ring under typical chloramination conditions. In the further investigation of bromination and chlorination, the KIE was found to also occur in the bromination of Tyr. More importantly, the different reactivity orders of HOX reacting with the phenol ring and the amino group in Tyr are related to the hardness of both HOX and substrates, which can be evaluated from the energy gap (ELUMO–HOMO) between the LUMO and HOMO energies. Following the “like–attracts–like” principle, the halogenating agent prefers the substrate with a similar ELUMO–HOMOvalue. The results are helpful in further understanding the iodination mechanism and identifying various halogenated products.

Dichloroacetonitrile (DCAN) as one of the potentially prioritized regulated DBPs has drawn great attention; however, understanding its formation, especially the C–C bond cleavage mechanisms, is limited. In this study, DCAN formation mechanisms from long-chain primary amines, amino acids, and dipeptides during chlorination were investigated by a combined computational and experimental approach. The results indicate that nitriles initially generate for all of the above precursors, then they undergo β-C-hydroxylation or/and α-C-chlorination processes, and finally, DCAN is produced through the Cα–Cβbond cleavage. For the first time, the underlying mechanism of the C–C bond cleavage was unraveled to be electron transfer from the O–anion into its attached C atom in the chlorinated nitriles, leading to the strongly polarized Cα–Cβbond heterocleavage and DCAN–formation. Moreover, DCAN molar yields of precursors studied in the present work were found to be determined by their groups at the γ-site of the amino group, where the carbonyl group including −CO2–, −COR, and −CONHR, the aromatic group, and the −OH group can all dramatically facilitate DCAN formation by skipping over or promoting the time-consuming β-C-hydroxylation process and featuring relatively lower activation free energies in the C–C bond cleavage. Importantly, 4-amino-2-hydroxybutyric acid was revealed to possess the highest DCAN yield among all the known aliphatic long-chain precursors to date during chlorination. Additionally, enonitriles, (chloro-)isocyanates, and nitriles can be generated during DCAN formation and should be of concern due to their high toxicities.

Objective: Gastrointestinal stromal tumors (GISTs) can rapidly proliferate through angiogenesis. Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis. This study aimed to explore the specific mechanism by which microRNA-409-5p (miR-409-5p) contributes to GIST. Methods: To identify genes potentially involved in the development and progression of GIST, the differences of miR-409-5p between tumors and adjacent tissues were first analyzed. Following this analysis, target genes were predicted. To further investigate the function of miRNA in GIST cells, two GIST cell lines (GIST-T1 and GIST882) were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA (negative control). Later, the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes. Results: In GISTs, there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues. It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β (HIF1β) and vascular endothelial growth factor A (VEGF-A). Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3′-UTR of Lysine-specific demethylase 4D (KDM4D) mRNA. Moreover, the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis. Conclusion: This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.

•Whole genome sequencing of 36 Hodgkin lymphoma (HL) families identifies 33 coding and 11 noncoding HL-risk variants.•Recurrent damaging variants are observed in known (KDR and KLHDC8B) and novel (PAX5, GATA3, and POLR1E) predisposing loci.

With ca. 250 extant species, Radulais one of the largest genera of the Porellales and the sole extant genus of the leafy liverwort family Radulaceae, widely distributed around the world. The earliest fossils of Radulawere described from the mid-Cretaceous Kachin amber of Myanmar, namely R. cretaceaand R. heinrichsii. Here, we report two new exquisitely preserved specimens of R. heinrichsiifrom Kachin amber, yielding new morphological characters for an extended description of this taxon. Cladistic analysis based on a matrix of fourteen morphological characters and a molecular backbone constraint suggests its close relationship with extant species of Radulasubgenus Amentuloradula. But due to distinctive morphological characters in R. heinrichsiiand the younger estimated age for the crown group, it is likely that R. heinrichsiirepresents a stem group of the subgenus Amentuloradula. The genus Radulais characterized by a high degree of morphological homoplasy, which makes the assignment of fossils to this extant taxon difficult and requires profound knowledge of the morphology of fossils.

The present study compares the pharmacokinetics of amoxicillin and clavulanate potassium suspension (200 mg/28.5 mg) during fasting and postprandial conditions, and the sample adds a stabilizer study. Two randomized, crossover trials were conducted in an open‐label, single‐center study (a fasting trial and a postprandial trial). In each part of the study, the subjects were randomly assigned to receive either test or reference products (200 mg/28.5 mg) in a 1:1:1 ratio, followed by the alternative products after a 7‐day washout period. Plasma amoxicillin and clavulanic acid concentrations were analyzed by liquid chromatography–tandem mass spectrometry. WinNonlin software was used to evaluate the pharmacokinetic parameters (noncompartmental model). The formulations were considered bioequivalent if the geometric means of area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) of amoxicillin and clavulanic acid were within the predetermined bioequivalence range established by average bioequivalence (ABE) or reference‐scaled ABE. Tolerability was assessed throughout the study. The postprandial trial and the fasting study each had 12 volunteers. Under fasting and postprandial conditions, the 90%CI for the ratio of geometric means of amoxicillin of Cmax, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity were within the ABE acceptance limits (80%‐125%); the geometric means of clavulanic acid of Cmax(critbound, –0.03; point estimate, 1.07) were within the reference‐scaled ABE acceptance limits, and the AUC from time 0 to the last measurable concentration and AUC from time 0 to infinity were within the ABE acceptance limits (80%–125%). Time to maximum concentration of amoxicillin was delayed 1.0 hour with high‐fat meals compared to fasting conditions. Meantime, high‐fat meals decreased the exposure of clavulanic acid by nearly 40%. No serious adverse events were found among the subjects. The bioequivalence of test and reference amoxicillin and clavulanate potassium for suspension was validated in this study under fasting and postprandial conditions.

Electric shock injuries, a category of severe industrial accidents, often entail the risk of multi-organ damage. In the present unique case report, the infrequent occurrence of a right scapular fracture stemming from an electric shock accident is described. A male patient in his early 30s accidentally received an electric shock while working, resulting in pain in the right upper limb and shoulder. Although he had no obvious external injuries, physical examination revealed a decrease in muscle strength in the right upper limb. Following magnetic resonance imaging and computed tomography, a comminuted fracture of the scapula was diagnosed. The patient received emergency symptomatic treatment, including pain relief, anti-infection measures, and nutritional support for the myocardium, and subsequent orthopaedic surgical intervention for fracture fixation. The patient recovered well after surgery, with muscle strength gradually returning. This report documents the rarely-described occurrence of non-traumatic unilateral scapular fractures following an electric shock. Medical practitioners should be aware of the wide range of potential injuries, including fractures, when evaluating patients with electric shock injuries.

• Implicit algorithms is established based on Boltzmann model equation. • The DRIA gas surface interaction model is incorporated in the implicit algorithms. • The effects of energy accommodation at various surface thermal states on flow fields are explored. To study the influence of energy accommodation of scattering gas molecules on flow fields during large expired spacecraft reentry, a more elaborated gas-surface interaction model, compared with full Maxwellian diffuse model, is employed in implicit algorithms based on Boltzmann model equation. The characteristic distributions around cylinder at different fluid regimes are accordingly obtained by implicit algorithms, Navier-Stokes solver and DSMC ((Direct Simulation Monte Carlo) method. And the consistency of these results is verified. It is confirmed that present algorithms are capable of solving external flow problems covering various fluid regimes. Then the simulation results see that under current conditions set in the paper, pressure and temperature are proportional to wall activation (ω = T w / T ∞ , T w is surface temperature, T ∞ denotes as free stream temperature), but their amplitudes alter with ω at different fluid regimes. As for the effects of energy accommodation coefficients (α e), both pressure and temperature profiles vary in a linear way with α e. However, the variation ranges of these parameters are diverse with regard to different fluid regimes. These observations are favor to the construction of efficient forecasting software, which could predict the flight path of large defunct spacecraft. In this forecasting software, the external ballistics computations and aerothermodynamic simulations are synchronously carried out. [ABSTRACT FROM AUTHOR]

Hypochlorous acid (HOCl) released from activated leukocytes not only plays a significant role in the human immune system but is also implicated in numerous diseases including atherosclerosis and some cancers due to its inappropriate production. Histidine (His) and carnosine (Car), as a respective mediator and protective agent of HOCl damage, have attracted considerable attention; however, their detailed reaction mechanisms are still unclear. In this study, using a His residue with two peptide bond groups (HisRes) as a model, the reaction mechanisms of HisRes and Car including NεH and NδH tautomers with HOCl along with the chlorination reactivity of N-chlorinated intermediates were investigated by quantum chemical methods. The obtained results indicate that in the imidazole side chain, the pyridine-like N is the most reactive site rather than the pyrrole-like N, and the kinetic order of all of the possible reaction sites in HisRes follows pyridine-like N > imidazole Cδ≫ imidazole Cε> pyrrole-like N, while that in Car is pyridine-like N ≫ imidazole Cδ≫ amide N. As for N-chlorinated intermediates at imidazole, although the unprotonated form has a low chlorination reactivity as expected, it can still chlorinate tyrosine. Especially, the protonated form exhibits similar ability to HOCl, causing secondary damage in vivo. N-Chlorinated Car features higher internal chlorine migration ability than its intermolecular transchlorination, preventing further HOCl-induced damage. Additionally, a generally overlooked nucleophilic Cl–shift is also found in N-chlorinated Car/HisRes, indicating that nucleophilic sites in biomolecules also need to be considered. The outcomes of this study are expected to expand our understanding of secondary damage and protective mechanisms involved in HOCl in humans.

• Gas kinetic unified algorithm (GKUA) is constructed based on Boltzmann model equation. • The Maxwellian gas surface interaction model is implemented in GKUA. • The effects of reflected gas state on aerodynamic properties of spacecraft debris are revealed during Tianzhou-5 spacecraft reentry. The work is devoted to researching the effects of reflected gas molecules' states on aerodynamic properties and surface characteristic quantities distributions. Within the framework of GUKA, the Maxwellian type gas surface interaction model is implemented. After the validation of the GKUA in representative cases, the simple geometry model is initially introduced to study the variations of aerodynamic properties with different gas molecules states. Then the simulations around simplified Tianzhou-5 cargo spacecraft and its symbolic components are conducted at typical reentry trajectory points. The results are useful to predict the disintegration trajectories and evaluate the distributions of survival spacecraft objects falling down the ground. [ABSTRACT FROM AUTHOR]

The rapid Cretaceous diversification of flowering plants remains Darwin’s ‘abominable mystery’ despite numerous fossil flowers discovered in recent years. Wildfires were frequent in the Cretaceous and many such early flower fossils are represented by charcoalified fragments, lacking complete delicate structures and surface textures, making their similarity to living forms difficult to discern. Furthermore, scarcity of information about the ecology of early angiosperms makes it difficult to test hypotheses about the drivers of their diversification, including the role of fire in shaping flowering plant evolution. We report the discovery of two exquisitely preserved fossil flower species, one identical to the inflorescences of the extant crown-eudicot genus Phylicaand the other recovered as a sister group to Phylica, both preserved as inclusions together with burned plant remains in Cretaceous amber from northern Myanmar (~99 million years ago). These specialized flower species, named Phylica piloburmensissp. nov. and Eophylica priscastellatagen. et sp. nov., exhibit traits identical to those of modern taxa in fire-prone ecosystems such as the fynbos of South Africa, and provide evidence of fire adaptation in angiosperms.

N-n-Butyl haloperidol iodide (F2) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F2against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl4) or thioacetamide (TAA). The mice received F2(0.75, 1.5 or 3 mg·kg−1·d−1, ip) for 4 weeks of fibrosis induction. We showed that F2administration dose-dependently ameliorated CCl4- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-β receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F2(0.1, 1, 10 μM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F2inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-β signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-β1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-β signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F2suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-β signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F2against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1. F2may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFHcells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFHcell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFHcells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of TFHcell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFHcells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a(which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of TFHcells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFHcell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs.

Chimeric antigen receptor (CAR)–T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR–T-cell expansion and memory-like cell formation. This leads to improved CAR-T–mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1–deficient CAR-T cells into TCF-1+ precursor exhausted T cells (TPEX) characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 messenger RNA (mRNA); its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR–T-cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1− CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR–T-cell population. Our findings demonstrate the pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR–T-cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR–T-cell longevity and potency that may be manipulated for improved therapeutic efficacy.

AbstractA cordycipitoid fungus infecting Hepialidae sp. in Nepal was supposed to be identical to Cordyceps liangshanensis, originally described from southwestern China, and thus, transferred to the genus Metacordycepsor Papiliomycesin previous studies. However, our multi-gene (nrSSU-nrLSU-tef-1α-rpb1-rpb2) phylogenetic and morphological studies based on the type specimen and additional collections of C. liangshanensisrevealed that the fungus belongs to the genus Ophiocordyceps(Ophiocordycipitaceae). Therefore, a new combination O. liangshanensiswas made, and a detailed description of this species was provided.

Effects of ageing treatment on the microstructures, mechanical properties and corrosion behavior of the Mg-4.2Zn-1.7RE-0.8Zr-xCa-ySr [x=0, 0.2 (wt.%), y=0, 0.1, 0.2, 0.4 (wt.%)] alloys were investigated. Results showed that Ca or/and Sr additions promoted the precipitation hardening behavior of Mg-4.2Zn-1.7RE-0.8Zr alloy and shortened the time to reaching peak hardness from 13 h to 12 h. The maximum hardness of 77.1±0.6 HV for the peak-aged Mg-4.2Zn-1.7RE-0.8Zr-0.2Ca-0.2Sr alloy was obtained. The microstructures of peak-aged alloys mainly consist of α-Mg phase, Mg51Zn20phase and ternary T-phase. The Zn-Zr phase is formed within the α-Mg matrix, and the Mg2Ca phase is formed near T-phase due to the enrichment of Ca in front of the solid-liquid interface. Furthermore, fine short rod-shaped β′1phase is precipitated within the α-Mg matrix in the peak-aged condition. The peak-aged Mg-4.2Zn-1.7RE-0.8Zr-0.2Ca-0.2Sr alloy exhibits optimal mechanical properties with an ultimate tensile strength of 208 MPa, yield strength of 150 MPa and elongation of 3.5%, which is mainly attributed to precipitation strengthening. In addition, corrosion properties of experimental alloys in the 3.5wt.% NaCl solution were studied by the electrochemical tests, weight loss, hydrogen evolution measurement and corrosion morphology observation. The results suggest that peak-aged alloys show reduced corrosion rates compared with the as-cast alloys, and minor additions of Ca and/or Sr improve the corrosion resistance of the Mg-4.2Zn-1.7RE-0.8Zr alloy. The peak-aged Mg-4.2Zn-1.7RE-0.8Zr-0.2Ca-0.2Sr alloy possesses the best corrosion resistance, which is mainly due to the continuous and compact barrier wall constructed by the homogeneous and continuous second phases.

The Sichuan Basin is one of the largest petroliferous basins in China. The continental fluvial‒lacustrine sediments of the Upper Triassic Xujiahe Formation and the Lower Jurassic Zhenzhuchong Formation yield diverse fossil organisms and host one of the most important gas reservoirs in the basin. However, paleontological implication for the paleoenvironment and hydrocarbon source is less documented. Here, we report, for the first time for this basin, results from palynofacies analyses combined with thermal alteration data in the Early Mesozoic deposit of the Qilixia section, northeastern Sichuan Basin. The results show that, organic matters in sediments are dominated by phytoclasts, with less abundant palynomorphs and a few amorphous organic matters (AOMs). Four palynofacies assemblages were identified, reflecting depositional settings in a general proximal and oxic fluvial‒deltaic environment, with two distal–proximal sedimentary cycles. The prominent dominance of opaque phytoclasts within the lower Zhenzhuchong Formation may be related to frequent wildfires across the Triassic–Jurassic transition. Palynofacies data (especially the relative abundance of opaque phytoclasts) may reflect 405 kyr eccentricity cyclicity pattern. The palynofacies and thermal alteration index (TAI), combined with geochemical data indicate the presence of type III kerogen in mature to post-mature phases, suggesting gas potential of the Xujiahe and Zhenzhuchong formations in the northeastern Sichuan Basin. This study provides significant implications for better understanding the paleoenvironment variations during the Triassic–Jurassic transition and the future gas exploration in this area.

Hematopoietic stem cells (HSCs) maintain quiescence under steady state; however, they are compelled to proliferate and expand to replenish the blood system under stress. The molecular basis underlying stress hematopoiesis remains to be fully understood. In this study, we reported that IRF7 represents an important regulator of stress hematopoiesis. Interferon regulatory factor 7 (IRF7) was dispensable for normal hematopoiesis, whereas its deficiency significantly enhanced hematopoietic stem and progenitor cells (HSPCs) regeneration and improved long‐term repopulation of HSCs under stress. Mechanistic studies showed that CXCR4was identified as a downstream target of IRF7. Overexpression of CXCR4 abrogated the enhanced proliferation and regeneration of IRF7‐deficient HSPCs under stress. Similar results were obtained in HSCs from human umbilical cord blood. These observations demonstrated that IRF7 plays an important role in hematopoietic regeneration under stress.

The histone mark H3K27me3 and its reader/writer polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for hematopoietic development but are poorly understood. Here we show that the E3 ubiquitin ligase F-box only protein 11 (FBXO11) relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate bromo adjacent homology domain–containing 1 (BAHD1), an H3K27me3 reader that recruits transcriptional corepressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks at their promoters. In FBXO11−/−erythroblasts, these gene promoters bind BAHD1 and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2, and depletion of either component restores FBXO11-deficient erythroid gene expression. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at many developmentally poised bivalent genes during erythropoiesis.

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2–4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein–protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Tregsuppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101in mouse Tregcells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

A new species Pleuromeia shaoliniiZhang et Wang n. sp. was established under the family Pleuromeiaceae, based on eight specimens of stems and leaves, cones, rhizophores, and adventitious roots that were recently collected from the Middle Triassic Linjia Formation in Benxi, Northeast China. P. shaoliniin. sp. is similar to the type species P. sternbergii, in the morphology of the stem and rhizophore, but differs from it by the transversely rounded sporophylls organized in a heterosporous cone, and the two conspicuous triangular scars present on both sides of the vascular bundle scar. The Linjia flora, an only reliable Middle Triassic flora in Northeast China, was discovered 40 years ago. Although the Linjia Formation can be compared with the Middle Triassic Ermaying Formation from another area of the North China plate, its age was questionable due to the absence of the Early to Middle Triassic index fossil Pleuromeia. Based on the flora similarity, the zircon dating, lithologic characteristics, presence of a disconformity, and the occurrence of the Middle Triassic–Early Cretaceous insect fossil Sogdoblatta, the age of the Linjia Formation can be confirmed as Middle Triassic. The new species not only supplements our knowledge in biology and taxonomy of Pleuromeia, but also supports the Middle Triassic age assignment of the Linjia flora.

AimsWhether to perform hybrid surgery (HS) in contrast to anterior cervical discectomy and fusion (ACDF) when treating patients with multilevel cervical disc degeneration remains a controversial subject. To resolve this we have undertaken a meta-analysis comparing the outcomes from HS with ACDF in this condition.MethodsSeven databases were searched for studies of HS and ACDF from inception of the study to 1 September 2019. Both random-effects and fixed-effects models were used to evaluate the overall effect of the C2-C7 range of motion (ROM), ROM of superior/inferior adjacent levels, adjacent segment degeneration (ASD), heterotopic ossification (HO), complications, neck disability index (NDI) score, visual analogue scale (VAS) score, Japanese Orthopaedic Association (JOA) score, Odom’s criteria, blood loss, and operating and hospitalization time. To obtain more credible results contour-enhanced funnel plots, Egger’s and Begg’s tests, meta-regression, and sensitivity analyses were performed.ResultsIn total, 17 studies involving 861 patients were included in the analysis. HS was found to be superior to ACDF in maintaining C2-C7 ROM and ROM of superior/inferior adjacent levels, but HS did not reduce the incidence of associated level ASD. Also, HS did not cause a higher rate of HO than ACDF. The frequency of complications was similar between the two techniques. HS failed to achieve more favourable outcomes than ACDF using the NDI, VAS, JOA, and Odom’s scores. HS did not show any more advantages in operating or hospitalization time but did show reduction in blood loss.ConclusionAlthough HS maintained cervical kinetics, it failed to reduce the incidence of ASD. This finding differs from previous reports. Moreover, patients did not show more benefits from HS with respect to symptom improvement, prevention of complications, and clinical outcomes.Cite this article: Bone Joint J2020;102-B(8):981–996.

N-Chloro-α-amino acids formed in the chlorination disinfection treatment of water or wastewater and in living organisms have attracted extensive attention due to the potential toxicities of themselves and their decomposition products. The degradation mechanisms of three N-chloro-α-amino acids, i.e., N-chloro-glycine, N-chloro-alanine, and N-chloro-valine, have been systematically investigated using quantum chemical computations. The results indicate that N-chloro-α-amino acid anions undergo two competitive degradation pathways: a concerted Grob fragmentation (CGF) and β-elimination (β-E). Generally, the former predominates over the latter under neutral conditions and finally generates amines and carbonyls, while the latter is preferred under base-promoted conditions and mainly produces the respective α-keto acid anions or nitriles in the end. To gain deeper insights into the substitution effects, in view of the advantages of quantum chemical computations, a number of real or designed N-chloro-α-amino acids with traditional electron-donating groups (EDG) or electron-withdrawing groups (EWG) have been studied. All of the substituted N-chloro-α-amino acids, regardless of the type and position of substituents, are kinetically more favorable than N-monochloro-glycine for degradation via the CGF pathway. Moreover, conjugated EDG substituted on the N-terminal facilitate both CGF and β-E reactions, whereas conjugated EDG and EWG on the α-carbon are only favorable for the CGF and β-E reactions, respectively. These results are expected to expand our understanding of organic N-chloramine degradation mechanisms and chlorination reaction characteristics.

N-Nitrosodimethylamine (NDMA) formation from tertiary amines during chloramination has aroused widespread concern due to its unusually high toxicity and the high NDMA conversion yields of some tertiary amines especially for ranitidine. However, the formation mechanisms have not been fully understood yet. In this study, density functional theory (DFT) calculation as a useful complementary approach to the experiments was used to reinvestigate NDMA formation pathways from tertiary amines during chloramination. The results indicate that the formation of NDMA includes five processes: nucleophilic substitution, aminyl radical generation, oxidation of radical by O2, N-nitroso-compound cation formation and release of NDMA. In the first two processes, the tertiary amines are more likely to first react with dichloramine and the result of which then reacts with monochloramine to generate aminyl radicals. It is elucidated that dichloramine plays a pronounced role in NDMA formation. Moreover, the aminyl radical formation accompanied by the release of chlorine radicals predominates over that by the release of NH2radicals proposed in the literature mainly due to the lower homolytic bond dissociation energy of N–Cl relative to that of N–H. Importantly, the activation free energy of the release of NDMA from the N-nitroso-compound cation, which is fundamentally related to the previously reported heterolytic ONN(Me)2–R+bond dissociation energy, was found to be a key indication for distinguishing potential NDMA precursors from tertiary amines. The findings of this work are helpful for expanding the knowledge of NDMA formation mechanisms and predicting potential NDMA precursors during disinfection.

Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells1. Here we use an in vivo pooled CRISPR–Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8+T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8+T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR–Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8+T cells. By contrast, the targeting of additional signalling factors—including PTPN2 and SOCS1—improves the therapeutic efficacy of REGNASE-1-deficient CD8+T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.

A three-component annulation reaction and trifluoromethylation for the construction of 3-(trifluoromethyl)-4H-pyrans using β-CF3-1,3-enynes, BrCF2CO2Et, and sulfoxonium ylides as readily available substrates has been developed. This metal-free process involves two C–F bond cleavages of β-CF3-1,3-enynes and a CF3group generated in situfrom BrCF2CO2Et. This method is applicable to the late-stage modification of pharmaceutically active molecules.

Pseudotsuga Carrière is commonly known as Douglas-fir, a minor genus attributed to Pinaceae. Four extant species are included in this genus, with dispersed distribution in East Asia and western North America. Pseudotsugapossesses a number of fossil records of needled leaves, seed cones, and seeds. Nevertheless, few reliable fossil wood of this genus has been specifically investigated. Here, we describe some anatomically well-preserved petrified fossil wood from the lower Miocene of Lesvos Island, Greece, as Pseudotsuga lesvosensisn. sp. The studied fossil wood remains are characterized by the presence of normal axial and radial resin canals, piceoid cross-field pitting, along with distinctive helical thickenings in cell walls consistent with Pseudotsuga. The present fossil conifer further enriches the species diversity of the Miocene Petrified Forest in Lesvos. The first report of Pseudotsuga lesvosensisfrom the southern Europe in this study extends the tempo-spatial distribution patterns of Pseudotsugaand contributes to further understanding of its origin and evolutionary history. The occurrence of P. lesvosensisfossil wood, as well as other palaeontological macrofloral composition evidence, indicates a humid warm temperate to subtropical climatic condition during the early Miocene within the Lesvos, which differs significantly from the current Mediterranean climate.

The end-Triassic mass extinction is one of the five big extinction events in the Phanerozoic, and its impact on marine organisms has been extensively studied. However, whether the terrestrial ecosystem had begun to deteriorate or even collapsed prior to the end-Triassic mass extinction remains controversial and the related studies in Asia are very limited. In this study, we provide a comprehensive investigation of the sedimentary environments, their implications for floral changes, and the paleoecology during the Norian–Rhaetian transition in Xuanhan area, northeastern Sichuan Basin, Southwest China. The sedimentary environments and climatic conditions changed coupling the transgression and regression caused by the tectonic movements. Climatic oscillations were identified during the Norian–Rhaetian transition in the Xuanhan area, including a short-term cooling event. The diversity and composition of the plant communities changed through the Norian–Rhaetian transition in Xuanhan area, but the terrestrial ecosystem as a whole didn’t collapse or deteriorate prior to the end-Triassic mass extinction.

Structure properties of Al-Ti-C mother alloy which was prepared by TiH2 and graphite method were studied by various characterization methods.Results demonstrated that the synthesis process of Al-Ti-C alloy contained three stages.Firstly,TiH2 and graphite was respectively used as titanium and carbon sources.Secondly,titanium reacted with aluminum and graphite,producing Ti-Al,C-Al,Ti-C compounds.Finally,these compounds formed Al-Ti-C alloy.It was equiaxed or dendrite structure with grain size of 20～40μm.There were needle-like and elongated phases in alloy matrix.There are petal primary crystals containing Ti,C,Fe and Si on grain boundaries.Ti and C distribute evenly along grain boundaries and grains.Ti and C enrichment and segregation occurred close to the primary phase.Cryolites were conducive to wetting of carbon and aluminum, the second phase generated more fully in the grain.

X-ray diffraction, scanning electron microscopy, energy dispersive spectroscopy, differential scanning calorimetry, and thermogravimetric analysis were used to study the microstructure and properties of an Al-Ti-C parent alloy prepared using the villiaumite–woodchip method. The synthesis process of the Al-Ti-C parent alloy prepared using the villiaumite–woodchip method and aluminum liquid had the following stages: The first stage was the formation of titanium aluminum by titanium being displaced from the reaction between aluminum and villiaumite. The second stage was the dehydration and carbonization reactions of the woodchips at high temperatures. The third stage involved titanium aluminum, carbon aluminum, and titanium carbon compounds constitute the Al-Ti-C parent alloy with a refined effect water and carbon dioxide, which were the cracking products of the woodchips, reacted with aluminum to produce alumina and hydrogen, which accumulated in the grain boundary in the form of slag-gas pockets.

The microstructure of an Al-Ti-C-Ce alloy was studied by XRD, SEM, and EDS. This mother alloy consisted of α (Al),(AlTi),(TiC), and (Ti2Al20Ce) phases, and there was a second phase of a composite structure in the alloy. The TiC phase was the primary crystal nucleus, and the (TiAl) phase was segregated on the surface of TiC phase to form a TiC-(TiAl) composite crystal nucleus. Al formed a fine TiC-(TiAl)-α (Al) primary composite crystal nucleus by a peritectic reaction.The primary composite crystal nucleus with higher energy and larger cluster size was taken as the core,and other composite crystal nuclei were segregated on its surface to form a secondary composite crystal nucleus. Next, the secondary composite crystal nucleus formed the tertiary composite crystal nucleus, and so on, to form the titanium-enriched area of composite particles.

Although many recent studies describe the emergence and prevalence of “clonal hematopoiesis of indeterminate potential” in aged human populations, a systematic analysis of the numbers of clones supporting steady-state hematopoiesis throughout mammalian life is lacking. Previous efforts relied on transplantation of “barcoded” hematopoietic stem cells (HSCs) to track the contribution of HSC clones to reconstituted blood. However, ex vivo manipulation and transplantation alter HSC function and thus may not reflect the biology of steady-state hematopoiesis. Using a noninvasive in vivo color-labeling system, we report the first comprehensive analysis of the changing global clonal complexity of steady-state hematopoiesis during the natural murine lifespan. We observed that the number of clones (ie, clonal complexity) supporting the major blood and bone marrow hematopoietic compartments decline with age by ~30% and ~60%, respectively. Aging dramatically reduced HSC in vivo–repopulating activity and lymphoid potential while increasing functional heterogeneity. Continuous challenge of the hematopoietic system by serial transplantation provoked the clonal collapse of both young and aged hematopoietic systems. Whole-exome sequencing of serially transplanted aged and young hematopoietic clones confirmed oligoclonal hematopoiesis and revealed mutations in at least 27 genes, including nonsense, missense, and deletion mutations in Bcl11b, Hist1h2ac, Npy2r, Notch3, Ptprr, and Top2b.

Linear β-cyclodextrin polymer functionalized multiwalled carbon nanotubes (MWCNTs-CDP) were synthesized and employed as a novel nanoadsorbent to remove uranyl ions in wastewater solutions. The characterization of MWCNTs-CDP, with Fourier transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and Brunauer–Emmett–Teller (BET), suggested that the CDP was successfully modified on the MWCNTs surfaces. The removal efficiency of uranyl ions in aqueous solution by MWCNTs-CDP was investigated via varying various experimental conditions. We found that the removal of uranyl ions correlated with both pH and temperature, and the optimum pH and temperature were 6.0 and 323.15 K, respectively. The adsorption of uranyl ions was very fleet at the initial 1 h and then reached the adsorption equilibrium after 3 h. The data from the adsorption dynamics experiment could be commendably fitted by the pseudo-second-order model (R2> 0.982), suggesting that chemisorption might be the rate-controlling mechanism. The Langmuir model (R2> 0.995) manifested that the maximum adsorption capacity of uranyl ions on MWCNTs-CDP was boosted from 66.16 to 89.54 mg g–1upon the change of temperature from 293.15 to 323.15 K. This result was better than that of some reported adsorbents. The thermodynamics analysis proved that the adsorption of uranyl ions on MWCNTs-CDP was a spontaneous process and an endothermic one. The adsorption mechanism of uranyl ions on MWCNTs-CDP was verified to be dominated by inner-sphere surface complexation. Our results indicated that MWCNTs-CDP can be utilized as a novel nanoadsorbent for highly effective removal of uranyl ions in actual uranyl-bearing effluents.

UTX is a chromatin modifier required for development and neural lineage specification, but how it controls these biological processes is unclear. To determine the molecular mechanisms of UTX, we identified novel UTX protein interaction partners. Here we show that UTX and 53BP1 directly interact and co-occupy promoters in human embryonic stem cells and differentiating neural progenitor cells. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and disruption of the 53BP1–UTX interaction abrogated human, but not mouse, neurogenesis in vitro. The 53BP1–UTX interaction is required to upregulate key neurodevelopmental genes during the differentiation of human embryonic stem cells into neurons or into cortical organoids. 53BP1 promotes UTX chromatin binding, and in turn H3K27 modifications and gene activation, at a subset of genomic regions, including neurogenic genes. Overall, our data suggest that the 53BP1–UTX interaction supports the activation of key genes required for human neurodevelopment.

Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although the circadian cycle is implicated in aging, it is unknown whether natural variation in its function contributes to differences in lifespan between populations and whether the circadian clock of specific tissues is key for longevity. We have sequenced the genomes of Drosophila melanogasterstrains with exceptional longevity that were obtained via multiple rounds of selection from a parental strain. Comparison of genomic, transcriptomic, and proteomic data revealed that changes in gene expression due to intergenic polymorphisms are associated with longevity and preservation of skeletal muscle function with aging in these strains. Analysis of transcription factors differentially modulated in long-lived versus parental strains indicates a possible role of circadian clock core components. Specifically, there is higher periodand timelessand lower cycleexpression in the muscle of strains with delayed aging compared to the parental strain. These changes in the levels of circadian clock transcription factors lead to changes in the muscle circadian transcriptome, which includes genes involved in metabolism, proteolysis, and xenobiotic detoxification. Moreover, a skeletal muscle-specific increase in timelessexpression extends lifespan and recapitulates some of the transcriptional and circadian changes that differentiate the long-lived from the parental strains. Altogether, these findings indicate that the muscle circadian clock is important for longevity and that circadian gene variants contribute to the evolutionary divergence in longevity across populations.

Purpose: To evaluate the safety and the clinical efficacy of percutaneous vertebroplasty (PVP) in treating malignant spinal tumors and malignant vertebral compression fractures with epidural involvement.

The impact toughness of closed-cell aluminum foam with various densities was investigated. The impact load history revealed an elastic region followed by a rapid load drop region. The peak load and impact toughness of aluminum foam increases exponentially with density. The power exponents for impact toughness test are greater than that for compressive test. Fracture analysis indicated a mixed-rupture mode of quasi-cleavage and small shallow dimples. It can be attributed to the complex state of stress of notched specimens and elevated impact velocity under impact loading.

A set of Cu-10Ni-1Fe-1Mn alloys were prepared. Electromagnetic casting, DC casting ingot organization, properties and composition distribution of the alloy were studied using Optical Microscope (OM), Scanning Electron Microscopy (SEM), Energy spectrum analysis (EDS), Xray diffraction (XRD), Brinell Hardness Test, and electrochemical tests. The results suggested that homogenization of the Cu-10Ni-1Fe-1Mn alloy changed its properties and distribution of composition. The results also suggest that electromagnetic casting can refine casting organization, homogenize the composition of the alloy, and the casting mechanical performance is superior compared to those of DC casting. However, the composition between Dendritic branch and Dendrites was still not homogeneous. After 1 h of homogenization treatment at 950°C, the ingot composition distribution became more homogeneous, and its stiffness decreased. The tube prepared by squeezing the homogenized ingot, was soaked in 3.5% NaCl solution for 240 h, after which the tube blank surface remained a bright metal luster and XRD analysis indicated that a Cu2O protective film of high density covered the surface of the tube. The homogenization treatment significantly improved the corrosion resistant properties of the alloy tubes.

Evolution laws of structure and performance of Cu-10Ni-1Fe-1Mn alloy in the process of continuous casting-planetary rolling-drawing deformation were studied by OM, SEM, TEM, Brinell Hardness tester and universal material testing machine. Results demonstrated that the alloy ingot is composed of thick dendrites. The ingot makes grain crushing and dynamic recrystallization after planetary rolling. The hot rolling samples still have abundant fine recrystallization textures after multi-pass drawings. Due to roller-core head or internal-external mold opposite pressure, dislocations in different regions of sample move along the glide plane, forming a macroscopic slip band. Two adjacent macroscopic slip zones which move toward opposite directions compose the folded structures after the deformation. Refined crystalline strengthening, solution strengthening of Fe, Ni and Mn, work hardening, and iron-containing particle precipitation are major causes of alloy strengthening. SEM analysis of tensile fracture demonstrated that the material still maintained good plasticity after rolling and drawing deformation. However, material plasticity declined with the increase of cold processing-induced deformation.

This study compared the effects of viscosity and microscopic mechanism between different viscous agents. Based on macro-analysis and micro-analysis, the comparison were studied, and built the models to explain the results. The different viscous agents and proportion could change the situation around the bubbles and grain size differently. The study gave a new way to analyze the viscosity, further, these factors play an important in effects of viscosity.