Background and Aims
Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. Clinical trials use the NASH Clinical Research Network (CRN) system for semiquantitative ...histological assessment of disease severity. Interobserver variability may hamper histological assessment, and diagnostic consensus is not always achieved. We evaluate a second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) imaging‐based tool to provide an automated quantitative assessment of histological features pertinent to NASH.
Approach and Results
Images were acquired by SHG/TPEF from 219 nonalcoholic fatty liver disease (NAFLD)/NASH liver biopsy samples from seven centers in Asia and Europe. These were used to develop and validate qFIBS, a computational algorithm that quantifies key histological features of NASH. qFIBS was developed based on in silico analysis of selected signature parameters for four cardinal histopathological features, that is, fibrosis (qFibrosis), inflammation (qInflammation), hepatocyte ballooning (qBallooning), and steatosis (qSteatosis), treating each as a continuous rather than categorical variable. Automated qFIBS analysis outputs showed strong correlation with each respective component of the NASH CRN scoring (P < 0.001; qFibrosis r = 0.776, qInflammation r = 0.557, qBallooning r = 0.533, and qSteatosis r = 0.802) and high area under the receiver operating characteristic curve values (qFibrosis 0.870‐0.951; 95% confidence interval {CI}, 0.787‐1.000; P < 0.001, qInflammation 0.820‐0.838; 95% CI, 0.726‐0.933; P < 0.001), qBallooning 0.813‐0.844; 95% CI, 0.708‐0.957; P < 0.001, and qSteatosis 0.939‐0.986; 95% CI, 0.867‐1.000; P < 0.001) and was able to distinguish differing grades/stages of histological disease. Performance of qFIBS was best when assessing degree of steatosis and fibrosis, but performed less well when distinguishing severe inflammation and higher ballooning grades.
Conclusions
qFIBS is an automated tool that accurately quantifies the critical components of NASH histological assessment. It offers a tool that could potentially aid reproducibility and standardization of liver biopsy assessments required for NASH therapeutic clinical trials.
Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; ...however, the role of miRNA‐373‐3p (miR‐375‐3p) in CRC remains unclear. The current study aimed to explore the potential function of miR‐375‐3p in 5‐fluorouracil (5‐FU) resistance. MicroRNA‐375‐3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5‐FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR‐375‐3p, and TYMS knockdown exerted similar effects as miR‐375‐3p overexpression on the CRC cellular response to 5‐FU. Lipid‐coated calcium carbonate nanoparticles (NPs) were designed to cotransport 5‐FU and miR‐375‐3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR‐375 + 5‐FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR‐375‐3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5‐FU.
Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Our results suggest that the restoration of microRNA‐375‐3p levels could be a future novel therapeutic strategy to modulate and enhance chemosensitivity to 5‐fluorouracil treatment in CRC.
Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in ...glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.
Energy circulation in geospace lies at the heart of space weather research. In the inner magnetosphere, the steep plasmapause boundary separates the cold dense plasmasphere, which corotates with the ...planet, from the hot ring current/plasma sheet outside. Theoretical studies suggested that plasmapause surface waves related to the sharp inhomogeneity exist and act as a source of geomagnetic pulsations, but direct evidence of the waves and their role in magnetospheric dynamics have not yet been detected. Here, we show direct observations of a plasmapause surface wave and its impacts during a geomagnetic storm using multi-satellite and ground-based measurements. The wave oscillates the plasmapause in the afternoon-dusk sector, triggers sawtooth auroral displays, and drives outward-propagating ultra-low frequency waves. We also show that the surface-wave-driven sawtooth auroras occurred in more than 90% of geomagnetic storms during 2014-2018, indicating that they are a systematic and crucial process in driving space energy dissipation.
The aryl‐to‐vinyl nickel 1,4‐migration (1,4‐Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated ...brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4‐Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.
The 1,4‐nickel migration process from aryl to alkenyl groups is now reported for the first time. The alkenyl nickel intermediates generated by this highly stereoselective migration process can be coupled with brominated alkanes to form multisubstituted olefins. The current method provides a new and efficient approach for the synthesis of Z/E olefins with high stereoselectivity.
Perovskite solar cells (PSCs) may offer huge potential in photovoltaic conversion, yet their practical applications face one major obstacle: their low stability, or quick degradation of their initial ...efficiencies. Here, a new design scheme is presented to enhance the PSC stability by using low‐temperature hydrothermally grown hierarchical nano‐SnO2 electron transport layers (ETLs). The ETL contains a thin compact SnO2 layer underneath a mesoporous layer of SnO2 nanosheets. The mesoporous layer plays multiple roles of enhancing photon collection, preventing moisture penetration and improving the long‐term stability. Through such simple approaches, PSCs with power conversion efficiencies of ≈13% can be readily obtained, with the highest efficiency to be 16.17%. A prototypical PSC preserves 90% of its initial efficiency even after storage in air at room temperature for 130 d without encapsulation. This study demonstrates that hierarchical SnO2 is a potential ETL for fabricating low‐cost and efficient PSCs with long‐term stability.
Low‐temperature hydrothermally grown hierarchical SnO2
, a mesoporous layer of nanosheet arrays on a compact nanoparticle layer, is used as the electron transporting layer to enhance the long‐term stability of perovskite solar cells. A mesoporous device preserves 90% of its initial efficiency, even after storage in air for 130 d without encapsulation.
Prostaglandin E2 (PGE2)-induced coughs in vivo and vagal nerve depolarization in vitro are inhibited by systemic and local administration of prostaglandin EP3 receptor (L-798106) and TRPV1 ...antagonists (JNJ 17203212). These results indicate a modulating effect of TRPV1 on the EP3 receptor-mediated cough responses to PGE2 likely through the vagal sensory nerve. This study aimed to determine whether 1) inhalation of aerosolized JNJ 17203212 and L-798106 affected cough responses to citric acid (CA, mainly stimulating TRPV1) and PGE2; 2) TRPV1 and EP3 receptor morphologically are co-expressed and electrophysiologically functioned in the individual of vagal pulmonary C-neurons (cell bodies of bronchopulmonary C-fibers in the nodose/jugular ganglia); and 3) there was a cross-effect of TRPV1 and EP3 receptor on these neural excitations. To this end, aerosolized CA or PGE2 was inhaled by unanesthetized guinea pigs pretreated without or with each antagonist given in aerosol form. Immunofluorescence was applied to identify the co-expression of TRPV1 and EP3 receptor in vagal pulmonary C-neurons (retrogradely traced by DiI). Whole-cell voltage patch clamp approach was used to detect capsaicin (CAP)- and PGE2-induced currents in individual vagal pulmonary C-neurons and determine the effects of the TRPV1 and EP3 receptor antagonists on the evoked currents. We found that PGE2-induced cough was attenuated by JNJ 17203212 or L-798106 and CA-evoked cough greatly suppressed only by JNJ 17203212. Approximately 1/4 of vagal pulmonary C-neurons co-expressed EP3 with a cell size < 20 μm. Both CAP- and PGE2-induced currents could be recorded in the individuals of some vagal pulmonary C-neurons. The former was largely inhibited only by JNJ 17203212, while the latter was suppressed by JNJ 17203212 or L-798106. The similarity of the cross-effect of both antagonists on cough and vagal pulmonary C-neural activity suggests that a subgroup of vagal pulmonary C-neurons co-expressing TRPV1 and EP3 receptor is, at least in part, responsible for the cough response to PGE2.
•Quality changes in frozen shrimp were studied during temperature fluctuations.•Saccharides improved the water-holding capacity of shrimp muscle.•Saccharides slowed the damage caused to muscle ...tissues by large ice crystals.•Saccharides suppressed the growth and recrystallization of ice-crystals.
The cryoprotective effects of trehalose and alginate oligosaccharides on peeled shrimp were investigated during frozen storage upon exposure to temperature fluctuations. The results indicated that significant improvements were found in thawing and cooking loss, myofibrillar protein content, Ca2+-ATPase activity, textural variables, and tissue microstructure in trehalose- and alginate oligosaccharide-treated shrimp as compared to those of water-treated samples. The overall cryoprotective effects were also better than that observed in Na4P2O7-treated samples. Inhibition of ice growth by trehalose and alginate oligosaccharides might play an important role in the cryoprotection of frozen shrimp subjected to temperature fluctuations. It was proposed that trehalose and alginate oligosaccharide molecules combine with ice crystals via the hydrogen bonds, hydrophobic, and/or electrostatic interactions, which suppressed the growth and recrystallization of ice crystals. Meanwhile, these incorporated saccharides affected the distribution and mobility of water molecules around muscle proteins, protecting them from mechanical damage caused by the large ice crystals.
This paper presents the background, scientific objectives, experimental design, and preliminary achievements of the Third Tibetan Plateau (TP) Atmospheric Scientific Experiment (TIPEX-III) for 8–10 ...years. It began in 2013 and has expanded plateau-scale observation networks by adding observation stations in data-scarce areas; executed integrated observation missions for the land surface, planetary boundary layer, cloud–precipitation, and troposphere–stratosphere exchange processes by coordinating ground-based, air-based, and satellite facilities; and achieved noticeable progress in data applications. A new estimation gives a smaller bulk transfer coefficient of surface sensible heat over the TP, which results in a reduction of the possibly overestimated heat intensity found in previous studies. Summer cloud–precipitation microphysical characteristics and cloud radiative effects over the TP are distinguished from those over the downstream plains. Warm rain processes play important roles in the development of cloud and precipitation over the TP. The lower-tropospheric ozone maximum over the northeastern TP is attributed to the regional photochemistry and long-range ozone transports, and the heterogeneous chemical processes of depleting ozone near the tropopause might not be a dominant mechanism for the summer upper-tropospheric–lower-stratospheric ozone valley over the southeastern TP. The TP thermodynamic function not only affects the local atmospheric water maintenance and the downstream precipitation and haze events but also modifies extratropical atmospheric teleconnections like the Asia–Pacific Oscillation, subtropical anticyclones over the North Pacific and Atlantic, and temperature and precipitation over Africa, Asia, and North America. These findings provide new insights into understanding land–atmosphere coupled processes over the TP and their effects, improving model parameterization schemes, and enhancing weather and climate forecast skills.
A copper-catalyzed radical cross-coupling of oxime esters and activated alkenes is accomplished for the synthesis of cyanoalkylsulfonylated oxindoles and cyanoalkyl amides via an aryl migration ...strategy. Specifically, the subsequent mechanism research indicates that the unique desulfonylation and sulfone addition processes were involved in the transformation. This transformation is identified as having good functional group applicability with two different quaternary stereocenter in a regioselective manner, which is controlled by the substituent group of the nitrogen.
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