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BackgroundBreast cancer has a major disease burden in the female population, and it is a highly genome-associated human disease. However, in genetic studies of complex diseases, modern geneticists face challenges in detecting interactions among loci. ObjectiveThis study aimed to investigate whether variations of single-nucleotide polymorphisms (SNPs) are associated with histopathological tumor characteristics in breast cancer patients. MethodsA hybrid Taguchi-genetic algorithm (HTGA) was proposed to identify the high-order SNP barcodes in a breast cancer case-control study. A Taguchi method was used to enhance a genetic algorithm (GA) for identifying high-order SNP barcodes. The Taguchi method was integrated into the GA after the crossover operations in order to optimize the generated offspring systematically for enhancing the GA search ability. ResultsThe proposed HTGA effectively converged to a promising region within the problem space and provided excellent SNP barcode identification. Regression analysis was used to validate the association between breast cancer and the identified high-order SNP barcodes. The maximum OR was less than 1 (range 0.870-0.755) for two- to seven-order SNP barcodes. ConclusionsWe systematically evaluated the interaction effects of 26 SNPs within growth factor–related genes for breast carcinogenesis pathways. The HTGA could successfully identify relevant high-order SNP barcodes by evaluating the differences between cases and controls. The validation results showed that the HTGA can provide better fitness values as compared with other methods for the identification of high-order SNP barcodes using breast cancer case-control data sets.

AIM: To compare relative peripheral refraction (RPR) in Chinese school children with different refractive errors using multispectral refraction topography (MRT). METHODS: A total of 713 eyes of primary school children [172 emmetropia (E), 429 low myopia (LM), 80 moderate myopia (MM), and 32 low hypermetropia (LH)] aged 10 to 13y were analyzed. RPRs were measured using MRT without mydriasis. MRT results showed RPR at 0-15° (RPR 0-15), 15°-30° (RPR 15-30), and 30°-45° (RPR 30-45) annular in the inferior (RPR-I), superior (RPR-S), nasal (RPR-N), and temporal (RPR-T) quadrants. Spherical equivalent (SE) was detected and calculated using an autorefractor. RESULTS: There were significant differences of RPR 15-30 between groups MM [0.02 (-0.12; 0.18)] and LH [-0.13 (-0.36; 0.12)] (P

Abstract The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Abstract The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

With the development of digitalization in China, the social assistance environment has also undergone tremendous changes in the digital era, which requires social managers to achieve high-quality and efficient assistance through digital transformation. The research introduces the theory of entropy change, constructs a two-dimensional quadrant method, and demonstrates that the orderly digital transformation of social assistance is achieved by negative entropy reduction offsetting positive entropy increase. Based on the current situation and case study of the digital transformation of social assistance in China, the entropy change of social assistance system has the characteristics of variability, uncertainty and complexity. Based on these three characteristics, the optimization path of the digital transformation of the social assistance system is proposed from the perspectives of negative entropy increase and positive entropy flow.

Abstract Purpose Previous studies have suggested that obesity defined by body mass index(BMI) is a protective factor for bone mineral density(BMD), but have overlooked the potential influence of different types of obesity. This study aims to evaluate the correlation between abdominal obesity index A Body Shape Index(ABSI) and adolescent bone density, and analyze the relationship between abdominal obesity and bone metabolism. Methods A total of 1557 adolescent participants were included in NHANES from 2007 to 2018. Calculate the ABSI using a specific formula that takes into account waist circumference and BMI. A weighted multiple linear regression model is used to evaluate the linear correlation between ABSI and BMD. Forest plots are used to analyze the correlations between subgroups, and cubic splines are limited to evaluate the nonlinear correlations and saturation effects between ABSI and BMD. Results After adjusting for confounding factors, there was a significant linear correlation (P

Abstract Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While plant extraction of these compounds suffers from uncertain supply, efficient chemical synthesis approaches are in high demand. Here, we present concise, divergent, and scalable syntheses of veratramine and cyclopamine with 11% and 6.2% overall yield, respectively, from inexpensive dehydro-epi-androsterone. Our synthesis readily provides gram quantities of both target natural products by utilizing a biomimetic rearrangement to form the C-nor-D-homo steroid core and a stereoselective reductive coupling/(bis-)cyclization sequence to establish the (E)/F-ring moiety.

Abstract Domesticated herbivores are an important agricultural resource that play a critical role in global food security, particularly as they can adapt to varied environments, including marginal lands. An understanding of the molecular basis of their biology would contribute to better management and sustainable production. Thus, we conducted transcriptome sequencing of 100 to 105 tissues from two females of each of seven species of herbivore (cattle, sheep, goats, sika deer, horses, donkeys, and rabbits) including two breeds of sheep. The quality of raw and trimmed reads was assessed in terms of base quality, GC content, duplication sequence rate, overrepresented k-mers, and quality score distribution with FastQC. The high-quality filtered RNA-seq raw reads were deposited in a public database which provides approximately 54 billion high-quality paired-end sequencing reads in total, with an average mapping rate of ~93.92%. Transcriptome databases represent valuable resources that can be used to study patterns of gene expression, and pathways that are related to key biological processes, including important economic traits in herbivores.

Abstract Shigella flexneri is a Gram-negative bacterium causing severe bloody dysentery. Its pathogenesis is largely dictated by a plasmid-encoded type III secretion system (T3SS) and its associated effectors. Among these, the effector OspG has been shown to bind to the ubiquitin conjugation machinery (E2~Ub) to activate its kinase activity. However, the cellular targets of OspG remain elusive despite years of extensive efforts. Here we show by unbiased phosphoproteomics that a major target of OspG is CAND1, a regulatory protein controlling the assembly of cullin-RING ubiquitin ligases (CRLs). CAND1 phosphorylation weakens its interaction with cullins, which is expected to impact a large panel of CRL E3s. Indeed, global ubiquitome profiling reveals marked changes in the ubiquitination landscape when OspG is introduced. Notably, OspG promotes ubiquitination of a class of cytoskeletal proteins called septins, thereby inhibiting formation of cage-like structures encircling cytosolic bacteria. Overall, we demonstrate that pathogens have evolved an elaborate strategy to modulate host ubiquitin signaling to evade septin-cage entrapment.

BackgroundThere is accumulating evidence regarding the benefits of the 5-HT3 receptor antagonist ondansetron for the treatment of critical illness due to its potential anti-inflammatory effect. This study attempted to determine the potential targets and molecular mechanisms of ondansetron’s action against critical illnesses.MethodsA bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets and the signaling pathways of ondansetron action against the most common critical illnesses such as acute kidney injury (AKI), sepsis, and acute respiratory distress syndrome (ARDS). Experiments of LPS-stimulated rat neutrophils with ondansetron treatment were conducted to further validate the relevant hypothesis.ResultsA total of 198, 111, and 26 primary causal targets were identified from the data for the action of ondansetron against AKI, sepsis, and ARDS respectively. We found that the pathway of neutrophil extracellular traps (NETs) formation is statistically significantly involved in the action of ondansetron against these three critical illnesses. In the pathway of NETs formation, the common drug-disease intersection targets in these three critical illnesses were toll-like receptor 8 (TLR8), mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B1 (NFKB1), neutrophil elastase (NE), and myeloperoxidase (MPO). Considering these bioinformatics findings, we concluded that ondansetron anti-critical illness effects are mechanistically and pharmacologically implicated with suppression of neutrophils-associated inflammatory processes. It was also showed that after treatment of LPS-stimulated rat neutrophils with ondansetron, the key proteins NE, MPO, and Peptide Arginine Deaminase 4 (PAD4) in the NETs formation were significantly reduced, and the inflammatory factors IL-6, IL-1β, TNF-α, and chemokine receptor (CXCR4) were also significantly decreased.ConclusionThe excessive formation of NETs may have important research value in the development and progression of critical illness. Ondansetron may reduce excessive inflammatory injury in critical diseases by reducing the formation of NETs via influencing the five targets: TLR8, NFKB1, MAPK14, NE, and MPO. Ondansetron and these primary predictive biotargets may potentially be used to treat critical illness in future clinical practice.

Objective(MSU) crystals usually in the kidney tubules especially collecting ducts in the medulla. Previous animal models have not fully reproduced the impact of MSU on kidneys under non-hyperuricemic conditions.MethodsIn the group treated with MSU, the upper pole of the rat kidney was injected intrarenally with 50 mg/kg of MSU, while the lower pole was injected with an equivalent volume of PBS solution. The body weight and kidney mass of the rats were observed and counted. H&E staining was used to observe the pathological damage of the kidney and to count the number of inflammatory cells. Masoon staining was used to observe the interstitial fibrosis in the kidneys of the rat model. Flow cytometric analysis was used for counting inflammatory cells in rats. ElISA was used to measure the concentration of serum and urine uric acid, creatinine and urea nitrogen in rats.ResultsAt the MSU injection site, a significantly higher infiltration of inflammatory cells and a substantial increase in the area of interstitial fibrosis compared to the control group and the site of PBS injection were observed. The serum creatinine level was significantly increased in the MSU group. However, there were no significant differences in the rats’ general conditions or blood inflammatory cell counts when compared to the control group.ConclusionThe injection of urate crystals into the kidney compromised renal function, caused local pathological damage, and increased inflammatory cell infiltration and interstitial fibrosis. Intrarenal injection of MSU crystals may result in urate nephropathy. The method of intrarenal injection did not induce surgical infection or systemic inflammatory response.

This study aimed to clarify the differences in the decomposition rates, soil carbon and nitrogen contents, soil enzyme activities, and the structure of the soil bacterial community between the four Asteraceae invasive plants (AIPs), Bidens pilosa L., Conyza canadensis (L.) Cronq., Solidago canadensis L., and Symphyotrichum subulatum (Michx.) G.L. Nesom, and the native plant Pterocypsela laciniata (Houtt.) Shih under the artificially modeled nitrogen with four forms (including nitrate, ammonium, urea, and the mixed nitrogen forms with an equal mixture of three individual nitrogen forms). The mixed nitrogen forms significantly increased the decomposition rate of the four AIPs and P. laciniata. The positive effects of the mixed nitrogen forms on the decomposition rate of the four AIPs and P. laciniata were obviously greater than those of individual nitrogen forms. Nitrogen with four forms visibly up- or down-regulated the dominant role of predominant soil bacterial biomarkers, and significantly increased the species number, richness, and phylogenetic diversity of the soil bacterial community, as well as the number of most of the functional gene pathways of the soil bacterial communities involved in the decomposition process. The decomposition rate of the four AIPs was similar to that of P. laciniata. The leaves of C. canadensis decomposed more easily than those of S. subulatum. The decomposition process of the four AIPs caused remarkable changes in the relative abundance of several taxa of the soil bacterial community and soil bacterial beta diversity, and caused apparent up- or down-regulation in the dominant role of predominant soil bacterial biomarkers and the number of several functional gene pathways of the soil bacterial communities involved in the decomposition process.

Abstract ADP-ribosylation is a reversible post-translational modification involved in various cellular activities. Removal of ADP-ribosylation requires (ADP-ribosyl)hydrolases, with macrodomain enzymes being a major family in this category. The pathogen Legionella pneumophila mediates atypical ubiquitination of host targets using the SidE effector family in a process that involves ubiquitin ADP-ribosylation on arginine 42 as an obligatory step. Here, we show that the Legionella macrodomain effector MavL regulates this pathway by reversing the arginine ADP-ribosylation, likely to minimize potential detrimental effects caused by the modified ubiquitin. We determine the crystal structure of ADP-ribose-bound MavL, providing structural insights into recognition of the ADP-ribosyl group and catalytic mechanism of its removal. Further analyses reveal DUF4804 as a class of MavL-like macrodomain enzymes whose representative members show unique selectivity for mono-ADP-ribosylated arginine residue in synthetic substrates. We find such enzymes are also present in eukaryotes, as exemplified by two previously uncharacterized (ADP-ribosyl)hydrolases in Drosophila melanogaster. Crystal structures of several proteins in this class provide insights into arginine specificity and a shared mode of ADP-ribose interaction distinct from previously characterized macrodomains. Collectively, our study reveals a new regulatory layer of SidE-catalyzed ubiquitination and expands the current understanding of macrodomain enzymes.

Abstract The application of near-infrared spectroscopy (NIRS) for rapid quantitative analysis of soil total nitrogen (STN) is of great significance to recycling nitrogen in the ecosystem and crops growth. However, collecting thousands of soil samples and chemical analysis are impracticable, more importantly a deviation from NIRS advantages of rapid, inexpensive and nondestructive. To more efficiently improve the estimation performance and reduce uncertainty of the model when working with small sample sizes (less than 100), solutions from soil particle size decomposition and model fusion were investigated. Elaborately, 123 Latosols samples were collected and decomposed them according to particle sizes to extend limited data at multiple scales. Based on all soil groups decomposed, a hyperspectral data recapture and model decision fusion method were implemented. The results demonstrated that the proposed method increased the scale of spectral data, extracted more STN-related spectral information, improved estimation accuracy, and reduced uncertainty. The fused model based on data from all decomposed groups yielded the best estimated results (root mean square error $$(RMSE) = 0.075g.kg^{-1}$$ ( R M S E ) = 0.075 g . k g - 1 , $$R^2 = 0.784$$ R 2 = 0.784 , and a ratio of performance to inter-quartile distance $$(RPIQ) = 3.787$$ ( R P I Q ) = 3.787 ) on the validation set. Through a tenfold cross-validation, the weighted fusion model with six groups of particle sizes data showed an improvement of 0.307 in $$R^2_cv$$ R c 2 v and an improved RPIQ of 1.015 compared to models constructed using conventional machine learning (ML) techniques and limited pristine data ( $$R^2_cv = 0.442, RMSE = 0.119$$ R c 2 v = 0.442 , R M S E = 0.119 ). Therefore, when utilizing NIRS to build rapid and accurate STN predictive models, the proposed method demonstrates great potential in improving the reliability of soil spectral models under small sample sizes. Graphical Abstract

Abstract Environmentally adaptive hydrogels that are capable of reconfiguration in response to external stimuli have shown great potential toward bioinspired actuation and soft robotics. Previous efforts have focused mainly on either the sophisticated design of heterogeneously structured hydrogels or the complex manipulation of external stimuli, and achieving self-regulated reversal shape deformation in homogenous hydrogels under a constant stimulus has been challenging. Here, we report the molecular design of structurally homogenous hydrogels containing simultaneously two spiropyrans that exhibit self-regulated transient deformation reversal when subjected to constant illumination. The deformation reversal mechanism originates from the molecular sequential descending-ascending charge variation of two coexisting spiropyrans upon irradiation, resulting in a macroscale volumetric contraction-expansion of the hydrogels. Hydrogel film actuators were developed to display complex temporary bidirectional shape transformations and self-regulated reversal rolling under constant illumination. Our work represents an innovative strategy for programming complex shape transformations of homogeneous hydrogels using a single constant stimulus.

Abstract Background Observational studies have suggested that sedentary behaviors and sleep status are associated with frailty. However, it remains unclear whether these associations are causal. Methods Using summary statistics from genome-wide association studies, we evaluated the causal effect of modifiable risk factors, including leisure sedentary behaviors and sleep status on the frailty index (FI) using two-sample univariable and multivariable Mendelian randomization (MR) analyses. Genetic correlations were tested between the correlated traits. Results We identified potential causal associations between the time spent watching television (β = 0.26, 95% confidence interval [CI]: 0.21–0.31, P = 3.98e-25), sleep duration (β = -0.18, 95%CI: -0.26, -0.10; P = 6.04e-06), and daytime napping (β = 0.29, 95%CI: 0.18–0.41, P = 2.68e-07) and the FI based on the inverse-variance-weighted method. The estimates were consistent across robust and multivariate MR analyses. Linkage disequilibrium score regression detected a genetic correlation between the time spent watching television (Rg = 0.43, P = 6.46e-48), sleep duration (Rg = -0.20, P = 5.29e-10), and daytime napping (Rg = 0.25, P = 3.34e-21) and the FI. Conclusions Genetic predispositions to time spent watching television and daytime napping were positively associated with the FI, while sleep duration was negatively associated with the FI. Our findings offer key insights into factors influencing biological aging and suggest areas for interventions to promote healthy aging and slow down the aging process.

Abstract Background Thymidine analogs have long been recognized for their ability to randomly incorporate into DNA. However, the precise mechanisms through which thymidine analogs facilitate cell fate transition remains unclear. Results Here, we discovered a strong correlation between the dosage dependence of thymidine analogs and their ability to overcome reprogramming barrier. The extraembryonic endoderm (XEN) state seems to be a cell's selective response to DNA damage repair (DDR), offering a shortcut to overcome reprogramming barriers. Meanwhile, we found that homologous recombination repair (HRR) pathway causes an overall epigenetic reshaping of cells and enabling them to overcome greater barriers. This response leads to the creation of a hypomethylated environment, which facilitates the transition of cell fate in various reprogramming systems. We term this mechanism as Epigenetic Reshaping through Damage (ERD). Conclusion Overall, our study finds that BrdU/IdU can activate the DNA damage repair pathway (HRR), leading to increased histone acetylation and genome-wide DNA demethylation, regulating somatic cell reprogramming. This offers valuable insights into mechanisms underlying cell fate transition. Graphical Abstract

The experiment aimed to evaluate the effects of different ratios of Clostridium autoethanogenum protein (CAP) used in the diets on the growth performance, muscle quality, serum indexes, and mTOR pathway of white feather broilers. Four hundred and eighty 1-day-old Arbor Acres (AA) broilers, comprising equal numbers of males and females, were randomly assigned to one of four treatments, and each treatment consisted of 12 replicates of 10 birds. Four diets were formulated based on isoenergetic and isonitrogenous principles. The control group (CAP 0) did not receive any CAP, while the experimental groups received 2% (CAP 2), 3% (CAP 3), and 4% (CAP 4) of CAP for six weeks. Compared with the CAP0, (1) The feed conversion ratio (FCR) was lower (p

Legionella pneumophila strains harboring wild-type rpsL such as Lp02rpsLWT cannot replicate in mouse bone marrow-derived macrophages (BMDMs) due to induction of extensive lysosome damage and apoptosis. The bacterial factor directly responsible for inducing such cell death and the host factor involved in initiating the signaling cascade that leads to lysosome damage remain unknown. Similarly, host factors that may alleviate cell death induced by these bacterial strains have not yet been investigated. Using a genome-wide CRISPR/Cas9 screening, we identified Hmg20a and Nol9 as host factors important for restricting strain Lp02rpsLWT in BMDMs. Depletion of Hmg20a protects macrophages from infection-induced lysosomal damage and apoptosis, allowing productive bacterial replication. The restriction imposed by Hmg20a was mediated by repressing the expression of several endo-lysosomal proteins, including the small GTPase Rab7. We found that SUMOylated Rab7 is recruited to the bacterial phagosome via SulF, a Dot/Icm effector that harbors a SUMO-interacting motif (SIM). Moreover, overexpression of Rab7 rescues intracellular growth of strain Lp02rpsLWT in BMDMs. Our results establish that L. pneumophila exploits the lysosomal network for the biogenesis of its phagosome in BMDMs.

Abstract Efficient energy storage systems are crucial for the optimal utilization of renewable energy. Sodium‐ion batteries (SIBs) are considered potential substitutes for next‐generation low‐cost energy storage systems due to the low cost and abundance of sodium resources. However, the industrialization of SIBs faces a great challenge in terms of the anode. Hard carbon could be a promising anode material due to its high capacity and low cost which originates from biomass. This study used pre‐treatment and template carbonization methods to extract a hard carbon material from a large amount of discarded biomass in bamboo powder waste. This material has a good initial Coulombic efficiency of 78.6 % and good cycling stability when applied to sodium ion batteries.Typically, the optimal hard carbon material is used as the anode to prepare sodium ion battery prototypes to demonstrate their potential applications. The anode exhibited excellent sodium storage performance with a reversible capacity of 303 mAh ⋅ g−1 at 1 C rate and good cycling performance, retaining 92.0 % of its capacity after 100 cycles. These results demonstrate that BPPHC is a promising candidate for anode material in sodium‐ion batteries. This work suggests that bamboo powder could be a low‐cost anode material for SIBs.

Abstract Background Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in vitro definition fully predicts mucosal colonization in vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis. Results Germ-free inflammation-susceptible interleukin-10-deficient (Il10 −/− ) and inflammation-resistant WT mice were colonized with a consortium of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10 −/− mice. These E. coli expand in Il10 −/− mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. Conclusions Our findings establish the in vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in vivo colonization dynamics of patient-derived bacteria in murine models. Video Abstract

The age-hardening behavior and precipitation evolution of an isothermal aged Mg−5Sm−0.6Zn−0.5Zr (wt.%) alloy have been systematically investigated by means of transmission electron microscopy (TEM) and atomic-resolution high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM). The Vickers hardness of the present alloy increases first and then decreases with ageing time. The sample aged at 200 °C for 10 h exhibits a peak-hardness of 90.5 HV. In addition to the dominant β0′ precipitate (orthorhombic, a = 0.642 nm, b = 3.336 nm and c = 0.521 nm) formed on {11-20}α planes, a certain number of γ” precipitate (hexagonal, a = 0.556 nm and c = 0.431 nm) formed on basal planes are also observed in the peak-aged alloy. Significantly, the basal γ” precipitate is more thermostable than prismatic β0′ precipitate in the present alloy. β0′ precipitates gradually coarsened and were even likely to transform into β1 phase (face centered cubic, a = 0.73 nm) with the increase of ageing time, which accordingly led to a gradual decrease in number density of precipitates and finally resulted in the decreased hardness and mechanical property in the over-aged alloys.

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 (5) and AZD5099 (6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 (6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure–activity relationships of the compounds were also studied.

AbstractEpigallocatechin gallate (EGCG) is a main component in green tea extract, which possesses multiple bioactivities. The present research studied the effects of EGCG on the laying performance, egg quality, immune status, antioxidant capacity, and hepatic metabolome of Linwu laying ducks reared under high temperature. A total of 180 42-w-old healthy Linwu laying ducks were allocated into control or EGCG-treated groups. Each treatment had 6 replicates with 15 ducks in each replicate. Diets for the two groups were basal diets supplemented with 0 or 300 mg/kg EGCG, respectively. All ducks were raised in the high temperature condition (35 ± 2 °C for 6 h from 10:00 to 16:00, and 28 ± 2 °C for the other 18 h from 16:00 to 10:00 the next day) for 21 days. Results showed that EGCG increased the egg production rate (p = 0.014) and enhanced the immunocompetence by improving serum levels of immunoglobulin A (p = 0.008) and immunoglobulin G (p = 0.006). EGCG also fortified the antioxidant capacity by activating superoxide dismutase (p = 0.012), catalase (p = 0.009), and glutathione peroxidase (p = 0.021), and increasing the level of heat-shock protein 70 (p = 0.003) in laying ducks’ liver. At the same time, hepatic metabolomics result suggested that EGCG increased the concentration of several key metabolites, such as spermidine (p = 0.031), tetramethylenediamine (p = 0.009), hyoscyamine (p = 0.026), β-nicotinamide adenine dinucleotide phosphate (p = 0.038), and pantothenic acid (p = 0.010), which were involved in the metabolic pathways of glutathione metabolism, arginine and proline metabolism, β-alanine metabolism, and tropane, piperidine, and pyridine alkaloid biosynthesis. In conclusion, 300 mg/kg dietary EGCG showed protection effects on the laying ducks reared in high temperature by improving the immune and antioxidant capacities, which contributed to the increase of laying performance of ducks. The potential mechanism could be that EGCG modulate the synthesis of key metabolites and associated metabolic pathways.

AbstractContext Clerodendranthus spicatus Thunb. (Labiatae) (CS), a perennial traditional Chinese medicinal herb that can reduce serum uric acid (sUA) levels and ameliorate renal function is widely used to treat hyperuricaemic nephropathy (HN).Objective To investigate the molecular mechanism of action of CS in HN treatment using in vivo and in vitro experiments.Materials and methods Sprague-Dawley rats were randomly divided into control, HN, CS and positive control allopurinol groups. The HN group was intraperitoneally injected with 750 mg/kg oxonic acid potassium (OA), whereas the CS group was injected with OA along with a gavage of CS (low dose 3.125 g/kg, high dose 6.25 g/kg) for five weeks. For in vitro studies, uric acid-treated HK2 cells were used to verify the therapeutic mechanism of CS in HN.Results HN rats exhibit pathological phenotypes of elevated sUA levels and renal injury. CS significantly improved these symptoms and sUA (p

With the improvement of thermal efficiency and the lightweight tendency of engine blades, Ni-based superalloy is widely used owing to its excellent performance in high-temperature atmospheres. This work studied the effects of surface oxidation, internal environmental attack, and matrix damage on the failure mechanism in a thin-walled casting Ni-based superalloy at 980 °C/160 Mpa. At the edge of the fracture, the sample suffered a severe environmental attack, resulting in the oxidation-affected zone forms. However, the loss of effective bear area induced by surface damage could not be the main reason for the sample's failure. At the interior of the matrix, voids were preferably initiated at the interface of MC carbides. As the increase of creep deformation, dynamic recrystallization (DRX) occurred at the tip of the voids, which increased the transverse grain boundaries and promoted crack propagation. Moreover, the DRX provided a short penetration path for the nitrogen, causing internal nitridation with AlN and Ti(Ta)N to precipitate. EBSD analysis confirmed that nitrides induced significant dislocations to accumulate at the boundaries of nitrides/γ, accelerating the failure of the sample.

Abstract Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.

Psathyrostachys huashanica Keng (2n=2x=14, NsNs) is regarded as a valuable wild relative species for common wheat cultivar improvement because of its abundant beneficial agronomic traits. However, although the development of many wheat–P. huashanica-derived lines provides a germplasm base for the transfer of excellent traits, the lag in the identification of P. huashanica chromosomes in the wheat background has limited the study of these lines. In this study, three novel nondenaturing fluorescence in situ hybridization (ND-FISH)-positive oligo probes were developed. Among them, HS-TZ3 and HS-TZ4 could specifically hybridize with P. huashanica chromosomes, mainly in the telomere area, and HS-CHTZ5 could hybridize with the chromosomal centromere area. We sequentially constructed a P. huashanica FISH karyotype and idiogram that helped identify the homologous groups of introduced P. huashanica chromosomes. In detail, 1Ns and 2Ns had opposite signals on the short and long arms, 3Ns, 4Ns, and 7Ns had superposed two-color signals, 5Ns and 6Ns had fluorescent signals only on their short arms, and 7Ns had signals on the intercalary of the long arm. In addition, we evaluated different ways to identify alien introgression lines by using low-density single nucleotide polymorphism (SNP) arrays and recommended the SNP homozygosity rate in each chromosome as a statistical pattern. The 15K SNP array is widely applicable for addition, substitution, and translocation lines, and the 40K SNP array is the most accurate for recognizing transposed intervals between wheat and alien chromosomes. Our research provided convenient methods to distinguish the homologous group of P. huashanica chromosomes in a common wheat background based on ND-FISH and SNP arrays, which is of great significance for efficiently identifying wheat–P. huashanica-derived lines and the further application of Ns chromosomes.

The deposition of nitrogen in soil may be influenced by the presence of different nitrogen components, which may affect the accessibility of soil nitrogen and invasive plant–soil microbe interactions. This, in turn, may alter the success of invasive plants. This study aimed to clarify the influences of the invasive plant Bidens pilosa L. on the physicochemical properties, carbon and nitrogen contents, enzymatic activities, and bacterial communities in soil in comparison to the native plant Pterocypsela laciniata (Houtt.) Shih treated with simulated nitrogen deposition at 5 g nitrogen m−2 yr−1 in four forms (nitrate, ammonium, urea, and mixed nitrogen). Monocultural B. pilosa resulted in a notable increase in soil pH but a substantial decrease in the moisture, electrical conductivity, ammonium content, and the activities of polyphenol oxidase, β-xylosidase, FDA hydrolase, and sucrase in soil in comparison to the control. Co-cultivating B. pilosa and P. laciniata resulted in a notable increase in total soil organic carbon content in comparison to the control. Monocultural B. pilosa resulted in a notable decrease in soil bacterial alpha diversity in comparison to monocultural P. laciniata. Soil FDA hydrolase activity and soil bacterial alpha diversity, especially the indices of Shannon’s diversity, Simpson’s dominance, and Pielou’s evenness, exhibited a notable decline under co-cultivated B. pilosa and P. laciniata treated with nitrate in comparison to those treated with ammonium, urea, and mixed nitrogen.

Drought may facilitate the invasion process of invasive plants, mainly because invasive plants can obtain a stronger growth competitiveness than native plants under drought. It is therefore imperative to illuminate the mechanisms underlying the successful invasion of invasive plants under drought, with a particular focus on the differences in the resistance of invasive and native plants to drought. This study aimed to elucidate the differences in the resistance between the invasive plant Amaranthus spinosus L. and the native plant A. tricolor L. to drought under a gradient of drought. The resistance of co-cultivated A. spinosus to drought was significantly higher than that of co-cultivated A. tricolor under light drought. Hence, A. spinosus may obtain a stronger competitive advantage than A. spinosus under co-cultivation conditions when treated with light drought. The resistance of the two plants to drought may be predominantly influenced by their height and biomass. This present study also defines a method for evaluating the stress resistance of a given plant species to stress by calculating the stress resistance index. This present study offers a robust theoretical foundation for determining the stress resistance of a given plant species and the environmental management of A. spinosus under drought.

One of the key reasons for the success of invasive plants is the functional differences between invasive plants and native plants. However, atmospheric nitrogen deposition may disrupt the level of available nitrogen in soil and the functional differences between invasive plants and native plants, which may alter the colonization of invasive plants. Thus, there is a pressing necessity to examine the effects of atmospheric nitrogen deposition containing different nitrogen components on the functional differences between invasive plants and native plants. However, the progress made thus far in this field is not sufficiently detailed. This study aimed to elucidate the effects of artificially simulated nitrogen deposition containing different nitrogen components (i.e., nitrate, ammonium, urea, and mixed nitrogen) on the functional differences between the Asteraceae invasive plant Bidens pilosa L. and the Asteraceae native plant Pterocypsela laciniata (Houtt.) Shih. The study was conducted over a four-month period using a pot-competitive co-culture experiment. The growth performance of P. laciniata, in particular with regard to the sunlight capture capacity (55.12% lower), plant supporting capacity (45.92% lower), leaf photosynthetic area (51.24% lower), and plant growth competitiveness (79.92% lower), may be significantly inhibited under co-cultivation condition in comparison to monoculture condition. Bidens pilosa exhibited a more pronounced competitive advantage over P. laciniata, particularly in terms of the sunlight capture capacity (129.43% higher), leaf photosynthetic capacity (40.06% higher), and enzymatic defense capacity under stress to oxidative stress (956.44% higher). The application of artificially simulated nitrogen deposition was found to facilitate the growth performance of monocultural P. laciniata, particularly in terms of the sunlight capture capacity and leaf photosynthetic area. Bidens pilosa exhibited a more pronounced competitive advantage (the average value of the relative dominance index of B. pilosa is ≈ 0.8995) than P. laciniata under artificially simulated nitrogen deposition containing different nitrogen components, especially when treated with ammonium (the relative dominance index of B. pilosa is ≈ 0.9363) and mixed nitrogen (the relative dominance index of B. pilosa is ≈ 0.9328). Consequently, atmospheric nitrogen deposition, especially the increased relative proportion of ammonium in atmospheric nitrogen deposition, may facilitate the colonization of B. pilosa via a stronger competitive advantage.