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Background: The aim of the study is to observe the anti‐inflammatory and antioxidative stress effects of metformin on bleomycin (BLM)‐induced pulmonary fibrosis in mice. Methods: Mice with BLM‐induced pulmonary fibrosis were treated with pirfenidone, metformin, pirfenidone plus metformin and the NADPH oxidase 4 (NOX4) inhibitor diphenyleneiodonium chloride (DPI). Pathological changes and hydroxyproline (HPO) levels were examined in the lung tissue of mice with pulmonary fibrosis. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) levels in lung tissue were determined. Results: Compared with pirfenidone, pirfenidone plus metformin could reduce alveolar damage and collagen fibre deposition and alleviate BLM‐induced pulmonary fibrosis. Lung HPO levels were significantly lower in the PFD + MET group than in the BLM group (p < 0.05). SOD levels in the lungs of mice were increased in the PFD + MET group than in the BLM group (p < 0.05). Metformin and pirfenidone plus metformin can reduce MDA levels (p < 0.05). Pirfenidone plus metformin could reduce HPO levels, increase SOD levels, and reduce MDA levels in the lungs of mice. There was a significant correlation between the HPO level and the Ashcroft score (r = 0.520, p < 0.001). Conclusion: Metformin enhanced the antifibrotic effects of pirfenidone on BLM‐treated mice. Moreover, these findings provide an experimental basis for examining whether metformin can improve the antifibrotic effects of pirfenidone on patients with idiopathic pulmonary fibrosis (IPF). It has broad therapeutic prospects for patients with IPF. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical features and potential pathogenesis mechanism of de novo CLPTM1 variants associated with epilepsy. Methods: Identify de novo genetic variants associated with epilepsy by reanalyzing trio‐based whole‐exome sequencing data. We analyzed the clinical characteristics of patients with these variants and performed functional in vitro studies in cells expressing mutant complementary DNA for these variants using whole‐cell voltage‐clamp current recordings and outside‐out patch‐clamp recordings from transiently transfected human embryonic kidney (HEK) cells. Results: Two de novo missense variants related to epilepsy were identified in the CLPTM1 gene. Functional studies indicated that CLPTM1‐p.R454H and CLPTM1‐p.R568Q variants reduced the γ‐aminobutyric acid A receptor (GABAAR) current response amplitude recorded under voltage clamp compared to the wild‐type receptors. These variants also reduced the charge transfer and altered the time course of desensitization and deactivation following rapid removal of GABA. The surface expression of the GABAAR γ2 subunit from the CLPTM1‐p.R568Q group was significantly reduced compared to CLPTM1‐WT. Significance: This is the first report of functionally relevant variants within the CLPTM1 gene. Patch‐clamp recordings showed that these de novo CLPTM1 variants reduce GABAAR currents and charge transfer, which should promote excitation and hypersynchronous activity. This study may provide insights into the molecular mechanisms of the CLPTM1 variants underlying the patients' phenotypes, as well as for exploring potential therapeutic targets for epilepsy. [ABSTRACT FROM AUTHOR]

We investigate a set of Energy Exascale Earth System Model Multi‐scale modeling framework (MMF) (E3SM‐MMF) simulations that vary the dimensionality and momentum transport configurations of the embedded cloud‐resolving models (CRMs), including unusually ambitious 3D configurations. Issues endemic to all MMF simulations include too much Intertropical Convergence Zone rainfall and too little over the Amazon. Systematic MMF improvements include more on‐equatorial rainfall across the Warm Pool. Interesting sensitivities to the CRM domain are found in the regional time‐mean precipitation pattern over the tropics. The 2D E3SM‐MMF produces an unrealistically rainy region over the northwestern tropical Pacific; this is reduced in computationally ambitious 3D configurations that use 1,024 embedded CRM grid columns per host cell. Trajectory analysis indicates that these regional improvements are associated with desirably fewer tropical cyclones and less extreme precipitation rates. To understand why and how the representation of precipitation improved in 3D, we propose a framework that dilution is stronger in 3D. This viewpoint is supported by multiple indirect lines of evidence, including a delayed moisture‐precipitation pickup, smaller precipitation efficiency, and amplified convective mass flux profiles and more high clouds. We also demonstrate that the effects of varying embedded CRM dimensionality and momentum transport on precipitation can be identified during the first few simulated days, providing an opportunity for rapid model tuning without high computational cost. Meanwhile the results imply that other less computationally intensive ways to enhance dilution within MMF CRMs may also be strategic tuning targets. Plain Language Summary: The resolution of current climate models is not sufficient to resolve cloud and convective processes. Global cloud‐resolving models (CRMs) have resolutions fine enough to represent individual cloud events but require too much computing power to be practical for large ensemble multi‐decadal climate projection. Multi‐scale modeling framework (MMF) is used to simulate climate by embedding thousands of small CRMs interactively in each grid column of a planetary model. Trade‐offs in CRM configurations can influence the resulting emergent behavior. To examine this issue, we explore the effects of unusually ambitious 3D CRM configurations. Results show some interesting differences in the regional precipitation over the tropics. The 2D MMF produces an unrealistically rainy region over the northwestern tropical Pacific. Such biases are significantly reduced in 3D due to fewer tropical cyclones. To understand why and how the representation of precipitation improved in 3D, we propose a framework in which mixing being stronger in 3D is a major part of the story. This favored explanation is hard to prove directly but a few lines of circumstantial evidence support the case. Additionally, rapid effects of mixing that is seen in the first few days of global cloud resolving simulations provide opportunities for optimizing longer‐term statistics. Key Points: Dimensionality of cloud‐resolving models in the Energy Exascale Earth System Model Multi‐scale modeling framework (MMF) exhibits a striking effect on mean state precipitation patterns in subregions of the tropicsMMFs tend to produce too many precipitating events but the use of 3D leads to fewer and is associated with an enhanced dilution in 3DFast precursors of these climatological sensitivities are found that point to calibration targets for convection permitting global models [ABSTRACT FROM AUTHOR]

Summary: Verticillium wilt, one of the most devastating diseases of cotton (Gossypium hirsutum), causes severe yield and quality losses. Given the effectiveness of plant polygalacturonase‐inhibiting proteins (PGIPs) in reducing fungal polygalacturonase (PG) activity, it is necessary to uncover the key functional amino acids to enhance cotton resistance to Verticillium dahliae. To identify novel antifungal proteins, the selectivity of key amino acids was investigated by screening against a panel of relevant PG‐binding residues. Based on the obtained results, homologous models of the mutants were established. The docking models showed that hydrogen bonds and structural changes in the convex face in the conserved portion of leucine‐rich repeats (LRRs) may be essential for enhanced recognition of PG. Additionally, we successfully constructed Cynanchum komarovii PGIP1 (CkPGIP1) mutants Asp176Val, Pro249Gln, and Asp176Val/Pro249Gln and G. hirsutum PGIP1 (GhPGIP1) mutants Glu169Val, Phe242Gln, and Glu169Val/Phe242Gln with site‐directed mutagenesis. The proteins of interest can effectively inhibit VdPG1 activity and V. dahliae mycelial growth in a dose‐dependent manner. Importantly, mutants that overproduced PGIP in Arabidopsis and cotton showed enhanced resistance to V. dahliae, with reduced Verticillium‐associated chlorosis and wilting. Furthermore, the lignin content was measured in mutant‐overexpressing plants, and the results showed enhanced lignification of the xylem, which blocked the spread of V. dahliae. Thus, using site‐directed mutagenesis assays, we showed that mutations in CkPGIP1 and GhPGIP1 give rise to PGIP versatility, which allows evolving recognition specificities for PG and is required to promote Verticillium resistance in cotton by restricting the growth of invasive fungal pathogens. Significance statement: By using site‐directed mutagenesis assays, demonstrated that mutations in CkPGIP1 and GhPGIP1 give rise to PGIP versatility, which allows evolving recognition specificities for PG and is required to promote Verticillium resistance in cotton by restricting the growth of invasive fungal pathogens. [ABSTRACT FROM AUTHOR]

Loss of plant diversity with increased anthropogenic nitrogen (N) deposition in grasslands has occurred globally. In most cases, competitive exclusion driven by preemption of light or space is invoked as a key mechanism. Here, we provide evidence from a 9-yr N-addition experiment for an alternative mechanism: differential sensitivity of forbs and grasses to increased soil manganese (Mn) levels. In Inner Mongolia steppes, increasing the N supply shifted plant community composition from grass-forb codominance (primarily Stipa krylovii and Artemisia frigida, respectively) to exclusive dominance by grass, with associated declines in overall species richness. Reduced abundance of forbs was linked to soil acidification that increased mobilization of soil Mn, with a 10-fold greater accumulation of Mn in forbs than in grasses. The enhanced accumulation of Mn in forbs was correlated with reduced photosynthetic rates and growth, and is consistent with the loss of forb species. Differential accumulation of Mn between forbs and grasses can be linked to fundamental differences between dicots and monocots in the biochemical pathways regulating metal transport. These findings provide a mechanistic explanation for N-induced species loss in temperate grasslands by linking metal mobilization in soil to differential metal acquisition and impacts on key functional groups in these ecosystems. [ABSTRACT FROM AUTHOR]

ABSTRACT Rolled copper foil is widely used in high frequency and speed transmission of fine line printed circuit board, because of its high strength, good toughness and high density. In this paper, a theoretical model for copper foil rolling in mixed lubrication regime was developed on the basis of the average volume flow model and asperity flattening model. A more accurate relation for the variation of the lubricant viscosity with pressure and temperature was considered. The cold rolled copper foil experiment was carried on with different viscosity of rolling oil and pass reduction. The effects of rolling oil viscosity and pass reduction on lubricant pressure, contact area ratio and film thickness ratio were studied. The calculation results agree well with the measured data from copper foil rolling experiment. For obtaining higher surface quality, the rolling oil viscosity is about 10 mm2/s, and the pass reduction is about 30%. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The Drosophila sex comb (SC) has been hailed as a powerful tool for integrative studies in development, evolution, and behavior, but its ontogeny is poorly understood, even in the model organism Drosophila melanogaster. Using 4D live imaging and other techniques, we carried out a detailed analysis of the cellular events that take place during the development of the SC. We showed that the comb and other contiguous bristle formations assemble from noncontiguous precursor cells, which join together through intercalation. Most of the rotation of the SC (which has a longitudinal orientation in D. melanogaster but is initially transverse) occurs after this stage, when the structure is a single unit. We have provided evidence that male-specific convergent extension through cell rearrangement is responsible for both this rotation and another sexually dimorphic bristle trait. Contiguous bristle formations act as barriers to cell movement within the epithelium, and we demonstrated that a particularly rapid rotation of the proximal region of the comb is associated with the presence of a constricted area between a portion of the SC and a transverse row of contiguous bristle precursors. Our results suggest that the cell dynamics in the neighborhood of the SC may have biased its evolution. [ABSTRACT FROM AUTHOR]

The most complex and diverse secondary sexual character in Drosophila is the sex comb (SC), an arrangement of modified bristles on the forelegs of a subclade of male fruit flies. We examined SC formation in six representative nonmodel fruit fly species, in an effort to understand how the variation in comb patterning arises. We first compared SC development in two species with relatively small combs, Drosophila takahashii, where the SCs remain approximately transverse, and Drosophila biarmipes, where two rows of SC teeth rotate and move in an anterior direction relative to other bristle landmarks. We then analyzed comb ontogeny in species with prominent extended SCs parallel to the proximodistal axis, including Drosophila ficusphila and species of the montium subgroup. Our study allowed us to identify two general methods of generating longitudinal combs on the tarsus, and we showed that a montium subgroup species ( Drosophila nikananu) with a comb convergently similar in size, orientation and position to the model organism Drosophila melanogaster, forms its SC through a different developmental mechanism. We also found that the protein product of the leg patterning gene, dachshund (dac), is strongly reduced in the SC in all species, but not in other bristles. Our results suggest that an apparent constraint on SC position in the adult may be attributable to at least two different lineage-specific developmental processes, although external forces could also play a role. [ABSTRACT FROM AUTHOR]

Constantly exploring and improving the photoelectric properties of functional materials is of paramount importance for the development of the optoelectronics industry. Herein, a new strategy to extend the spectral response range and enhance the photoelectric properties of functional materials using high pressure is presented. In addition, the successful application of this strategy to the regulation of the photoelectric properties of 2D layered semiconductor iodine is reported. The maximum photocurrent is four orders of magnitude higher than that measured under initial pressure, with visible‐light illumination. Impressively, the light‐response range of iodine is successfully extended to the near‐infrared (1064 nm) with the application of pressure, and the photoresponse properties are also significantly enhanced with compression. These dramatically enhanced photoelectric activities are attributed to charge delocalization as well as an increased charge density in the regions between parallel molecules, which occur as a result of pressure‐induced charge transfer in the iodine molecules. These findings can be extended to guide the modification of the spectral response range and photoelectric properties of other functional materials. [ABSTRACT FROM AUTHOR]

The preparation of ultra–small silver nanoparticles (average diameter ≤10 nm) is a technical problem because of their aggregation tendency. Therefore, the preparation conditions are usually harsh and complex. It is widely recognized that covalent organic frameworks (COFs) represent a novel class of porous crystalline compounds with broad applications in various fields. In this work, an environmentally and economically friendly new method has been developed for synthesizing ultra–small silver nanoparticles by reducing silver ions in ethanol solution with a covalent organic framework (TPB–DMTP–COF) as a template and reductant at room temperature. Interestingly, the TPB–DMTP–COF not only serves as a template and reductant but also functions as a stabilizer. Moreover, the TPB–DMTP–COF can be utilized repeatedly as a reductant. The morphology and structure of the silver nanoparticles were examined using transmission electron microscopy and showed that they were spherical with an average particle size of approximately 7.5 nm. Compared with the previously reported silver nanoparticles, the silver nanoparticles synthesized by this new method are not coated with Surfactant, such as Polyvinylpyrrolidone (PVP). As a result, they possess a larger exposed surface area, exhibit increased activity, and demonstrate excellent antimicrobial properties against both Gram–negative Escherichia coli and Gram–positive bacteria Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

Developing a reliable synthesis strategy to concurrently realize electronic structure modulation and two‐dimensionalization of materials is of paramount significance yet still challenging. Herein, a facile and universal strategy is reported to fabricate defect‐abundant atomic‐layered materials with unique electronic structures by mechanical shear‐assisted exfoliation. As a proof‐of‐concept demonstration, atomic‐layered defect‐rich LiCoO2 nanosheets (AD‐LCO) are successfully synthesized, which enable accelerated oxygen evolution kinetics with a substantially decreased oxygen evolution reaction overpotential by 184 and 216 mV at 10 and 50 mA cm–2, respectively. X‐ray absorption spectroscopy suggests that AD‐LCO possesses more d‐band holes and enhanced Co‐O covalency. Density functional theory calculations reveal that the presence of Co lattice vacancies can optimize the adsorption kinetics of intermediates, consequently lowering the energy barrier of the rate‐determining step. Importantly, this method has universal applicability to the fabrication of other ultrathin defect‐rich 2D materials such as BN, WS2, and MoS2. The study has potential implications for offering novel insights into the rational design of ultrathin 2D materials with abundant surface defects for various applications. [ABSTRACT FROM AUTHOR]

Enhanced deposition of atmospheric nitrogen (N) leads to loss of plant diversity in grassland ecosystems. Numerous theories have provided potential explanations for the negative effects of N enrichment on plant diversity. However, the relative importance of each mechanism and the time‐scales of responses for the different functional groups remain unclear.We investigated the temporal responses of plant community in a temperate steppe to N enrichment by linking above‐ground to below‐ground processes using a series of field N‐addition and greenhouse experiments.The N enrichment‐induced declines in plant diversity of grasslands were phase‐based, functional group‐dependent and driven by three below‐ground processes. The rapid accumulation of NH4+-N by N addition inhibited photosynthetic rates of broad‐leaf non‐rhizomatous forbs, contributing to loss of these N‐sensitive species during early phase of N enrichment (≤3 years). The N‐induced changes in this phase were independent of soil pH as evidenced by results from application of lime to mitigate N‐evoked soil acidification. With progression of N addition, manganese (Mn) toxicity to narrow‐leaf non‐rhizomatous forbs due to soil acidification‐induced Mn2+ mobilization in soil accounted for their loss in the second phase of N enrichment (~4–9 years). When N addition proceeded longer than ~10 years, N enrichment stimulated below‐ground meristem differentiation and rhizome growth of the rhizomatous species, leading to the dominance by rhizomatous sedges/grasses in the community at the later phase of N enrichment.Synthesis. The hierarchical mechanisms not only provide a comprehensive explanation for the N enrichment‐induced diversity decline in grasslands, but can also facilitate us to understand the differential sensitivities of ecosystems to chronic N enrichment, and predict future ecosystem dynamics. [ABSTRACT FROM AUTHOR]

Background: Robust data regarding genotype–phenotype correlations in left ventricular noncompaction cardiomyopathy (LVNC) are lacking. Methods: About 72 cardiomyopathy‐related genes were comprehensively screened in a cohort of LVNC patients using targeted sequencing. Baseline and follow‐up data were collected. The primary endpoint was a composite of death and heart transplantation. Results: A total of 83 unrelated adult patients were included in analyses. Following stringent classification according to the American College of Medical Genetics and Genomics (ACMG) guidelines, 36 pathogenic variants of 14 genes were detected in 32 patients. Among them, 12 patients carried at least one nonsarcomere variant (NSV). At baseline, NSV carriers had a higher frequency of atrial fibrillation, but lower left ventricular ejection fraction, than did noncarriers. During a median follow‐up of 4.2 years, NSV carriers experienced a higher rate of the primary endpoint compared with noncarriers. There was no significant difference in the rate between carriers of sarcomere variant (SV) and noncarriers, as well as between carriers of SV and NSV. The presence of NSV was associated with an increased risk of the primary endpoint independent of age, sex, and cardiac function (hazard ratio: 3.61, 95% confidence interval: 1.42–9.19, p = .002). Conclusion: NSV may act as a genetic modifier and worsen the clinical phenotype in patients with LVNC. [ABSTRACT FROM AUTHOR]

Background: Hemizygous mutations in GRIA3 encoding the GluA3 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are known to be associated with neurodevelopmental disorders, including intellectual disability, hypotonia, an autism spectrum disorder, sleep disturbances, and epilepsy in males.Objective: To describe a new and consistent phenotype in 4 affected male patients associated with an undescribed deleterious variant in GRIA3.Methods: We evaluated a large French family in which segregate a singular phenotype according to an apparent X-linked mode of inheritance. Molecular analyses using next generation sequencing and in vitro functional studies using 2-electrode voltage clamp recordings on Xenopus laevis oocytes and a β-lactamase reporter assay in transfected human embryonic kidney (HEK293) cells were performed.Results: In addition to mild intellectual disability and dysarthria, affected patients presented a tightly consistent early-onset movement disorder combining an exaggerated startle reflex with generalized chorea and multifocal myoclonus. The unreported GRIA3 missense variant c.2477G > A; p.(Gly826Asp) affecting the fourth transmembrane domain of the protein was identified in index patients and their unaffected mothers. Functional studies revealed that variant receptors show decreased current response evoked by agonist (ie, kainic acid and glutamate) and reduced expression on the cell surface in favor of pathogenicity by a loss-of-function mechanism.Conclusions: Taken together, our results suggest that apart from known GRIA3-related disorders, an undescribed mutation-specific singular movement disorder does exist. We thus advocate considering GRIA3 mutations in the differential diagnosis of hyperekplexia and generalized chorea with myoclonus. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Ultrathin few‐layer materials have attracted intensive research attention because of their distinctive and unique properties. Few‐layer GeP (FL‐GP) is potentially interesting for application in electronics and optoelectronics because of its appropriate band gap and good stability under ambient conditions. Nevertheless, it is a challenge to achieve ultrathin few‐layer or single layer GeP from exfoliation of bulk crystals. Here, a lithiation‐assisted chemical exfoliation technique is employed to achieve FL‐GP, in which the interlayer spacing can be efficiently enlarged after a preliminary lithium ion intercalation, allowing the bulk crystal to be readily exfoliated in a following ultrasonication. As a result, ultrathin FL‐GP is obtained. In a demonstration, the FL‐GP/reduced graphene oxide (rGO) demonstrates remarkable sodium storage performance. The FL‐GP with a two‐dimensional structure shortens the ion transport pathways and alleviates the volume variation during sodiation. Meanwhile, the rGO in the composite improves the conductivity of the whole electrode. The as‐prepared FL‐GP/rGO electrode exhibits a high capacity of 504.2 mAh g−1 at 100 mA g−1, remarkable rate performance, and superior cycling stability in the half cells. FL‐GP/rGO//Na3V2(PO4)3 full cells are also assembled and demonstrated satisfactory electrochemical performance, indicating potential application of the as‐prepared anode materials. [ABSTRACT FROM AUTHOR]

Enhanced deposition of atmospheric nitrogen (N) has profound impacts on ecosystem processes such as above-ground productivity and community structure in grasslands across the globe. But how N deposition affects below-ground processes of grasslands is less well known., Here, we evaluated the effects of chronic N amendment at a relatively low rate (20 kg ha−1 year−1) on root traits (root productivity, root biomass, root/shoot ratio) in Inner Mongolia steppes by rhizotron and ingrowth core and soil monolith techniques at levels of individual species, functional groups and ecosystem., For 8 years, N amendment suppressed above-ground net primary production ( ANPP), photosynthetic rates and root biomass of forbs, but enhanced ANPP and root biomass of grasses. This led to an overall reduction in below-ground productivity of the grassland by 24-33%, while ANPP remained unchanged., Nitrogen amendment acidified soil and subsequently increased extractable soil manganese (Mn) concentration. Nitrogen amendment increased foliar Mn concentrations in forb, but not grass species, leading to a significant inhibition of photosynthetic rates in forb species., Synthesis. These findings highlight the importance of the differentiating responses of plant functional groups to long-term N deposition and the important consequences of these responses for below-ground productivity and long-term soil C sequestration. [ABSTRACT FROM AUTHOR]