The application of probiotics as an eco-friendly alternative to antibiotics is an emerging strategy for sustainable aquaculture. In the present study, Rummeliibacillus stabekisii was isolated from ...the gut of Nile tilapia, and the effects of R. stabekisii on the growth, innate immunity, disease resistance, and gut microbiota of Nile tilapia (Oreochromis niloticus) were investigated. The results showed significantly increased weight gain (WG), feed conversion ratio (FCR), and feed efficiency (FE) in Nile tilapia fed R. stabekisii for 8 weeks compared to those in fish fed a control diet. Intestinal digestive enzymes such as protease, cellulase, and xylanase were also significantly increased in the R. stabekisii-administered groups. Enhanced cumulative survival was exhibited in fish fed R. stabekisii after challenge with Aeromonas hydrophila and Streptococcus iniae. Immune parameters such as the phagocytic activity, respiratory bursts, and superoxide dismutase of head kidney leukocytes; serum lysozyme activity; and expression of the cytokine genes interleukin-1β, tumor necrosis factor-α, transforming growth factor-β, and heat shock protein 70 were significantly elevated in fish fed R. stabekisii. Administration of R. stabekisii considerably increased the abundance of potential probiotics (Bacillus and Lactobacillus spp.) and reduced abundances of potential pathogenic bacteria (Streptococcus and Staphylococcus spp.) in fish intestines. The present study indicated that dietary supplementation with R. stabekisii improved the growth, immunity, disease resistance, and gut microflora of Nile tilapia. This research is the first study reporting that the genus Rummeliibacillus is a potential probiotic in animals, suggesting that R. stabekisii can be used as a feed additive to enhance the growth and health status in tilapia.
•Rummeliibacillus stabekisii produces protease and xylanase was investigated as a probiotic.•Dietary supplementation of R. stabekisii enhanced fish growth performance.•R. stabekisii as a probiotic increased the survival of fish challenged with A. hydrophila and S. iniae.•R. stabekisii as a probiotic improved innate immunity against bacterial infection.•Dietary supplementation of R. stabekisii improved intestinal microbiota.
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Herein, a one-pot wet-chemical route was used to prepare well-defined dendritic core-shell gold@gold-palladium nanoflowers supported on reduced graphene oxide (Au@AuPd NFs/rGO), using ...2, 4-dihydroxypyridine (2, 4-DHP) asa new stabilizer and structure-director. Their morphology, size, composition, and crystal structure were characterized by a set of characterization techniques. Control experiments demonstrated that the molar ratio of the metal precursors and the dosage of 2,4-DHP play essential roles in this synthesis. The growth mechanism of dendritic core-shell Au@AuPd nanoflowers was investigated in details. The synthesized branched architectures exhibited enlarged electrochemically active surface area (ECSA), improved catalytic properties, enhanced stability and durability toward glycerol oxidation in alkaline media when compared to the home-made Au26Pd74 nanocrystals (NCs)/rGO and Au78Pd22 NCs/rGO, along with commercially available Pd/C catalyst.
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In this work, well-defined bimetallic AuPd alloyed nanocrystals (AuPd NCs) were facilely synthesized by a straightforward and controllable one-step wet-chemical strategy, using a ...biomolecule (L-hydroxyproline, L-Hyp) as the green stabilizer and the structure-directing agent. Their morphology, size, composition, crystal structures and growth mechanism were investigated by a series of techniques. The synthesized architectures exhibited enlarged electrochemically active surface area (ECSA), improved catalytic activity, enhanced durability and stability towards ethylene glycol oxidation reaction (EGOR) and glycerol oxidation reaction (GOR) in alkaline electrolytes in comparison with commercial Pd black catalyst.
ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and ...many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications.
Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of ...arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.
The role of surface hydroxyls is significant for understanding catalytic performance of metallic oxides for CO2 electroreduction reaction (CO2ER). This Communication describes, employing SnO x as a ...model system, how to moderate coverage of hydroxyl to derive a stable Sn branches catalyst for CO2ER with a 93.1% Faradaic efficiency (FE) of carbonaceous products. With use of in situ attenuated total reflection surface enhanced infrared adsorption spectroscopy (ATR-SEIRAS) and density functional theory (DFT) calculations, we found that a proper amount of surface hydroxyls offered effective sites to boost CO2 adsorption via hydrogen bond. However, a higher surface coverage of hydroxyls leads to self-reduction of Sn–OH. We also explained the competition between self-reduction and CO2 reduction over Sn-based catalysts. The findings revealed the quantitative correlation between surface coverage of hydroxyl and CO2ER activity and suggested a logical extension to other metal oxide catalysts for CO2ER.
ProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1-2 μm in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PML
is successfully ...purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 Å) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLa
cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RARα (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RARα-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.
Partially oxidizing methane into syngas via a two-step chemical looping scheme is a promising option for methane transformation. Providing the optimum lattice oxygen to selectively produce syngas ...represents the major challenge for the development of oxygen carrier materials in chemical looping processes. This paper describes the design of WO3-based oxygen carriers as the primary source of lattice oxygen with high melting points and attractive syngas selectivity. To further enhance the lattice oxygen availability and methane conversion capacity, NiO nanoclusters are introduced, considering the doping effect on chemical bonding disruption in both bulk and surface regions. For Ni0.5WO x /Al2O3, the nickel cations incorporated into the bulk of WO3 can strongly weaken the tungsten–oxygen bond strength and increase the availability of lattice oxygen. The surface-grafted nickel species can effectively activate methane molecules and catalyze the partial oxidation reaction. Total methane conversion and syngas yield can be substantially increased by about 2.7-fold in comparison with unmodified WO3/Al2O3. This work demonstrates that the bulk and surface modifications are feasible to tailor the active lattice oxygen of oxygen-carrying materials in chemical looping processes.
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to ...its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of ...inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.
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•ATO rescues multiple p53 mutants effectively in various assays•The structural mechanism of how mutant p53 function is restored by ATO is described•Most p53 mutants are stabilized structurally but only some are transcriptionally rescued•Widely applicable, yet has individual p53 mutation-based therapeutic potential
Chen et al. show that ATO, an FDA-approved drug, robustly rescues mutant p53, uncover the underlying molecular mechanism, and report the rescue pattern among frequent p53 mutants.
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