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Perovskite semiconductor materials have attracted significant attention in the fields of photovoltaics and luminescence due to their excellent photoelectric properties, such as high carrier mobility, high absorption coefficient, and high fluorescence quantum yield. In particular, low-dimensional metal-halide perovskite microcrystalline materials have been reported to exhibit low-dimensional lasing phenomena and laser devices due to their high gain and widely tunable bandgap. In this Letter, one-dimensional (1-D) ZnO microwires with their ultraviolet lasing emissions are utilized as an excitation source to pump CsPbBr3 microwire on hybrid ZnO-CsPbBr3 microscale structures. At higher excitation, the amplified spontaneous emission (ASE) behaviors from CsPbBr3 microwire are realized with ultralow threshold by indirect pumping from the ZnO lasing emission for the first time, to the best of our knowledge. In comparison, the ASE behaviors from the CsPbBr3 microwire directly pumped by Nd:YAG Q-switched laser and continuous wave laser are also performed at room temperature. There are also no multimode lasing behaviors observed. The paper provides a new method to achieve a low threshold on-chip microlaser by a high-quality perovskite micro-nano structure.
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Background: Colorectal cancer (CRC) has a high morbidity and mortality. Ferroptosis is a phenomenon in which metabolism and cell death are closely related. The role of ferroptosis-related genes in the progression of CRC is still not clear. Therefore, we screened and validated the ferroptosis-related genes which could determine the prevalence, risk and prognosis of patients with CRC. Methods: We firstly screened differentially expressed ferroptosis-related genes by The Cancer Genome Atlas (TCGA) database. Then, these genes were used to construct a risk-score model using the least absolute shrinkage and selection operator (LASSO) regression algorithm. The function and prognosis of the ferroptosis-related genes were confirmed using multi-omics analysis. The gene expression results were validated using publicly available databases and qPCR. We also used publicly available data and ferroptosis-related genes to construct a prognostic prediction nomogram. Results: A total of 24 differential expressed genes associated with ferroptosis were screened in this study. A three-gene risk score model was then established based on these 24 genes and GPX3, CDKN2A and SLC7A11 were selected. The significant prognostic value of this novel three-gene signature was also assessed. Furthermore, we conducted RT-qPCR analysis on cell lines and tissues, and validated the high expression of CDKN2A, GPX3 and low expression of SLC7A11 in CRC cells. The observed mRNA expression of GPX3, CDKN2A and SLC7A11 was consistent with the predicted outcomes. Besides, eight variables including selected ferroptosis related genes were included to establish the prognostic prediction nomogram for patients with CRC. The calibration plots showed favorable consistency between the prediction of the nomogram and actual observations. Also, the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. Conclusions: The present study constructed and validated a novel ferroptosis-related three-gene risk score signature and a prognostic prediction nomogram for patients with CRC. Also, we screened and validated the ferroptosis-related genes GPX3, CDKN2A, and SLC7A11 which could serve as novel biomarkers for patients with CRC.
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Sistema de Transporte de Aminoácidos y+ , Biomarcadores de Tumor , Neoplasias Colorrectales , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Nomogramas , Humanos , Ferroptosis/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Pronóstico , Biomarcadores de Tumor/genética , Sistema de Transporte de Aminoácidos y+/genética , Masculino , Femenino , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Persona de Mediana Edad , Perfilación de la Expresión Génica , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , AncianoRESUMEN
This paper introduces a method for analyzing the spatiotemporal progression of laser-induced shock waves using the beam deflection technique. This method allows for the accurate measurement of the shock wave evolution and can replace high-speed cameras. The results demonstrate the detection signals at various distances and energies, as well as the extraction and reconstruction of the shock wave velocities and propagation trajectories. The characteristic velocities of the shock waves propagating in air from various metals and energetic materials were measured and compared with the results obtained from high-speed cameras. The study also predicts the macroscopic detonation velocity of energetic materials based on the characteristic velocity. Overall, this approach offers a reliable and cost-effective method for studying the shock waves and has potential applications in various fields.
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The real-time online quantitative analysis instrument is highly desirable for many industrial fields. Herein, a new laser-induced breakdown spectroscopy (LIBS) setup with optimized optical route and high accuracy algorithm is designed and applied in a real industrial site. The components of total iron (TFe), silica (SiO2), aluminum oxide (Al2O3), and phosphorus (P) are quantitatively determined by the online LIBS system. The key optical part is a Maksutov-Cassegrain telescope, in which, two aspherical mirrors are specially designed and fabricated to reflect the broadband emission from ultraviolet 240â nm to infrared 890â nm with reflectivity over 90%, and pass the excited laser line of 1064â nm. The system could automatically adjust the focal length in the range of 780 mm to 940 mm. Based on the online LIBS system, the spectral pretreatment algorithm is also optimized including baseline removal and spectral normalization. The overlapped window slide (OWS) algorithm avoids the deformation of emission peaks in spectral baseline removal, in addition, two normalization steps by total back area and total spectral intensity within the sub-channel are applied to improve the spectral data stabilization. The calibration and validation are performed by utilizing the emissions that are insensitive to the detection distance. Compared with the traditional method, the prediction result shows that the root of mean square error of prediction (RMSEP) decreased from 5.091% to 1.2328%, and the mean absolute error (MAE) reduced from 4.801% to 0.9126% for TFe. Eventually, the online measurement shows good agreement with the official standard results. The high-precision online determination system based on LIBS will upgrade low frequency sampling of traditional detection to high-frequency real online determination in many industrial fields.
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Chemical exchange saturation transfer (CEST) imaging is an emerging molecular magnetic resonance imaging (MRI) technique that has been developed and employed in numerous diseases. Based on the unique saturation transfer principle, a family of CEST-detectable biomolecules in vivo have been found capable of providing valuable diagnostic information. However, CEST MRI needs a relatively long scan time due to the common long saturation labeling module and typical acquisition of multiple frequency offsets and signal averages, limiting its widespread clinical applications. So far, a plethora of imaging schemes and techniques has been developed to accelerate CEST MRI. In this review, the key acquisition and reconstruction methods for fast CEST imaging are summarized from a practical and systematic point of view. The first acquisition sequence section describes the major development of saturation schemes, readout patterns, ultrafast z-spectroscopy, and saturation-editing techniques for rapid CEST imaging. The second reconstruction method section lists the important advances of parallel imaging, compressed sensing, sparsity in the z-spectrum, and algorithms beyond the Fourier transform for speeding up CEST MRI.
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Algoritmos , Imagen por Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Análisis de Fourier , Fantasmas de ImagenRESUMEN
Chemical exchange saturation transfer (CEST) imaging benefits from a longer saturation duration and a higher saturation duty cycle. Dielectric shading effects occur when the radiofrequency (RF) wavelength approaches the object size. Here, we proposed a simultaneous parallel transmission-based CEST (pTx-CEST) sequence to prolongate the saturation duration at a 100% duty cycle and improve the RF saturation homogeneity in CEST imaging. The simultaneous pTx-CEST sequence was implemented by switching the CEST saturation module from the non-pTx to pTx mode, using the pTx functionality with both transmit channels being driven simultaneously (instead of time-interleaved). The optimization of amplitude ratio and phase difference settings between RF channels for best B1 homogeneity was performed in phantoms of two different sizes mimicking the human brain and abdomen. The optimal amplitude and phase settings generating the best B1 homogeneity in the phantoms were used in pTx-CEST scans of the human study. The comparison of the maximum achievable saturation duration between the non-pTx-CEST and pTx-CEST sequences was performed in a protein phantom, healthy volunteers, and a metastatic brain tumor patient. The optimal amplitude ratio and phase difference setting between transmit channels manifested circular and elliptical polarization in the head-sized and abdomen-sized phantoms. In the brain, the maximum saturation durations achieved at a 100% duty cycle using the simultaneous pTx-CEST sequence were prolonged to 2240, 3220, and 4200 ms compared with 980 ms using the non-pTx-CEST sequence at repetition times of 3, 4, and 5 s, respectively. The longer saturation duration helped improve the image contrast between the tumor and the normal tissue in the patient. The optimized elliptical polarization mode saturation pulses yielded improved uniformity of CEST signals acquired from the human abdomen. The proposed simultaneous pTx-CEST sequence enabled essentially arbitrarily long saturation duration at a 100% duty cycle and helped reduce the dielectric shading effects with the optimized RF setting.
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Neoplasias Encefálicas , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Aumento de la Imagen/métodos , Concentración de Iones de Hidrógeno , Fantasmas de Imagen , AlgoritmosRESUMEN
BACKGROUND: Oscillating gradient diffusion MRI (dMRI) enables measurements at a short diffusion-time (td ), but it is challenging for clinical systems. Particularly, the low b-value and low resolution may give rise to cerebrospinal fluid (CSF) contamination. PURPOSE: To assess the effect of CSF partial volume on td -dMRI measurements and efficacy of inversion-recovery (IR) prepared oscillating and pulsed gradient dMRI sequence to improve td -dMRI measurements in the human brain. STUDY TYPE: Prospective. SUBJECTS: Ten normal volunteers and six glioma patients. FIELD STRENGTH/SEQUENCE: A 3 T; three-dimensional (3D) IR-prepared oscillating gradient-prepared gradient spin-echo (GRASE) and two-dimensional (2D) IR-prepared oscillating gradient echo-planar imaging (EPI) sequences. ASSESSMENT: We assessed the td -dependent patterns of apparent diffusion coefficient (ADC) in several gray and white matter structures, including the hippocampal subfields (head, body, and tail), cortical gray matter, thalamus, and posterior white matter in normal volunteers. Pulsed gradient (0 Hz) and oscillating gradients at frequencies of 20 Hz, 40 Hz, and 60 Hz dMRI were acquired with GRASE and EPI sequences with or without the IR module. We also tested the td -dependency patterns in glioma patients using the EPI sequence with or without the IR module. STATISTICAL TESTS: The differences in ADC across the different td s were compared by one-way ANOVA followed by post hoc pairwise t-tests with Bonferroni correction. RESULTS: In the healthy subjects, brain regions that were possibly contaminated by CSF signals, such as the hippocampus (head, body, and tail) and cortical gray matter, td -dependent ADC changes were only significant with the IR-prepared 2D and 3D sequences but not with the non-IR sequences. In brain glioblastomas patients, significantly higher td -dependence was observed in the tumor region with the IR module than that without IR (slope = 0.0196 µm2 /msec2 vs. 0.0034 µm2 /msec2 ). CONCLUSION: The IR-prepared sequence effectively suppressed the CSF partial volume effect and significantly improved the td -dependent measurements in the human brain. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.
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Neoplasias Encefálicas , Glioma , Humanos , Estudios Prospectivos , Encéfalo/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagenRESUMEN
The ERK pathway is one of the most important signaling cascades involved in tumorigenesis. So far, eight noncovalent inhibitors of RAF and MEK kinases in the ERK pathway have been approved by the FDA for the treatment of cancers; however, their efficacies are limited due to various resistance mechanisms. There is an urgent need to develop novel targeted covalent inhibitors. Here we report a systematic study of the covalent ligandabilities of the ERK pathway kinases (ARAF, BRAF, CRAF, KSR1, KSR2, MEK1, MEK2, ERK1, and ERK2) using constant pH molecular dynamics titration and pocket analysis. Our data revealed that the hinge GK (gate keeper)+3 cysteine in RAF family kinases (ARAF, BRAF, CRAF, KSR1, and KSR2) and the back loop cysteine in MEK1 and MEK2 are reactive and ligandable. Structure analysis suggests that the type II inhibitors belvarafenib and GW5074 may be used as scaffolds for designing pan-RAF or CRAF-selective covalent inhibitors directed at the GK+3 cysteine, while the type III inhibitor cobimetinib may be modified to label the back loop cysteine in MEK1/2. The reactivities and ligandabilities of the remote cysteine in MEK1/2 and the DFG-1 cysteine in MEK1/2 and ERK1/2 are also discussed. Our work provides a starting point for medicinal chemists to design novel covalent inhibitors of the ERK pathway kinases. The computational protocol is general and can be applied to the systematic evaluation of covalent ligandabilities of the human cysteinome.
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Quinasas Quinasa Quinasa PAM , Sistema de Señalización de MAP Quinasas , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Cisteína/metabolismo , Transducción de Señal , Quinasas raf/metabolismoRESUMEN
Predictive modeling and understanding of chemical warhead reactivities have the potential to accelerate targeted covalent drug discovery. Recently, the carbanion formation free energies as well as other ground-state electronic properties from density functional theory (DFT) calculations have been proposed as predictors of glutathione reactivities of Michael acceptors; however, no clear consensus exists. By profiling the thiol-Michael reactions of a diverse set of singly- and doubly-activated olefins, including several model warheads related to afatinib, here we reexamined the question of whether low-cost electronic properties can be used as predictors of reaction barriers. The electronic properties related to the carbanion intermediate were found to be strong predictors, e.g., the change in the Cß charge accompanying carbanion formation. The least expensive reactant-only properties, the electrophilicity index, and the Cß charge also show strong rank correlations, suggesting their utility as quantum descriptors. A second objective of the work is to clarify the effect of the ß-dimethylaminomethyl (DMAM) substitution, which is incorporated in the warheads of several FDA-approved covalent drugs. Our data suggest that the ß-DMAM substitution is cationic at neutral pH in solution and promotes acrylamide's intrinsic reactivity by enhancing the charge accumulation at Cα upon carbanion formation. In contrast, the inductive effect of the ß-trimethylaminomethyl substitution is diminished due to steric hindrance. Together, these results reconcile the current views of the intrinsic reactivities of acrylamides and contribute to large-scale predictive modeling and an understanding of the structure-activity relationships of Michael acceptors for rational TCI design.
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Descubrimiento de Drogas , Compuestos de Sulfhidrilo , Relación Estructura-Actividad , Afatinib , Glutatión/químicaRESUMEN
The nation's opioid overdose deaths reached an all-time high in 2021. The majority of deaths are due to synthetic opioids represented by fentanyl. Naloxone, which is a FDA-approved reversal agent, antagonizes opioids through competitive binding at the µ-opioid receptor (mOR). Thus, knowledge of the opioid's residence time is important for assessing the effectiveness of naloxone. Here, we estimated the residence times (τ) of 15 fentanyl and 4 morphine analogs using metadynamics and compared them with the most recent measurement of the opioid kinetic, dissociation, and naloxone inhibitory constants (Mann et al. Clin. Pharmacol. Therapeut. 2022, 120, 1020-1232). Importantly, the microscopic simulations offered a glimpse at the common binding mechanism and molecular determinants of dissociation kinetics for fentanyl analogs. The insights inspired us to develop a machine learning approach to analyze the kinetic impact of fentanyl's substituents based on the interactions with mOR residues. This proof-of-concept approach is general; for example, it may be used to tune ligand residence times in computer-aided drug discovery.
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Analgésicos Opioides , Naloxona , Analgésicos Opioides/farmacología , Naloxona/farmacología , Naloxona/metabolismo , Fentanilo/metabolismo , Fentanilo/farmacología , Morfina/química , Receptores Opioides mu/metabolismo , Antagonistas de NarcóticosRESUMEN
Determination of macroscale detonation parameters of energetic materials (EMs) in a safe and rapid way is highly desirable. However, traditional experimental methods suffer from tedious operation, safety hazards and high cost. Herein, we present a micro-scale approach for high-precision diagnosis of explosion parameters based on radiation spectra and dynamic analysis during the interaction between laser and EMs. The intrinsic natures of micro-explosion dynamics covering nanosecond to millisecond and chemical reactions in laser-induced plasma are revealed, which reveal a tight correlation between micro-detonation and macroscopic detonation based on laser-induced plasma spectra and dynamics combined with statistic ways. As hundreds to thousands of laser pulses ablate on seven typical tetrazole-based high-nitrogen compounds and ten single-compound explosives, macroscale detonation performance can be well estimated with a high-speed and high-accuracy way. Thereby, the detonation pressure and enthalpies of formation can be quantitatively determined by the laser ablation processes for the first time to our knowledge. These results enable us to diagnose the performance of EMs in macroscale domain from microscale domain with small-dose, low-cost and multiple parameters.
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Prolonged exposure to high altitudes above 2500 m above sea level (a.s.l.) can cause cognitive and behavioral dysfunctions. Herein, we sought to investigate the effects of chronic exposure to plateau hypoxia on the hippocampus in a rat model by using voxel-based morphometry, creatine chemical exchange saturation transfer (CrCEST) and dynamic contrast-enhanced MR imaging techniques. 58 healthy 4-week-old male rats were randomized into plateau hypoxia rats (H group) as the experimental group and plain rats (P group) as the control group. H group rats were transported from Chengdu (500 m a.s.l.), a city in a plateau located in southwestern China, to the Qinghai-Tibet Plateau (4250 m a.s.l.), Yushu, China, and then fed for 8 months there, while P group rats were fed in Chengdu (500 m a.s.l.), China. After 8 months of exposure to plateau hypoxia, open-field and elevated plus maze tests revealed that the anxiety-like behavior of the H group rats was more serious than that of the P group rats, and the Morris water maze test revealed impaired spatial memory function in the H group rats. Multimodal MR imaging analysis revealed a decreased volume of the regional gray matter, lower CrCEST contrast and higher transport coefficient Ktrans in the hippocampus compared with the P group rats. Further correlation analysis found associations of quantitative MRI parameters of the hippocampus with the behavioral performance of H group rats. In this study, we validated the viability of using noninvasive multimodal MR imaging techniques to evaluate the effects of chronic exposure to a plateau hypoxic environment on the hippocampus.
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Hipocampo , Hipoxia , Animales , Cognición , Hipocampo/diagnóstico por imagen , Hipoxia/complicaciones , Imagen por Resonancia Magnética , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/etiología , RatasRESUMEN
PURPOSE: To correct the temporal B0 drift in chemical exchange saturation transfer (CEST) imaging in real-time with extra free-induction-decay (FID) readout. THEORY AND METHODS: The frequency stabilization module of the recently proposed frequency-stabilized CEST (FS-CEST) sequence was further simplified by replacing the original three k-space lines of gradient-echo (GRE) readout with a single k-space line of FID readout. The B0 drift was quantified using the phase difference between the odd and even parts of the FID signal in the frequency stabilization module and then used to update the B0 frequency in the succeeding modules. The proposed FS-CEST sequence with FID readout (FID FS-CEST) was validated in phantoms and 16 human subjects on cross-vendor scanners. RESULTS: In the Siemens experiments, the FID FS-CEST sequence successfully corrected the user-induced B0 drift, generating consistent amide proton transfer-weighted (APTw) images and magnetization transfer ratio asymmetry (MTRasym ) spectra with those from the non-frequency-stabilized CEST (NFS-CEST) sequence without B0 drift. In the Philips experiments, the FID FS-CEST sequence produced more stable APTw images and MTRasym spectra than the NFS-CEST sequence in the presence of practical B0 drift. Quantitatively, the SD of the APTw signal values in the deep gray matter from 15 subjects was 0.26% for the FID FS-CEST sequence compared to 1.03% for the NFS-CEST sequences, with the fluctuations reduced by nearly three-quarters. CONCLUSIONS: The proposed FS-CEST sequence with FID readout can effectively correct the temporal B0 drift on cross-vendor scanners.
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Imagen por Resonancia Magnética , Protones , Amidas , Humanos , Fantasmas de ImagenRESUMEN
Micro/nano optoelectronic devices are widely studied as basic building blocks for on-chip integrated microsystem and multichannel logic units with excellent optoelectronic properties that are especially important part for interconnection route construction. Here, based on anisotropic waveguides, an optical switch with an on/off ratio of 2.14 is built up in a 2D CdS branched nanowire array. Because the branches are obliquely distributed at the same side of the trunk in a highly ordered form, the guided photoluminescence (PL) intensity from the trunk into the branch tightly relates to its angle. Based on the different intensity of the guided PL emitted from the end of each branch, the position of the incident spot in the backbone area can be identified accurately, making a feasible construction of an on-chip position-sensitive detector to realize an all-optical information process.
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PURPOSE: To achieve fast whole-brain chemical exchange saturation transfer (CEST) imaging with negligible susceptibility artifact. METHODS: An optimized turbo spin echo readout module, also known as sampling perfection with application optimized contrasts by using different flip angle evolutions (SPACE), was deployed in the CEST sequence. The SPACE-CEST sequence was tested in a phantom, 6 healthy volunteers, and 3 brain tumor patients on a 3T human scanner. A dual-echo gradient echo sequence was used for B0 inhomogeneity mapping. In addition, the proposed SPACE-CEST sequence was compared with the widely used turbo spin echo-CEST sequence for amide proton transfer-weighted (APTw) images. RESULTS: The SPACE-CEST sequence generated highly consistent APTw maps to those of the turbo spin echo-CEST sequence in the phantom. In healthy volunteers, the SPACE-CEST sequence yielded whole-brain 2.8-mm isotropic APTw source images within 5 minutes, with no discernible susceptibility artifact. As for the B0 maps in the whole brain, its mean, median, and standard deviation B0 offset values were 5.0 Hz, 5.6 Hz, and 16 Hz, respectively. Regarding the APTw map throughout the whole brain, its mean, median, and standard deviation values were 0.78%, 0.56%, and 1.74%, respectively. The SPACE-CEST sequence was also successfully applied to a postsurgery brain tumor patient, suggesting no disease progression. In addition, on the newly diagnosed brain tumor patients, the SPACE-CEST and turbo spin echo-CEST sequences yielded essentially identical APTw values. CONCLUSION: The proposed SPACE-CEST technique can rapidly generate whole-brain CEST source images with negligible susceptibility artifact.
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Encéfalo , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Imagen Eco-Planar , Humanos , Imagenología Tridimensional , Fantasmas de ImagenRESUMEN
Exceptional points (EPs), branch points of complex energy surfaces at which eigenvalues and eigenvectors coalesce, are ubiquitous in non-Hermitian systems. Many novel properties and applications have been proposed around the EPs. One of the important applications is to enhance the detection sensitivity. However, due to the lack of single-handed superchiral fields, all of the proposed EP-based sensing mechanisms are only useful for the nonchiral discrimination. Here, we propose theoretically and demonstrate experimentally a new type of EP, which is called a radiation vector EP, to fulfill the homogeneous superchiral fields for chiral sensing. This type of EP is realized by suitably tuning the coupling strength and radiation losses for a pair of orthogonal polarization modes in the photonic crystal slab. Based on the unique modal-coupling property at the vector EP, we demonstrate that the uniform superchiral fields can be generated with two beams of lights illuminating the photonic crystal slab from opposite directions. Thus, the designed photonic crystal slab, which supports the vector EP, can be used to perform surface-enhanced chiral detection. Our findings provide a new strategy for ultrasensitive characterization and quantification of molecular chirality, a key aspect for various bioscience and biomedicine applications.
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Broad-spectrum antiviral drugs are urgently needed to stop the Coronavirus Disease 2019 pandemic and prevent future ones. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is related to the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused the previous outbreaks. The papain-like protease (PLpro) is an attractive drug target due to its essential roles in the viral life cycle. As a cysteine protease, PLpro is rich in cysteines and histidines, and their protonation/deprotonation modulates catalysis and conformational plasticity. Here, we report the pKa calculations and assessment of the proton-coupled conformational dynamics of SARS-CoV-2 in comparison to SARS-CoV and MERS-CoV PLpros using the recently developed graphical processing unit (GPU)-accelerated implicit-solvent continuous constant pH molecular dynamics method with a new asynchronous replica-exchange scheme, which allows computation on a single GPU card. The calculated pKa's support the catalytic roles of the Cys-His-Asp triad. We also found that several residues can switch protonation states at physiological pH among which is C270/271 located on the flexible blocking loop 2 (BL2) of SARS-CoV-2/CoV PLpro. Simulations revealed that the BL2 can open and close depending on the protonation state of C271/270, consistent with the most recent crystal structure evidence. Interestingly, despite the lack of an analogous cysteine, BL2 in MERS-CoV PLpro is also very flexible, challenging a current hypothesis. These findings are supported by the all-atom fixed-charge simulations and provide a starting point for more detailed studies to assist the structure-based design of broad-spectrum inhibitors against CoV PLpros.
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Antivirales/farmacología , Betacoronavirus/enzimología , Diseño de Fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/enzimología , Simulación de Dinámica Molecular , Papaína/química , Papaína/metabolismo , Protones , Secuencia de Aminoácidos , Histidina , Concentración de Iones de Hidrógeno , Papaína/antagonistas & inhibidores , Dominios Proteicos , SARS-CoV-2RESUMEN
Investigating the local micromagnetic structure of ferromagnetic nanowires (NWs) at the nanoscale is essential to study the structure-property relationships and can facilitate the design of nanostructures for technology applications. Herein, we synthesized high-quality iron and cobalt NWs and investigated the magnetic properties of these NWs using off-axis electron holography. The Fe NWs are about 100 nm in width and a few micrometers in length with a preferential growth direction of [100], while the Co NWs have a higher aspect-ratio with preferential crystal growth along the [110] direction. It is noted that compact passivation surface layers of oxides protect these NWs from further oxidation, even after nearly two years of exposure to ambient conditions; furthermore, these NWs display homogeneous ferromagnetism along their axial direction revealing the domination of shape anisotropy on magnetic behavior. Importantly, the average value of magnetic induction strengths of Fe NWs (2.07 {±} 0.10 T) and Co NWs (1.83 {±} 0.15 T) is measured to be very close to the respective theoretical value, and it shows that the surface oxide layers do not affect the magnetic moments in NWs. Our results provide a useful synthesis approach for the fabrication of single-crystalline, defect-free metal NWs and give insight into the micromagnetic properties in ferromagnetic NWs based on the transmission electron microscopy measurements.
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BACKGROUND: Understanding the origin of genetic variation is the key to predict how species will respond to future climate change. The genus Quercus is a species-rich and ecologically diverse woody genus that dominates a wide range of forests and woodland communities of the Northern Hemisphere. Quercus thus offers a unique opportunity to investigate how adaptation to environmental changes has shaped the spatial genetic structure of closely related lineages. Furthermore, Quercus provides a deep insight into how tree species will respond to future climate change. This study investigated whether closely related Quercus lineages have similar spatial genetic structures and moreover, what roles have their geographic distribution, ecological tolerance, and historical environmental changes played in the similar or distinct genetic structures. RESULTS: Despite their close relationships, the three main oak lineages (Quercus sections Cyclobalanopsis, Ilex, and Quercus) have different spatial genetic patterns and occupy different climatic niches. The lowest level and most homogeneous pattern of genetic diversity was found in section Cyclobalanopsis, which is restricted to warm and humid climates. The highest genetic diversity and strongest geographic genetic structure were found in section Ilex, which is due to their long-term isolation and strong local adaptation. The widespread section Quercus is distributed across the most heterogeneous range of environments; however, it exhibited moderate haplotype diversity. This is likely due to regional extinction during Quaternary climatic fluctuation in Europe and North America. CONCLUSIONS: Genetic variations of sections Ilex and Quercus were significantly predicted by geographic and climate variations, while those of section Cyclobalanopsis were poorly predictable by geographic or climatic diversity. Apart from the different historical environmental changes experienced by different sections, variation of their ecological or climatic tolerances and physiological traits induced varying responses to similar environment changes, resulting in distinct spatial genetic patterns.
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Cloroplastos/genética , Ilex/genética , Quercus/genética , Cambio Climático , Ecología , Europa (Continente) , Bosques , Estructuras Genéticas , Variación Genética , Haplotipos , Ilex/citología , Ilex/crecimiento & desarrollo , América del Norte , Filogenia , Quercus/citología , Quercus/crecimiento & desarrolloRESUMEN
The infant brain undergoes drastic morphological and functional development during the first year of life. Three-dimensional T1-weighted Magnetic Resonance Imaging (3D T1w-MRI) is a major tool to characterize the brain anatomy, which however, manifests inherently low and rapidly changing contrast between white matter (WM) and gray matter (GM) in the infant brains (0-12 month-old). Despite the prior efforts made to maximize tissue contrast in the neonatal brains (≤1 months), optimization of imaging methods in the rest of the infancy (1-12 months) is not fully addressed, while brains in the latter period exhibit even more challenging contrast. Here, we performed a systematic investigation to improve the contrast between cortical GM and subcortical WM throughout the infancy. We first performed simultaneous T1 and proton density mapping in a normally developing infant cohort at 3T (nâ¯=â¯57). Based on the evolution of T1 relaxation times, we defined three age groups and simulated the relative tissue contrast between WM and GM in each group. Age-specific imaging strategies were proposed according to the Bloch simulation: inversion time (TI) around 800â¯ms for the 0-3 month-old group, dual TI at 500â¯ms and 700â¯ms for the 3-7 month-old group, and TI around 700â¯ms for 7-12 month-old group, using a centrically encoded 3D-MPRAGE sequence at 3T. Experimental results with varying TIs in each group confirmed improved contrast at the proposed optimal TIs, even in 3-7 month-old infants who had nearly isointense contrast. We further demonstrated the advantage of improved relative contrast in segmenting the neonatal brains using a multi-atlas segmentation method. The proposed age-specific optimization strategies can be easily adapted to routine clinical examinations, and the improved image contrast would facilitate quantitative analysis of the infant brain development.