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TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinogênese/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Quinases Semelhantes a Duplacortina , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
Further improvements in perovskite solar cells require better control of ionic defects in the perovskite photoactive layer during the manufacturing stage and their usage1-5. Here we report a living passivation strategy using a hindered urea/thiocarbamate bond6-8 Lewis acid-base material (HUBLA), where dynamic covalent bonds with water and heat-activated characteristics can dynamically heal the perovskite to ensure device performance and stability. Upon exposure to moisture or heat, HUBLA generates new agents and further passivates defects in the perovskite. This passivation strategy achieved high-performance devices with a power conversion efficiency (PCE) of 25.1 per cent. HUBLA devices retained 94 per cent of their initial PCE for approximately 1,500 hours of ageing at 85 degrees Celsius in nitrogen and maintained 88 per cent of their initial PCE after 1,000 hours of ageing at 85 degrees Celsius and 30 per cent relative humidity in air.
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The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.
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Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.
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Kagome materials have recently garnered substantial attention due to the intrinsic flat band feature and the stimulated magnetic and spin-related many-body physics. In contrast to their bulk counterparts, two-dimensional (2D) kagome materials feature more distinct kagome bands, beneficial for exploring novel quantum phenomena. Herein, we report the direct synthesis of an ultrathin kagome-structured Co-telluride (Co9Te16) via a molecular beam epitaxy (MBE) route and clarify its formation mechanism from the Co-intercalation in the 1T-CoTe2 layers. More significantly, we unveil the flat band states in the ultrathin Co9Te16 and identify the real-space localization of the flat band states by in situ scanning tunneling microscopy/spectroscopy (STM/STS) combined with first-principles calculations. A ferrimagnetic order is also predicted in kagome-Co9Te16. This work should provide a novel route for the direct synthesis of ultrathin kagome materials via a metal self-intercalation route, which should shed light on the exploration of the intriguing flat band physics in the related systems.
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Ultrathin PtSe2 ribbons can host spin-polarized edge states and distinct edge electrocatalytic activity, emerging as a promising candidate for versatile applications in various fields. However, the direct synthesis is still challenging and the growth mechanism is still unclear. Herein, the arrayed growth of ultrathin PtSe2 ribbons on bunched vicinal Au(001) facets, via a facile chemical vapor deposition (CVD) route is reported. The ultrathin PtSe2 flakes can transform from traditional irregular shapes to desired ribbon shapes by increasing the height of bunched and unidirectionally oriented Au steps (with step height hstep) is found. This crossover, occurring at hstep ≈ 3.0 nm, defines the tailored growth from step-flow to single-terrace-confined modes, as validated by density functional theory calculations of the different system energies. On the millimeter-scale single-crystal Au(001) films with aligned steps, the arrayed ultrathin PtSe2 ribbons with tunable width of ≈20-1000 nm, which are then served as prototype electrocatalysts for hydrogen evolution reaction (HER) is achieved. This work should represent a huge leap in the direct synthesis and the mechanism exploration of arrayed ultrathin transition-metal dichalcogenides (TMDCs) ribbons, which should stimulate further explorations of the edge-related physical properties and practical applications.
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Brassinosteroids (BRs) are plant hormones that are essential in plant growth and development. BRASSINOSTEROID-INSENSITIVE 1 (BRI1) and BRI1 ASSOCIATED RECEPTOR KINASE 1 (BAK1), which are located on the plasma membrane, function as co-receptors that accept and transmit BR signals. PROHIBITIN 3 (PHB3) was identified in both BRI1 and BAK1 complexes by affinity purification and LC-MS/MS analysis. Biochemical data showed that BRI1/BAK1 interacted with PHB3 in vitro and in vivo. BRI1/BAK1 phosphorylated PHB3 in vitro. When the Thr-80 amino acid in PHB3 was mutated to Ala, the mutant protein was not phosphorylated by BRI1 and the mutant protein interaction with BRI1 was abolished in the yeast two-hybrid assay. BAK1 did not phosphorylate the mutant protein PHB3T54A . The loss-of-function phb3 mutant showed a weaker BR signal than the wild-type. Genetic analyses revealed that PHB3 is a BRI1/BAK1 downstream substrate that participates in BR signalling. PHB3 has five homozygous in tomato, and we named the closest to AtPHB3 as SlPHB3.1. Biochemical data showed that SlBRI1/SlSERK3A/SlSERK3B interacted with SlPHB3.1 and SlPHB3.3. The CRISPR-Cas9 method generated slphb3.1 mutant led to a BR signal stunted relatively in tomatoes. PHB3 is a new component of the BR signal pathway in both Arabidopsis and tomato.
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Proteínas de Arabidopsis , Arabidopsis , Solanum lycopersicum , Arabidopsis/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Brassinosteroides/metabolismo , Solanum lycopersicum/genética , Proteínas Quinases/metabolismo , Fosforilação , Proteínas de Arabidopsis/metabolismo , Cromatografia Líquida , Proibitinas , Espectrometria de Massas em Tandem , Transdução de Sinais/fisiologia , Proteínas MutantesRESUMO
We demonstrate a circulator-free thin-film lithium niobate (TFLN) dispersion compensator based on the cascading 2 × 2 multimode interferometer (MMI) and two identical chirped Bragg gratings (CBGs). The cascaded MMI-CBG structure provides a dispersion value of 920â ps/nm/m over a 20â nm bandwidth covering 1537 to 1557â nm, featuring a compact footprint of 1â mm × 0.7â mm. Utilizing this device within a TFLN electro-optic time-lens system, we successfully generate 863-fs pulses at a 37â GHz repetition rate. Our compact, scalable, low-loss, and circulator-free dispersion compensator is the building block for the efficient generation of high-peak-power femtosecond laser pulses.
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A photoacoustic (PA) imaging technique using the second near-infrared (NIR-II) window has attracted more and more attention because of its merits of deeper penetration depth and higher signal-to-noise (S/N) ratio than that using the first near-infrared (NIR-I) one. However, the design and development of high-performance PA imaging contrast agents in the NIR-II window is still a challenge. A semiconducting polymer, constructed by asymmetric units, exhibits regiorandom characteristics that effectively increase the distortion of the backbone. This increase in the degree of twist can regulate the twisted intramolecular charge transfer (TICT) effect, resulting in an enhancement of the PA signal. In this paper, an asymmetric structural acceptor strategy is developed to improve the PA signals of the resulting semiconducting polymer (PATQ-MP) in the NIR-II window with improved brightness, higher S/N ratio, and better photothermal conversion efficiency compared to polymers with the same main-chain structure containing a symmetric acceptor. DFT analysis showed that PATQ-MP containing an asymmetric acceptor monomer had a larger dihedral angle, which effectively improved the PA signal intensity by enhancing the TICT effect. The PEG-encapsulated PATQ-MP nanoparticles exhibit promising performance in the PA imaging of mouse tumors in vivo, demonstrating the clear identification of microvessels as small as 100 µm along with rapid metabolism within a span of 5 h. Therefore, this work provides a unique molecular design strategy for improving the signal intensity of PA imaging in the NIR-II window.
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Técnicas Fotoacústicas , Polímeros , Semicondutores , Técnicas Fotoacústicas/métodos , Animais , Camundongos , Polímeros/química , Quinoxalinas/química , Feminino , Humanos , Tiadiazóis/química , Raios Infravermelhos , Camundongos Nus , Camundongos Endogâmicos BALB C , Meios de Contraste/químicaRESUMO
The secondary structures of polypeptides, such as an α-helix and a ß-sheet, often impart specific properties and functions, making the regulation of their secondary structures of great significance. Particularly, water-soluble polypeptides bearing a ß-sheet conformation are rare and challenging to achieve. Here, a series of oligo(ethylene glycol)-modified lysine N-carboxylic anhydrides (EGmK-NCA, where m = 1-3) and the corresponding polymers EGmKn are synthesized, with urethane bonds as the linker between the side-chain EG and lysine. The secondary structure of EGmKn is delicately regulated by both m and n, the length (number of repeating units) of EG and the degree of polymerization (DP), respectively. Among them, EG2Kn adopts a ß-sheet conformation with good water solubility at an appropriate DP and forms physically cross-linked hydrogels at a concentration as low as 1 wt %. The secondary structures of EG1Kn can be tuned by DP, exhibiting either a ß-sheet or an α-helix, whereas EG3Kn appears to a adopt pure and stable α-helix with no dependence on DP. Compared to previous works reporting EG-modified lysine-derived polypeptides bearing exclusively an α-helix conformation, this work highlights the important and unexpected role of the urethane connecting unit and provides useful case studies for understanding the secondary structure of polypeptides.
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Peptídeos , Conformação Proteica em Folha beta , Solubilidade , Água , Peptídeos/química , Água/química , Polietilenoglicóis/química , Lisina/química , Hidrogéis/química , Etilenoglicol/química , Estrutura Secundária de Proteína , PolimerizaçãoRESUMO
A novel Gram-stain-negative, rod-shaped, non-spore-forming, aerobic, motile bacterium with a single polar or subpolar flagellum, designated strain H3510T, was isolated from marine alga collected on sea shore of Yantai, PR China. The organism grew optimally at 28 °C and pH 7.0 and in presence of 3.0â% (w/v) NaCl. The strain exhibited positive catalase activity but negative oxidase and nitrate reduction activities. The predominant cellular fatty acids were C18â:â1 ω7c and/or C18â:â1 ω6c, 11-methyl C18â:â1 ω7c, and C16â:â0. Additionally, the major polar lipids were phosphatidylglycerol, phosphatidylmonomethylethanolamine, diphosphatidylglycerol, and phosphatidylethanolamine; the respiratory quinone was ubiquinone 10 (Q-10). The genomic DNA G+C content of strain H3510T was 54.2%. The novel strain showed the closest relationship with Roseibium polysiphoniae KMM 9699T with 98.2â% 16S rRNA gene sequence similarity. The calculated values for average nucleotide identity and DNA-DNA hybridization between strain H3510T and the phylogenetically related Roseibium species were in the range of 71.3-74.9â% and 13.7-19.9â%, respectively. Based on polyphasic analyses, strain H3510T was identified as representing a novel species of the genus Roseibium, for which the name Roseibium algae sp. nov. is proposed. The type strain is H3510T (=KCTC 8206T=MCCC 1K04325T). The heterologously expressed inositol 2-dehydrogenase gene from strain H3510T displayed high oxidation activity on myo-inositol and showed potential in the production of rare stereoisomers of inositol, such as scyllo-inositol.
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Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Rhodobacteraceae , Análise de Sequência de DNA , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , China , Ácidos Graxos/química , Rhodobacteraceae/isolamento & purificação , Rhodobacteraceae/classificação , Rhodobacteraceae/genética , Ubiquinona/análogos & derivados , Água do Mar/microbiologia , Rodófitas/microbiologiaRESUMO
With the development of large numbers of novel organophosphate esters (OPEs) alternatives, it is imperative to screen and identify those with high priority. In this study, surface water, biofilms, and freshwater snails were collected from the flow-in rivers of Taihu Lake Basin, China. Screened by target, suspect, and nontarget analysis, 11 traditional and 14 novel OPEs were identified, of which 5 OPEs were first discovered in Taihu Lake Basin. The OPE concentrations in surface water ranged from 196 to 2568 ng/L, with the primary homologue tris(2,4-ditert-butylphenyl) phosphate (TDtBPP) being newly identified, which was likely derived from the transformation of tris(2,4-ditert-butylphenyl) phosphite. The majority of the newly identified OPEs displayed substantially higher bioaccumulation and biomagnification potentials in the biofilm-snail food chain than the traditional ones. Quantitative structure-property relationship models revealed both hydrophobicity and polarity influenced the bioaccumulation and biomagnification of the OPEs, while electrostatic attraction also had a contribution to the bioaccumulation in the biofilm. TDtBPP was determined as the utmost priority by toxicological priority index scheme, which integrated concentration, bioaccumulation, biomagnification, acute toxicity, and endocrine disrupting potential of the identified OPEs. These findings provide novel insights into the behaviors of OPEs and scientific bases for better management of high-risk pollutants in aquatic ecosystem.
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Ésteres , Organofosfatos , Poluentes Químicos da Água , Relação Quantitativa Estrutura-Atividade , Animais , Monitoramento Ambiental , China , CaramujosRESUMO
Understanding the bioavailability of per- and polyfluoroalkyl substances (PFAS) in food is essential for accurate human health risk assessment. Given the rising incidence of inflammatory bowel disease (IBD), this study aimed to investigate the impacts of IBD on the bioavailability of PFAS in food using mice models. The relative bioavailability (RBA) of PFAS was the highest in the chronic IBD mice (64.3-144%), followed by the healthy (60.8-133%) and acute IBD mice (41.5-121%), suggesting that chronic IBD enhanced the PFAS exposure risk. In vitro tests showed that the intestinal micelle stability increased as a result of reduced content of short-chain fatty acids, thus promoting the PFAS bioaccessibility in the digestive fluid of chronic IBD. Additionally, increased pathogenic and decreased beneficial bacteria in the gut of IBD groups facilitated the intestinal permeability, thus enhancing PFAS absorption. These together explained the higher RBA of PFAS in the chronic IBD. However, remarkably lower enzymatic activities suggested severely impaired digestive ability in the acute IBD, which facilitated the excretion of PFAS from feces, thus lowering the RBA. Conversely, PFAS exposure might exacerbate IBD by changing the gut microbiota structures. This study hints that individuals with chronic intestinal inflammation might have higher PFAS exposure risk than the healthy population.
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Disponibilidade Biológica , Doenças Inflamatórias Intestinais , Camundongos , Animais , Microbioma Gastrointestinal , Fluorocarbonos , HumanosRESUMO
Near-infrared (NIR)-triggered shape memory hydrogels with promising mechanical strength hold immense potential in the field of biomedical applications and soft actuators. However, the optical and mechanical properties of currently reported hydrogels usually suffer from limited solubility and dispersion of commonly used photothermal additives in hydrogels, thus restricting their practical implementations. Here,, a set of NIR-responsive shape memory hydrogels synthesized by polyaddition of diisocyanate-terminated poly(ethylene glycol), imidazolidinyl urea (IU), and p-benzoquinone dioxime (BQDO) is reported. The introduction of IU, a hydrogen bond reinforcing factor, significantly enhances the mechanical properties of the hydrogels, allowing for their tunable ranges of the ultimate tensile strength (0.4-2.5 MPa), elongation at break (210-450%), and Young's modulus (190-850 kPa). The unique hydrogels exhibit an intrinsic photothermal effect because of the covalently incorporated photothermal moiety (BQDO), and the photothermal supramolecular hydrogel shows controllable shape memory capabilities characterized by rapid recovery speed and high recovery ratio (>90%). This design provides new possibilities for applying shape memory hydrogels in the field of soft actuators.
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Hidrogéis , Raios Infravermelhos , Hidrogéis/química , Hidrogéis/síntese química , Polietilenoglicóis/química , Estrutura Molecular , Resistência à Tração , Ureia/química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/síntese química , Materiais Inteligentes/químicaRESUMO
Preparation of materials that possess highly strong and tough properties simultaneously is a great challenge. Thermosetting resins as a type of widely used polymeric materials without synergistic strength and toughness limit their applications in some special fields. In this report, an effective strategy to prepare thermosetting resins with synergistic strength and toughness, is presented. In this method, the soft and rigid microspheres with dynamic hemiaminal bonds are fabricated first, followed by hot-pressing to crosslink at the interfaces. Specifically, the rigid or soft microspheres are prepared via precipitation polymerization. After hot-pressing, the resulting rigid-soft blending materials exhibit superior strength and toughness, simultaneously. As compared with the precursor rigid or soft materials, the toughness of the rigid-soft blending films (RSBFs) is improved to 240% and 2100%, respectively, while the strength is comparable to the rigid precursor. As compared with the traditional crushing, blending, and hot-pressing of rigid or soft materials to get the nonuniform materials, the strength and toughness of the RSBFs are improved to 168% and 255%, respectively. This approach holds significant promise for the fabrication of polymer thermosets with a unique combination of strength and toughness.
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Polimerização , Resinas Sintéticas/química , Microesferas , Polímeros/química , Temperatura , Teste de Materiais , Propriedades de Superfície , Tamanho da PartículaRESUMO
Per- and polyfluoroalkyl substances (PFAS) are recognized as emerging environmental pollutants due to their high persistence and toxicities to humans and animals. Understanding the temporal trend of PFAS in the environment is important for their pollution control and making appropriate policies. Many studies have reported the PFAS concentrations in Taihu Lake, the third largest lake in China, while their temporal trend during the years was seldom investigated. This study summarizes the PFAS concentrations in the water, sediment and organisms in Taihu Lake from 2009 to 2020 to depict their temporal trends. Meanwhile, the ecological model of AQUATOX was applied to evaluate and predict the potential risks of PFAS from 2012 to 2030. The results showed that the total PFAS concentrations varied but without distinct increase or decrease in both water and sediment during the years, while PFAS concentrations in organisms significantly decreased. The yearly mean concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in the water were 21.7-25.4 ng/L and 9.7-26.5 ng/L respectively, lower than the Standards for Drinking Water Quality of China and the suggested water quality criteria to protect the aquatic organisms. In sediment, PFOA and PFOS concentrations were 0.16-0.69 ng/g and 0.15-0.82 ng/g respectively, much lower than the recommended sediment quality guideline values. Based on the AQUATOX prediction, there will be no major threats caused by PFAS to the growth of biota in Taihu Lake in the near future, while the biomass of some species (e.g. carp) will be affected under the perturbation of PFAS. Both field investigation and AQUATOX simulation showed that PFOS concentrations in invertebrates and fish descend steadily, while no remarkable decrease in PFOA concentrations was expected. This study suggests a decreasing ecological risk of PFAS in Taihu Lake, while highlights the necessity of continuous monitoring of PFAS contamination.
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Ácidos Alcanossulfônicos , Monitoramento Ambiental , Fluorocarbonos , Sedimentos Geológicos , Lagos , Poluentes Químicos da Água , Fluorocarbonos/análise , China , Lagos/química , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Medição de Risco , Ácidos Alcanossulfônicos/análise , Animais , Sedimentos Geológicos/química , Sedimentos Geológicos/análise , Caprilatos/análiseRESUMO
A Gram-stain-negative, non-flagellated, aerobic, ovoid or rod-shaped bacterium with motility, designated B8T, was isolated from the sediment of Clam Island beach, Liaoning province, China. The optimum growth of strain B8T occurred at 35 oC, pH 7.0, and in the presence of 4.0-5.0% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain B8T formed a distinct lineage within the genus Sphingomicrobium and was closely related to Sphingomicrobium nitratireducens O-35T (98.3% sequence similarity), Sphingomicrobium aestuariivivum KCTC 42286T (96.9%), and Sphingomicrobium astaxanthinifaciens JCM 18551T (96.5%). The digital DNA-DNA hybridization and average nucleotide identity values between strain B8T and closely related strains were lower than 21.0% and 78.0%, much lower than the cutoff values of 70.0% and 95.0%, respectively, for bacterial species delineation. The dominant respiratory quinone of strain B8T was ubiquinone-10. The major fatty acids were Sum In Feature 8 (C18:1ω7c and/or C18:1ω6c), Sum In Feature 3 (C16â:â1ω7c and/or C16â:â1ω6c), C17:1ω6c, C18:1 2-OH, and C16:0. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, sphingoglycolipid, glycolipids, and four unknown polar lipids. The DNA G + C content of strain B8T was 63.9%. Based on the phenotypic, phylogenetic, and chemotaxonomic analyses, strain B8T is considered a new species of Sphingomicrobium, for which the name Sphingomicrobium clamense sp. nov. is proposed. The type strain is B8T (= CGMCC 1.19486T = KCTC 92052T).
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Fosfolipídeos , Água do Mar , Fosfolipídeos/química , Água do Mar/microbiologia , Filogenia , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Ácidos Graxos/química , Ubiquinona/química , Técnicas de Tipagem Bacteriana , Análise de Sequência de DNARESUMO
BACKGROUND: NARS2 as a member of aminoacyl-tRNA synthetases was necessary to covalently join a specific tRNA to its cognate amino acid. Biallelic variants in NARS2 were reported with disorders such as Leigh syndrome, deafness, epilepsy, and severe myopathy. CASE PRESENTATION: Detailed clinical phenotypes were collected and the NARS2 variants were discovered by whole exome sequencing and verified by Sanger sequencing. Additionally, 3D protein structure visualization was performed by UCSF Chimera. The proband in our study had early-onset status epilepticus with abnormal EEG and MRI results. She also performed global developmental delay (GDD) and myocardial dysfunction. Next-generation sequencing (NGS) and Sanger sequencing revealed compound heterozygous missense variants [NM_024678.6:exon14: c.1352G > A(p.Arg451His); c.707T > C(p.Phe236Ser)] of the NARS2 gene. The proband develops refractory epilepsy with GDD and hyperlactatemia. Unfortunately, she finally died for status seizures two months later. CONCLUSION: We discovered two novel missense variants of NARS2 in a patient with early-onset status epilepticus and myocardial dysfunction. The NGS enables the patient to be clearly diagnosed as combined oxidative phosphorylation deficiency 24 (COXPD24, OMIM:616,239), and our findings expands the spectrum of gene variants in COXPD24.
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Aspartato-tRNA Ligase , Epilepsia Resistente a Medicamentos , Epilepsia , Estado Epiléptico , Feminino , Humanos , Estado Epiléptico/diagnóstico , Estado Epiléptico/genética , Epilepsia Resistente a Medicamentos/genética , Mutação de Sentido Incorreto , RNA de Transferência , Mutação , Aspartato-tRNA Ligase/genéticaRESUMO
The rapid development of the Internet of Things (IoT) has brought many conveniences to our daily life. However, it has also introduced various security risks that need to be addressed. The proliferation of IoT botnets is one of these risks. Most of researchers have had some success in IoT botnet detection using artificial intelligence (AI). However, they have not considered the impact of dynamic network data streams on the models in real-world environments. Over time, existing detection models struggle to cope with evolving botnets. To address this challenge, we propose an incremental learning approach based on Gradient Boosting Decision Trees (GBDT), called GBDT-IL, for detecting botnet traffic in IoT environments. It improves the robustness of the framework by adapting to dynamic IoT data using incremental learning. Additionally, it incorporates an enhanced Fisher Score feature selection algorithm, which enables the model to achieve a high accuracy even with a smaller set of optimal features, thereby reducing the system resources required for model training. To evaluate the effectiveness of our approach, we conducted experiments on the BoT-IoT, N-BaIoT, MedBIoT, and MQTTSet datasets. We compared our method with similar feature selection algorithms and existing concept drift detection algorithms. The experimental results demonstrated that our method achieved an average accuracy of 99.81% using only 25 features, outperforming similar feature selection algorithms. Furthermore, our method achieved an average accuracy of 96.88% in the presence of different types of drifting data, which is 2.98% higher than the best available concept drift detection algorithms, while maintaining a low average false positive rate of 3.02%.
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Single-crystal X-ray diffraction analysis has emerged as the most reliable method for determining the structures of organic molecules. However, numerous analytes, such as liquid organic molecules, pose challenges in crystallization, making their structures directly elusive via X-ray crystallography methods. Herein, we introduced the rapid cocrystallization of a macrocycle named phenanthrene[2]arene (PTA, host) with 15 liquid organic molecules (guests). The guest liquid organic molecules were successively cocrystallized with the aid of the PTA host. Moreover, the chemical structures of the liquid organic molecules could be determined through single-crystal X-ray diffraction analysis. PTA exhibited high adaptivity and was capable of encapsulating liquid organic molecules without forming covalent bonds or strong directional interactions. The results revealed that the adaptive crystals of PTA exhibited excellent cocrystallization capacity. Weak noncovalent interactions between the host and guest molecules were crucial for organizing the guests in an ordered pattern.