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The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.
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Anticorpos Biespecíficos/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/genética , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/genética , COVID-19/imunologia , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Clonagem Molecular , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Epitopos , Humanos , Macaca mulatta , Camundongos , Testes de Neutralização , Engenharia de Proteínas/métodos , Relação Estrutura-AtividadeRESUMO
Carbon structures with covalent bonds connecting C60 molecules have been reported1-3, but their production methods typically result in very small amounts of sample, which restrict the detailed characterization and exploration necessary for potential applications. We report the gram-scale preparation of a new type of carbon, long-range ordered porous carbon (LOPC), from C60 powder catalysed by α-Li3N at ambient pressure. LOPC consists of connected broken C60 cages that maintain long-range periodicity, and has been characterized by X-ray diffraction, Raman spectroscopy, magic-angle spinning solid-state nuclear magnetic resonance spectroscopy, aberration-corrected transmission electron microscopy and neutron scattering. Numerical simulations based on a neural network show that LOPC is a metastable structure produced during the transformation from fullerene-type to graphene-type carbons. At a lower temperature, shorter annealing time or by using less α-Li3N, a well-known polymerized C60 crystal forms owing to the electron transfer from α-Li3N to C60. The carbon K-edge near-edge X-ray absorption fine structure shows a higher degree of delocalization of electrons in LOPC than in C60(s). The electrical conductivity is 1.17 × 10-2 S cm-1 at room temperature, and conduction at T < 30 K appears to result from a combination of metallic-like transport over short distances punctuated by carrier hopping. The preparation of LOPC enables the discovery of other crystalline carbons starting from C60(s).
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The development of next-generation electronics requires scaling of channel material thickness down to the two-dimensional limit while maintaining ultralow contact resistance1,2. Transition-metal dichalcogenides can sustain transistor scaling to the end of roadmap, but despite a myriad of efforts, the device performance remains contact-limited3-12. In particular, the contact resistance has not surpassed that of covalently bonded metal-semiconductor junctions owing to the intrinsic van der Waals gap, and the best contact technologies are facing stability issues3,7. Here we push the electrical contact of monolayer molybdenum disulfide close to the quantum limit by hybridization of energy bands with semi-metallic antimony ([Formula: see text]) through strong van der Waals interactions. The contacts exhibit a low contact resistance of 42 ohm micrometres and excellent stability at 125 degrees Celsius. Owing to improved contacts, short-channel molybdenum disulfide transistors show current saturation under one-volt drain bias with an on-state current of 1.23 milliamperes per micrometre, an on/off ratio over 108 and an intrinsic delay of 74 femtoseconds. These performances outperformed equivalent silicon complementary metal-oxide-semiconductor technologies and satisfied the 2028 roadmap target. We further fabricate large-area device arrays and demonstrate low variability in contact resistance, threshold voltage, subthreshold swing, on/off ratio, on-state current and transconductance13. The excellent electrical performance, stability and variability make antimony ([Formula: see text]) a promising contact technology for transition-metal-dichalcogenide-based electronics beyond silicon.
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Photothermal heating and photocatalytic treatment are two solar-driven water processing approaches by harnessing NIR and UV-vis light, respectively, which can fully utilize solar energy if integrated. However, it remains a challenge to achieve high performance in both approaches when integrated in a material due to uncontrollable heat diffusion. Here, we report a demonstration of heat confinement on photothermal sites and fluid cooling on photocatalysis sites at the nanoscale, within a well-designed heat and fluid confinement nanofiber reactor. Photothermal and photocatalytic nanostructures were alternatively aligned in electrospun nanofibers for on-demand nanofluidic thermal management as well as easy folding into 3D structures with enhanced light utilization and mass transfer. Such a design showed simultaneously high photothermal evaporation rate (2.59 kg m-2 h-1, exceeding the limit rate) and efficient photocatalytic upcycling of microplastics pollutant into valued products. Enabled by controlled photothermal heating, the valued main product (i.e., methyl acetate) can be evaporated out with 100% selectivity by in situ separation.
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The burgeoning crisis of antibiotic resistance has directed attention to bacteriophages as natural antibacterial agents capable of circumventing bacterial defenses. Central to this are the bacterial defense mechanisms, such as the BREX system, which utilizes the methyltransferase BrxX to protect against phage infection. This study presents the first in vitro characterization of BrxX from Escherichia coli, revealing its substrate-specific recognition and catalytic activity. We demonstrate that BrxX exhibits nonspecific DNA binding but selectively methylates adenine within specific motifs. Kinetic analysis indicates a potential regulation of BrxX by the concentration of its co-substrate, S-adenosylmethionine, and suggests a role for other BREX components in modulating BrxX activity. Furthermore, we elucidate the molecular mechanism by which the T7 phage protein Ocr (Overcoming classical restriction) inhibits BrxX. Despite low sequence homology between BrxX from different bacterial species, Ocr effectively suppresses BrxX's enzymatic activity through high-affinity binding. Cryo-electron microscopy and biophysical analyses reveal that Ocr, a DNA mimic, forms a stable complex with BrxX, highlighting a conserved interaction interface across diverse BrxX variants. Our findings provide insights into the strategic counteraction by phages against bacterial defense systems and offer a foundational understanding of the complex interplay between phages and their bacterial hosts, with implications for the development of phage therapy to combat antibiotic resistance.
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Proteínas de Escherichia coli , Escherichia coli , Proteínas Virais , Escherichia coli/virologia , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas Virais/metabolismo , S-Adenosilmetionina/metabolismo , Ligação Proteica , Bacteriófago T7/genética , Metiltransferases/metabolismo , CinéticaRESUMO
Influenza virus neuraminidase (NA) is an important target for antiviral development because it plays a crucial role in releasing newly assembled viruses. Two unique influenza-like virus genomes were recently reported in the Wuhan Asiatic toad and Wuhan spiny eel. Their NA genes appear to be highly divergent from all known influenza NAs, raising key questions as to whether the Asiatic toad influenza-like virus NA (tNA) and spiny eel NA (eNA) have canonical NA activities and structures and whether they show sensitivity to NA inhibitors (NAIs). Here, we found that both tNA and eNA have neuraminidase activities. A detailed structural analysis revealed that tNA and eNA present similar overall structures to currently known NAs, with a conserved calcium binding site. Inhibition assays indicated that tNA is resistant to NAIs, while eNA is still sensitive to NAIs. E119 is conserved in canonical NAs. The P119E substitution in tNA can restore sensitivity to NAIs, and, in contrast, the E119P substitution in eNA decreased its sensitivity to NAIs. The structures of NA-inhibitor complexes further provide a detailed insight into NA-inhibitor interactions at the atomic level. Moreover, tNA and eNA have unique N-glycosylation sites compared with canonical NAs. Collectively, the structural features, NA activities, and sensitivities to NAIs suggest that fish- and amphibian-derived influenza-like viruses may circulate in these vertebrates. More attention should be paid to these influenza-like viruses because their NA molecules may play roles in the emergence of NAI resistance.
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Influenza Humana , Orthomyxoviridae , Animais , Antivirais/farmacologia , Cálcio , Farmacorresistência Viral/genética , Enguias/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Neuraminidase/química , Neuraminidase/genética , Orthomyxoviridae/metabolismoRESUMO
Photothermal therapy (PTT) is a new treatment modality for tumors. However, the efficient delivery of photothermal agents into tumors remains difficult, especially in hypoxic tumor regions. In this study, an approach to deliver melanin, a natural photothermal agent, into tumors using genetically engineered bacteria for image-guided photothermal and immune therapy is developed. An Escherichia coli MG1655 is transformed with a recombinant plasmid harboring a tyrosinase gene to produce melanin nanoparticles. Melanin-producing genetically engineered bacteria (MG1655-M) are systemically administered to 4T1 tumor-bearing mice. The tumor-targeting properties of MG1655-M in the hypoxic environment integrate the properties of hypoxia targeting, photoacoustic imaging, and photothermal therapeutic agents in an "all-in-one" manner. This eliminates the need for post-modification to achieve image-guided hypoxia-targeted cancer photothermal therapy. Tumor growth is significantly suppressed by irradiating the tumor with an 808 nm laser. Furthermore, strong antitumor immunity is triggered by PTT, thereby producing long-term immune memory effects that effectively inhibit tumor metastasis and recurrence. This work proposes a new photothermal and immune therapy guided by an "all-in-one" melanin-producing genetically engineered bacteria, which can offer broad potential applications in cancer treatment.
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Imunoterapia , Melaninas , Animais , Imunoterapia/métodos , Camundongos , Escherichia coli/genética , Escherichia coli/metabolismo , Linhagem Celular Tumoral , Engenharia Genética , Terapia Fototérmica/métodos , Camundongos Endogâmicos BALB C , Fototerapia/métodos , Neoplasias/terapia , Feminino , Nanopartículas/químicaRESUMO
Antibodies specifically bind to antigens and are an essential part of the immune system. Hence, antibodies are powerful tools in research and diagnostics. High-throughput sequencing technologies have promoted comprehensive profiling of the immune repertoire, which has resulted in large amounts of antibody sequences that remain to be further analyzed. In this study, antibodies were downloaded from IMGT/LIGM-DB and Sequence Read Archive databases. Contributing features from antibody heavy chains were formulated as numerical inputs and fed into an ensemble machine learning classifier to classify the antigen specificity of six classes of antibodies, namely anti-HIV-1, anti-influenza virus, anti-pneumococcal polysaccharide, anti-citrullinated protein, anti-tetanus toxoid and anti-hepatitis B virus. The classifier was validated using cross-validation and a testing dataset. The ensemble classifier achieved a macro-average area under the receiver operating characteristic curve (AUC) of 0.9246 from the 10-fold cross-validation, and 0.9264 for the testing dataset. Among the contributing features, the contribution of the complementarity-determining regions was 53.1% and that of framework regions was 46.9%, and the amino acid mutation rates occupied the first and second ranks among the top five contributing features. The classifier and insights provided in this study could promote the mechanistic study, isolation and utilization of potential therapeutic antibodies.
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Sequência de Aminoácidos , Anticorpos/química , Aprendizado de Máquina , Especificidade de Anticorpos , Regiões Determinantes de Complementaridade , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Curva ROCRESUMO
Superhydrophobic materials have been widely applied in oil-water separation, self-cleaning, antifouling, and drag reduction; however, their role in liquid evaporation and drying remains unexplored. Inspired by the microstructure of the nonwetting legs of water striders, we designed a low-adhesion superhydrophobic cylindrical barrel (CB) derived from stainless-steel mesh (SSM) to enhance liquid thermal evaporation and drying. The CB was created by hydrothermally depositing zinc oxide (ZnO) with multilevel morphologies onto metal wires, followed by modification with low-surface-energy stearic acid (SA). We investigated the impact of the SSMCB on water evaporation and analyzed the decline in the liquid levels under varying porosities and temperatures through numerical normalization. A functional relationship was established between decline height, porosity, and temperature, revealing that the drop height increased from 3.7 to 25 mm as porosity increased from 0 to 0.5263. Moreover, the superhydrophobic coating demonstrated excellent resistance to friction and peeling, indicating improved mechanical stability.
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BACKGROUND: No universally recognized transperineal ultrasound parameters are available for evaluating stress urinary incontinence. The information captured by commonly used perineal ultrasound parameters is limited and insufficient for a comprehensive assessment of stress urinary incontinence. Although bladder neck motion plays a major role in stress urinary incontinence, objective and visual methods to evaluate its impact on stress urinary incontinence remain lacking. OBJECTIVE: To use a deep learning-based system to evaluate bladder neck motion using two-dimensional transperineal ultrasound videos, exploring motion parameters for diagnosing and evaluating stress urinary incontinence. We hypothesized that bladder neck motion parameters are associated with stress urinary incontinence and are useful for stress urinary incontinence diagnosis and evaluation. STUDY DESIGN: This retrospective study including 217 women involved the following parameters: maximum and average speeds of bladder neck descent, ß angle, urethral rotation angle, and duration of the Valsalva maneuver. The fitted curves were derived to visualize bladder neck motion trajectories. Comparative analyses were conducted to assess these parameters between stress urinary incontinence and control groups. Logistic regression and receiver operating characteristic curve analyses were employed to evaluate the diagnostic performance of each motion parameter and their combinations for stress urinary incontinence. RESULTS: Overall, 173 women were enrolled in this study (82, stress urinary incontinence group; 91, control group). No significant differences were observed in the maximum and average speeds of bladder neck descent and in the speed variance of bladder neck descent. The maximum and average speed of the ß and urethral rotation angles were faster in the stress urinary incontinence group than in the control group (151.2 vs 109.0 mm/s, P=0.001; 6.0 vs 3.1 mm/s, P <0.001; 105.5 vs 69.6 mm/s, P <0.001; 10.1 vs 7.9 mm/s, P=0.011, respectively). The speed variance of the ß and urethral rotation angles were higher in the stress urinary incontinence group (844.8 vs 336.4, P <0.001; 347.6 vs 131.1, P <0.001, respectively). The combination of the average speed of the ß angle, maximum speed of the urethral rotation angle, and duration of the Valsalva maneuver demonstrated a strong diagnostic performance (area under the curve, 0.87). When 0.481*ß anglea + 0.013*URAm + 0.483*Dval = 7.405, the diagnostic sensitivity was 70% and specificity was 92%, highlighting the significant role of bladder neck motion in stress urinary incontinence, particularly changes in the speed of the ß and urethral rotation angles. CONCLUSIONS: A system utilizing deep learning can describe the motion of the bladder neck in women with stress urinary incontinence during the Valsalva maneuver, making it possible to visualize and quantify bladder neck motion on transperineal ultrasound. The speeds of the ß and urethral rotation angles and duration of the Valsalva maneuver were relatively reliable diagnostic parameters.
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Metal-organic frameworks (MOFs) have recently emerged as ideal electrode materials and precursors for electrochemical energy storage and conversion (EESC) owing to their large specific surface areas, highly tunable porosities, abundant active sites, and diversified choices of metal nodes and organic linkers. Both MOF-based and MOF-derived materials in powder form have been widely investigated in relation to their synthesis methods, structure and morphology controls, and performance advantages in targeted applications. However, to engage them for energy applications, both binders and additives would be required to form postprocessed electrodes, fundamentally eliminating some of the active sites and thus degrading the superior effects of the MOF-based/derived materials. The advancement of freestanding electrodes provides a new promising platform for MOF-based/derived materials in EESC thanks to their apparent merits, including fast electron/charge transmission and seamless contact between active materials and current collectors. Benefiting from the synergistic effect of freestanding structures and MOF-based/derived materials, outstanding electrochemical performance in EESC can be achieved, stimulating the increasing enthusiasm in recent years. This review provides a timely and comprehensive overview on the structural features and fabrication techniques of freestanding MOF-based/derived electrodes. Then, the latest advances in freestanding MOF-based/derived electrodes are summarized from electrochemical energy storage devices to electrocatalysis. Finally, insights into the currently faced challenges and further perspectives on these feasible solutions of freestanding MOF-based/derived electrodes for EESC are discussed, aiming at providing a new set of guidance to promote their further development in scale-up production and commercial applications.
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Estruturas Metalorgânicas , Eletrodos , Estruturas Metalorgânicas/química , MetaisRESUMO
Two-dimensional (2D) MBenes have enormous potential in energy applications. Vanadium metal, with its versatile and tunable electronic states, can further enhance the electrochemical performance of MBenes. However, most MBenes are composed of a few atomic layers as the metal boron (MB) block, e.g., M2B2, which might lead to instability and poor mechanical response. Herein, we designed and predicted 2D V4B6 associated with different terminations (T = Cl, O, S) using a top-down method and global search for parental V4AB6. Among the A element candidates, the P-glued MAB phase exhibited high stability and easy synthesizability. Moreover, 2D V4B6 was feasibly formed and easily exfoliated owing to its weak V-P bonding. Most of the surface functionalization could improve both the mechanical and electrochemical properties of the V4B6 monolayer. In particular, 2D V4B6S2 exhibited a high potential as an anode material for lithium-ion batteries (LIBs) with high theoretical capacity (297 mA h g-1), low diffusion barrier (0.166 eV), and low open circuit voltage (0.136 V), outperforming a majority of MXenes and transition metal sulfide layers. This work offers a new strategy for designing desirable 2D layers from parental materials, and tuning their properties via composition and surface functionalization, which could shed light on the development of other 2D metal-ion anodes.
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In the Fig. 3b western blot of this Article, 'Myc-AlaRS' in row one should have been 'Myc-AAD Aars', 'AlaRS' in row two should have been 'Aars' and 'ANKRD16' in row four should have been 'Ankrd16'. In Fig. 4f, 'ANKRD16' and 'ANKRD16(3xR)' should have been 'Ankrd16' and 'Ankrd163xR; and in Fig. 3c the position of the molecular mass markers had shifted. These figures have been corrected online, and see Supplementary Information to the accompanying Amendment for the original figure.
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Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aars sti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aars sti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.
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Alanina-tRNA Ligase/genética , Alanina-tRNA Ligase/metabolismo , Mutação , Biossíntese de Proteínas , Células de Purkinje/enzimologia , Células de Purkinje/patologia , Alanina/metabolismo , Alanina-tRNA Ligase/química , Animais , Domínio Catalítico , Morte Celular , Feminino , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Células de Purkinje/metabolismo , Serina/metabolismoRESUMO
KEY MESSAGE: The weighted gene co-expression network analysis and antisense oligonucleotide-mediated transient gene silencing revealed that CsAAP6 plays an important role in amino acid transport during tea shoot development. Nitrogen transport from source to sink is crucial for tea shoot growth and quality formation. Amino acid represents the major transport form of reduced nitrogen in the phloem between source and sink, but the molecular mechanism of amino acid transport from source leaves to new shoots is not yet clear. Therefore, the composition of metabolites in phloem exudates collected by the EDTA-facilitated method was analyzed through widely targeted metabolomics. A total of 326 metabolites were identified in the phloem exudates with the richest variety of amino acids and their derivatives (93), accounting for approximately 39.13% of the total metabolites. Moreover, through targeted metabolomics, it was found that the content of glutamine, glutamic acid, and theanine was the most abundant, and gradually increased with the development of new shoots. Meanwhile, transcriptome analysis suggested that the expression of amino acid transport genes changed significantly. The WGCNA analysis identified that the expression levels of CsAVT1, CsLHTL8, and CsAAP6 genes located in the MEterquoise module were positively correlated with the content of amino acids such as glutamine, glutamic acid, and theanine in phloem exudates. Reducing the CsAAP6 in mature leaves resulted in a significant decrease in the content of glutamic acid, aspartic acid, alanine, leucine, asparagine, glutamine, and arginine in the phloem exudates, indicating that CsAAP6 played an important role in the source to sink transport of amino acids in the phloem. The research results will provide the theoretical basis and genetic resources for the improvement of nitrogen use efficiency and tea quality.
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Aminoácidos , Glutamina , Aminoácidos/metabolismo , Glutamatos/metabolismo , Chá , Perfilação da Expressão Gênica , Nitrogênio/metabolismoRESUMO
PURPOSE: To develop and validate a nomogram based on 3D-PDU parameters and clinical characteristics to predict LNM and LVSI in early-stage cervical cancer preoperatively. MATERIALS AND METHODS: A total of first diagnosis 138 patients with cervical cancer who had undergone 3D-PDU examination before radical hysterectomy plus lymph dissection between 2014 and 2019 were enrolled for this study. Multivariate logistic regression analyses were performed to analyze the 3D-PDU parameters and selected clinicopathologic features and develop a nomogram to predict the probability of LNM and LVSI in the early stage. ROC curve was used to evaluate model differentiation, calibration curve and Hosmer-Lemeshow test were used to evaluate calibration, and DCA was used to evaluate clinical practicability. RESULTS: Menopause status, FIGO stage and VI were independent predictors of LNM. BMI and maximum tumor diameter were independent predictors of LVSI. The predicted AUC of the LNM and LSVI models were 0.845 (95%CI,0.765-0.926) and 0.714 (95%CI,0.615-0.813). Calibration curve and H-L test (LNM groups P = 0.478; LVSI P = 0.783) all showed that the predicted value of the model had a good fit with the actual observed value, and DCA indicated that the model had a good clinical net benefit. CONCLUSION: The proposed nomogram based on 3D-PDU parameters and clinical characteristics has been proposed to predict LNM and LVSI with high accuracy, demonstrating for the first time the potential of non-invasive prediction. The probability derived from this nomogram may have the potential to provide valuable guidance for physicians to develop clinical individualized treatment plans of FIGO patients with early cervical cancer.
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Metástase Linfática , Nomogramas , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/diagnóstico , Metástase Linfática/patologia , Pessoa de Meia-Idade , Adulto , Imageamento Tridimensional/métodos , Histerectomia/métodos , Estadiamento de Neoplasias , Excisão de Linfonodo/métodos , Ultrassonografia/métodos , Invasividade Neoplásica , Linfonodos/patologia , Estudos Retrospectivos , Idoso , Valor Preditivo dos TestesRESUMO
Through dominant mutations, aminoacyl-tRNA synthetases constitute the largest protein family linked to Charcot-Marie-Tooth disease (CMT). An example is CMT subtype 2N (CMT2N), caused by individual mutations spread out in AlaRS, including three in the aminoacylation domain, thereby suggesting a role for a tRNA-charging defect. However, here we found that two are aminoacylation defective but that the most widely distributed R329H is normal as a purified protein in vitro and in unfractionated patient cell samples. Remarkably, in contrast to wild-type (WT) AlaRS, all three mutant proteins gained the ability to interact with neuropilin 1 (Nrp1), the receptor previously linked to CMT pathogenesis in GlyRS. The aberrant AlaRS-Nrp1 interaction is further confirmed in patient samples carrying the R329H mutation. However, CMT2N mutations outside the aminoacylation domain do not induce the Nrp1 interaction. Detailed biochemical and biophysical investigations, including X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange (HDX), switchSENSE hydrodynamic diameter determinations, and protease digestions reveal a mutation-induced structural loosening of the aminoacylation domain that correlates with the Nrp1 interaction. The b1b2 domains of Nrp1 are responsible for the interaction with R329H AlaRS. The results suggest Nrp1 is more broadly associated with CMT-associated members of the tRNA synthetase family. Moreover, we revealed a distinct structural loosening effect induced by a mutation in the editing domain and a lack of conformational impact with C-Ala domain mutations, indicating mutations in the same protein may cause neuropathy through different mechanisms. Our results show that, as with other CMT-associated tRNA synthetases, aminoacylation per se is not relevant to the pathology.
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Alanina-tRNA Ligase/metabolismo , Doença de Charcot-Marie-Tooth/genética , Neuropilina-1/metabolismo , Alanina-tRNA Ligase/química , Alanina-tRNA Ligase/genética , Aminoacilação/genética , Células Cultivadas , Doença de Charcot-Marie-Tooth/sangue , Cristalografia por Raios X , Medição da Troca de Deutério , Humanos , Linfócitos , Mutação , Neuropilina-1/genética , Cultura Primária de Células , Ligação Proteica/genética , Domínios Proteicos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Espalhamento a Baixo ÂnguloRESUMO
BACKGROUND: Hypertrophic obstructive cardiomyopathy (HOCM) is clinically symptomatic and prone to malignant arrhythmias and sudden cardiac death (SCD). Currently, an effective treatment is surgical resection of the hypertrophic ventricular septum to relieve the left ventricular outflow tract (LVOT) obstruction and mitral insufficiency. Our center performs an innovative, minimally invasive right infra-axillary thoracotomy for transaortic septal myectomy. Minimally invasive procedures rely more on perioperative transesophageal echocardiography (TEE). This study aimed to explore the use of echocardiography during the perioperative period of surgical intervention for HOCM. METHODS: Between August 2021 and April 2022, 27 patients with HOCM underwent cardiac surgery at our hospital. Minimally invasive transaortic septal resection (Morrow myectomy) was performed from the right axilla. The extent of myectomy and need for mitral valve repair were based on perioperative TEE assessment and surgical findings. The demographic parameters and clinical data of patients were recorded. The cardiopulmonary bypass time, aortic cross-clamp, and mechanical ventilation times were calculated. TEE was used to assess ventricular wall thickening and anatomical abnormalities of mitral regurgitation, assist in intravenous catheterization, and assess the postoperative gradients of the LVOT. RESULTS: Among the 27 patients with HOCM who underwent transaortic septal myectomy by minimally invasive right infra-axillary thoracotomy, 16 had LVOT obstruction, 2 had mid-LV obstruction, and 9 had both LVOT and mid-LV involvement. TEE provides information about the fine structure of the LV cavity and the etiology of the obstruction. In all cases, LVOT obstruction and mitral valve systolic anterior motion were resolved postoperatively, and the degree of mitral regurgitation was significantly reduced. CONCLUSION: Perioperative echocardiography provides valuable information regarding the complex etiology of LVOT obstruction during minimally invasive right infra-axillary thoracotomy for transaortic septal myectomy. It helps determine the extent of septal resection and assess the need for concomitant mitral valve repair.
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Oriented attachment (OA) plays an important role in the assembly of nanoparticles and the regulation of their size and morphology, which is expected to be an effective means to modulate the properties of nanodiamonds (NDs). However, there remains a dearth of comprehensive investigation into the OA mechanism of NDs. Using in situ transmission electron microscopy, we conducted atomic-resolution investigation on the OA events of ND pairs under electron beam irradiation. The occurrence of an OA event is contingent upon the alignment between two ND surfaces, and the coalesced particles undergo recrystallization to form spherical shapes. Both experimental observations and molecular dynamics (MD) simulations reveal that ND pairs exhibit a preference for coalescing along the {111} surfaces. Additionally, MD simulations indicate that kinetic factors, such as contact surface area and contact angle, also influence the coalescence process.
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Reactive oxygen species (ROS) widely participate in a variety of chemical reactions in biological and chemical applications. However, due to the extremely short lifetime of most ROS, conventional ROS-detecting techniques cannot show real-time dynamic changes of ROS-driven chemical reactions and identify the actual role of individual reactive species in these reactions. Herein, using in situ liquid cell TEM complemented by ex situ experiments, we directly visualize ROS-driven rapid etching of Prussian bule (PB) in real time and identify the dominant reactive species in etching processes. The results reveal that highly oxidative â¢OH is the dominant reactive radical in ROS-driven rapid chemical etching and hollow mesoporous PB nanoparticles can be synthesized on a minute-level time scale via â¢OH-dominated rapid etching. This work provides insight into ROS-related oxidation, which can continuously improve our understanding of ROS chemistry and make ROS more widely applicable in advanced chemical etching.