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Tenofovir alafenamide fumarate (TAF) is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing tenofovir (PMPA) has been accomplished on a ...
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Tenofovir alafenamide fumarate (TAF) is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing tenofovir (PMPA) has been accomplished on a 7 g scale. This reimagined synthesis of TAF, inspired by a hitherto uncharted retrosynthetic disconnection, centers on the P-alkylation of silylated diphenyl phosphonate 11 (as acceptor) with methylthiomethyl (MTM) ether derivative 12 (as donor) in the presence of NIS/TfOH combination as a promoter to construct the strategic carbon–phosphorus bond. This PMPA-free synthesis of TAF not only removes the intrinsic drawbacks encountered by the PMPA-dependent commercial process but also is beneficial to the diversification of the synthetic portfolio of TAF. Furthermore, this type of P-alkylation reaction with defined stereochemistry could be deployed for the late-stage modification of druglike molecules and natural products to access valuable phosphonate derivatives.
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Hazard recognition is mainly a visual search and cognitive process. Mental representations of hazards may impact mental states of hazard recognition. We assessed the effects of critical indicators of mental presentations of constr...
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Hazard recognition is mainly a visual search and cognitive process. Mental representations of hazards may impact mental states of hazard recognition. We assessed the effects of critical indicators of mental presentations of construction hazards on prefrontal cortex activation, a proxy for the mental states of hazard recognition. Students participated in a hazard inspection experiment, with near-infrared spectroscopy (NIRS) used to record prefrontal cortex activation. The effects of critical indicators of the hazards’ mental representations on prefrontal activation were analyzed. Results demonstrated that site familiarity, risk tolerance and safety knowledge have significant effects on medial prefrontal activation for hazards at a low visual clutter level. High levels of site familiarity and risk tolerance reduced medial prefrontal activation and saved cognitive resources. Theoretically, the findings supplement the knowledge of safety hazards’ mental representations; and practically, the findings guide provision of individual-specific guidance for improving workers’ hazard inspection performance.
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The use of arbuscular mycorrhizal (AM) fungi is considered as an effective approach to enhance plants’ growth; nevertheless, its efficacy may vary with the type of inoculum and its application method. The present study, for the f...
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The use of arbuscular mycorrhizal (AM) fungi is considered as an effective approach to enhance plants’ growth; nevertheless, its efficacy may vary with the type of inoculum and its application method. The present study, for the first time, investigates the effects of different mycorrhizal species applied through different methods on morpho-physiological growth, root system architecture, nutrient uptake, and root exudates of maize. Four AM fungi species viz., Claroideoglomus etunicatum (C.E), Rhizophagus intraradices (R.I), Funneliformis mosseae (F.M), and Diversispora versiformis (D.V) were applied to maize through seed coating, soil application, or seed coating+ soil application. A control without AM fungi was maintained for comparison. All the thirteen treatments were arranged in completely randomized design with three replications. Application of C.E, R.I, F.M, and D.V through different methods triggered the growth performance of maize by improving morpho-physiological characteristics and root morphology, modulating AM fungi colonization, enhancing the nutrient (N, P, K) uptake, and reducing the root exudates (oxalic, malonic, fumaric, malic, citric, and T-aconitic) compared with control. Among the different mycorrhizal species, F.M applied particularly through seed coating+ soil application was more effective in regulating maize growth as compared with C.E, R.I, or D.V species owing to better root system, higher root colonization, and greater nutrient uptake in this treatment. Interestingly, seed coating of F.M recorded statistically similar or higher shoot and root growth attributes compared with soil application particularly at 30?days after sowing. In crux, F.M applied through seed coating + soil application performed better than that of other mycorrhizal species. The obtained results also suggest that seed coating can be a cheap, viable, and efficient delivery system of AM fungi particularly for large scale application, as AM fungi seed coating had faster and greater effect on maize growth compared with soil application during early growth stages. ? 2021, Sociedad Chilena de la Ciencia del Suelo.
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The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the rational...
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The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the rational therapeutic strategies to combat tauopathy. Previous studies reported that curcumin (Cur, a molecule of a labile natural product) and epinephrine (EP, an important neurotransmitter) could effectively inhibit the formation of Tau fibrillar aggregates and disassociate preformed fibrils. However, the underlying molecular mechanisms remain elusive. In this study, we performed multiple molecular dynamics simulations for 17.5 μs in total to investigate the influence of Cur and EP on the C-shaped Tau protofibril associated with CTE. Our simulations show that the protofibrillar pentamer is the smallest stable Tau R3–R4 protofibril. Taking the pentamer as a protofibril model, we found that both Cur and EP molecules could affect the shape of the Tau pentamer by changing the β2–β3 and β7–β8 angles, leading to a more extended structure. Cur and EP display a disruptive effect on the local β-sheets and the formation of hydrogen bonds, and thus destabilize the global protofibril structure. The contact number analysis shows that Cur has a higher binding affinity with the Tau pentamer than EP, especially in the nucleating segment PHF6. Hydrophobic, π–π and cation–π interactions together facilitate the binding of Cur and EP with the Tau pentamer. Cur exhibits stronger hydrophobic and π–π interactions with Tau than EP, and EP displays a stronger cation–π interaction. Our findings provide molecular insights into the disruptive mechanisms of the Tau R3–R4 protofibrils by curcumin and epinephrine, which may be useful for the design of effective drug candidates for the treatment of CTE.
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The reactive nitrogen (N) loss of the rice cropping system in the arid region shows a different pattern from that of subtropical humid region due to different climate types and crop management. However, little attention has been p...
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The reactive nitrogen (N) loss of the rice cropping system in the arid region shows a different pattern from that of subtropical humid region due to different climate types and crop management. However, little attention has been paid to this region. To fill this knowledge gap, a two-year (2009-2010) field observation was conducted in the Ningxia irrigation region, northwest China, to explore the major pathway of N loss following local farmers' optimal practice. Further, we determined the site-specific emission factors of ammonia and nitrous oxide, rate of surface runoff and subsurface (leaching and seepage) to improve the inventory resolution of arid irrigation region. Results showed that ammonia volatilization (45%-49% of total N loss), leaching and seepage (30%-33% of total N loss) were proved to be the primary factors of N loss in rice paddy fields. The emission factor of ammonia (21%) and N leaching rate (7.5%) following farmers' practice were 2.1 and 5.4 times higher than the country-specific default value in China. The country-specific N runoff rate and emission factor of N_2O could be directly adopted in this region. A 20% reduction of N fertilizer to farmers' practice (300 kg N ha~(-1)) alongside the application of organic fertilizer (30% N in synthetic fertilizer was substituted by pig manure) were considered to be the optimal N rate in this region. Our study can narrow the gap between researches on N loss in arid regions and subtropical humid regions. Meanwhile, the results can provide specific advice on N loss mitigation for policy makers in arid irrigation regions.
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The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established th...
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The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established that the structure of the tau protofilament in Chronic traumatic encephalopathy (CTE) is similar to that of Alzheimer's disease (AD). In addition, a previous study found that purpurin, an anthraquinone, could inhibit and disassemble the pre-formed 306VQIVYK311 isoform of AD-tau protofilament. Herein, we used all-atom molecular dynamic (MD) simulation to investigate the distinctive features between CTE-tau and AD-tau protofilament and the influence of purpurin on CTE-tau protofilament. Our findings revealed notable differences at the atomic level between CTE-tau and AD-tau protofilaments, particularly in the β6–β7 angle and the solvent-accessible surface area (SASA) of the β4–β6 region. These structural disparities contributed to the distinct characteristics observed in the two types of tau protofilaments. Our simulations substantiated that purpurin could destabilize the CTE-tau protofilament and decrease β-sheet content. Purpurin molecules could insert the β4–β6 region and weaken the hydrophobic packing between β1 and β8 through π–π stacking. Interestingly, each of the three rings in purpurin exhibited unique binding preferences with the CTE-tau protofilament. Overall, our study sheds light on the structural distinctions between CTE-tau and AD-tau protofilaments, as well as the destabilizing mechanism of purpurin on CTE-tau protofilament, which may be helpful to the development of drugs to prevent CTE.
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Amyloid-β (Aβ) fibrillary plaques represent the main hallmarks of Alzheimer's disease (AD), in addition to tau neurofibrillary tangles. Disrupting early-formed Aβ protofibrils is considered to be one of the primary therapeutic ...
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Amyloid-β (Aβ) fibrillary plaques represent the main hallmarks of Alzheimer's disease (AD), in addition to tau neurofibrillary tangles. Disrupting early-formed Aβ protofibrils is considered to be one of the primary therapeutic strategies to interfere with AD. Our previous work showed that norepinephrine (NE), an important neurotransmitter in the brain, can effectively inhibit the aggregation of the Aβ1–42 peptide. However, whether and how NE molecules disassemble Aβ1–42 protofibrils remains to be elucidated. Herein we investigate the influence of NE (in protonated and deprotonated states) on the recently cryo-EM solved LS-shaped Aβ1–42 protofibrils and the underlying molecular mechanism by performing all-atom molecular dynamics simulations. Our simulations showed that protonated and deprotonated NE exhibited distinct disruptive mechanisms on Aβ1–42 protofibrils. Protonated NE could significantly disrupt the N-terminal (residues D1–H14) structure of Aβ1–42 protofibrils and destabilize the global structure of the protofibril. It preferentially bound with N-terminal residues of Aβ1–42 protofibrils and formed hydrogen bonds with E3, D7, E11, Q15, E22, and D23 residues and π–π stackings with H6, H13, and F20 residues, and thus destroyed the hydrogen bonds between H6 and E11 and increased the kink angle around Y10. Compared to protonated NE, deprotonated NE displayed a higher disruptive capability on Aβ1–42 protofibrils, and stronger hydrophobic and π–π stacking interactions with the protofibril structure. This study revealed the molecular mechanism of NE in the destruction of Aβ1–42 protofibrils, which may be helpful in the design of potent drug candidates against AD.
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The principle and performance of Synthetic Impulse and Antenna Radar(SIAR) are analyzed with the concept of 3D matched filtering. The discussion here is concentrated on the characteristics of SIAR in the case of three dimensions....
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The principle and performance of Synthetic Impulse and Antenna Radar(SIAR) are analyzed with the concept of 3D matched filtering. The discussion here is concentrated on the characteristics of SIAR in the case of three dimensions. The results obtained are helpful for designing this new style radar.
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Garcimultiflins A–C (1–3), three novel polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from the pericarps of Garcinia multiflora. Their structures and absolute configurations were established by comprehensiv...
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Garcimultiflins A–C (1–3), three novel polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from the pericarps of Garcinia multiflora. Their structures and absolute configurations were established by comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction. All three compounds are ring-opening derivatives of PPAPs with a caged tricyclo[3.3.1.1.4,8]decane skeleton. Compounds 1 and 2 are characterized by a 7-oxaspiro[4.5]decan-6-one core, compound 2 was the first example of a PPAP characterized by rearomatization and methyl migration, and compound 3 has a (decahydronaphthalen-2-yl)(phenyl)methanone core. A plausible biosynthetic pathway for these new skeleton compounds was proposed. Furthermore, in lipopolysaccharides plus nigericin-induced THP-1 macrophages, compound 2 dose-dependently suppressed the secretion of interleukin-1β and pyroptosis through inhibiting the activation of NLRP3 inflammasome.
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A surface plasmon resonance imaging (SPRi) platform integrated with a smartphone was constructed for the simultaneous and sensitive detection of acute kidney injury (AKI) biomarkers. The smartphone SPRi platform was developed with...
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A surface plasmon resonance imaging (SPRi) platform integrated with a smartphone was constructed for the simultaneous and sensitive detection of acute kidney injury (AKI) biomarkers. The smartphone SPRi platform was developed without the requirement of additional light and power sources. The LED flash of the smartphone was used as the light source for the excitation of surface plasmon resonance of a gold sensor chip based on the Kretschmann configuration, while the reflected light was collected by the camera of the smartphone. This smartphone SPRi system was conveniently fabricated by 3D printing and showed a sensitivity of 1.78 × 10?5 refractive index unit (RIU). In addition, based on a magnetic nanoparticle-enhanced sandwich immunoassay, the smartphone SPRi system with a gold array chip was employed for the detection of multiple AKI biomarkers, with a low limit of detection (LOD) of 0.19 ng ml?1, 0.51 ng ml?1 and 0.7 ng ml?1 for the simultaneous detection of neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and retinol-binding protein (RBP) in urine, respectively. The biosensors demonstrated high specificity and sensitivity for the simultaneous detection of multiple AKI biomarkers in PBST and urine. The smartphone SPRi system provided a portable and cost-effective platform for point-of-care diagnosis, in-field healthcare and environmental monitoring.
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