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Abstract Age-related hearing loss (ARHL) or presbycusis is associated with irreversible progressive damage in the inner ear, where the sound is transduced into electrical signal; but the detailed mechanism remains unclear. Here, we sought to determine the potential molecular mechanism involved in the pathogeneses of ARHL with bioinformatics methods. A single-cell transcriptome sequencing study was performed on the cochlear samples from young and aged mice. Detection of identified cell type marker allowed us to screen 18 transcriptional clusters, including myeloid cells, epithelial cells, B cells, endothelial cells, fibroblasts, T cells, inner pillar cells, neurons, inner phalangeal cells, and red blood cells. Cell-cell communications were analyzed between young and aged cochlear tissue samples by using the latest integration algorithms Cellchat. A total of 56 differentially expressed genes were screened between the two groups. Functional enrichment analysis showed these genes were mainly involved in immune, oxidative stress, apoptosis, and metabolic processes. The expression levels of crucial genes in cochlear tissues were further verified by immunohistochemistry. Overall, this study provides new theoretical support for the development of clinical therapeutic drugs.

BackgroundPrenatal drug use may cause toxicity to bone health in newborns. We aimed to examine whether birth outcomes mediate the association between medication use and neonatal metabolic bone disease (MBD).MethodsA prospective cohort of 10,801 pregnant women (17–49 years) and their infants followed at a single center from 1 January 2012 to 31 December 2021 were included. Based on four single drugs, comprehensive medication use was determined and categorized into three groups using latent-class analysis: group 1 included antibiotics and furosemide or less than two drugs except for MgSO4; group 2 included MgSO4 without antibiotics or furosemide; and group 3 encompassed dexamethasone and antibiotics. Mediation analysis was conducted to assess the mediating effects of prematurity, low birth weight (LBW), and small for gestational age (SGA).ResultsThere were 138 (1.3%) infants with MBD; 2,701 (25%) were born preterm, 1717 (15.9%) had LBW, and 303 (2.8%) were SGA. Pregnant women in groups 2 and 3 were 2.52 to 14.66 times more likely to deliver an infant with MBD than those in group 1. Only LBW showed a significant mediating effect on the association between comprehensive medication use and MBD, with a mediation proportion of 51.8% (45.0–64.1%, p

The heterostructured Al–Mg–Si–Cu alloy profile modified by TiB2–TiC particles was prepared by conventional extrusion and solution treatment, and the coupling effect of the heterostructure and the precipitates on the mechanical properties of the alloy profile was studied in this work. The results showed that the peak-aged alloy sample has high tensile strength (385 MPa) and yield strength (366 MPa) with low elongation (4.8%), while the pre-aged sample achieves higher tensile strength (426 MPa), yield strength (401 MPa), and also the elongation (8.0%). The better comprehensive mechanical properties of the pre-aged sample were attributed to the synergistic strengthening effect of precipitation strengthening and hetero-deformation induced (HDI) stress strengthening. The fine precipitates easy to shear in pre-aged sample are more advantageous than the precipitates in peak-aged sample for the heterostructured Al alloy, because they provided precipitation strengthening by hindering the slip of dislocations and did not prevent the accumulation of geometrically necessary dislocations (GNDs) resulting in HDI strengthening and HDI strain hardening. This work provides a new strategy for promoting the comprehensive mechanical properties of age-hardenable aluminum alloy with heterogeneous structure.

Arundo donax (family: Poaceae) is a perennial rhizomatous plant with considerable economic and ecological benefits. The plant is characterized by its fast growth, high yield, wide adaptability, and strong disease resistance. However, widespread cultivation is difficult because A. donax can only be asexually propagated. This study tested the efficacy of an aqua-based culture method with short duration and high rooting rate. The aqua-based culture protocol involved treating cane fragments with the commercial broad-spectrum rooting powder ABT-1 (No. 1 of the ABT series) at 100 mg/L for 24 h, followed by culturing in tap water for 19 days. We found that plant materials sampled from September to February of the following year were more suitable for aqua-based culturing than materials sampled from other months. Nodes on different parts of the cane did not vary significantly in the ability to form seedlings. The rooting percentage reached >95% after only 20 days, while the sprouting percentage was >93%. The seedlings obtained were strong, with high survival rates during cultivation and acclimation. No strict requirements for the growing media were necessary to achieve these results. In conclusion, this study provides an empirical foundation for a technique that could facilitate the factory production of high-quality A. donax seedlings.

ABSTRACTEnterotoxigenic Escherichia coli (ETEC) is one of the major pathogens contributing to piglet diarrhea, with significant implications for both piglet health and the economic aspects of the livestock industry. SW207 is an isolate of Bacillus halotolerans isolated from the cold- and disease-resistant Leixiang pigs in Northeastern China. We have discovered that SW207 can survive in the pig’s gastrointestinal fluid and under conditions of high bile salt concentration, displaying potent antagonistic activity against ETEC. In this study, we established a weaned piglet diarrhea model infected with ETEC to investigate the role of SW207 in preventing diarrhea and improving intestinal health. Results indicate that SW207 upregulates the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1, at both the transcriptional and translational levels. Furthermore, SW207 reduces serum endotoxin, D-lactic acid, and various oxidative stress markers while enhancing piglet mechanical barrier function. In terms of immune barrier, SW207 suppressed the activation of the TLR4/MyD88/NF-κB pathway, reducing the expression of various inflammatory factors and upregulating the expression of small intestine mucosal sIgA. Concerning the biological barrier, SW207 significantly reduces the content of E. coli in the intestines and promotes the abundance of beneficial bacteria, thereby mitigating the microbiota imbalance caused by ETEC. In summary, SW207 has the potential to prevent weaned piglet diarrhea caused by ETEC, alleviate intestinal inflammation and epithelial damage, and facilitate potential beneficial changes in the intestinal microbiota. This contributes to elucidating the potential mechanisms of host-microbe interactions in preventing pathogen infections.IMPORTANCEEnterotoxigenic Escherichia coli (ETEC) has consistently been one of the significant pathogens causing mortality in weaned piglets in pig farming. The industry has traditionally relied on antibiotic administration to control ETEC-induced diarrhea. However, the overuse of antibiotics has led to the emergence of drug-resistant zoonotic bacterial pathogens, posing a threat to public health. Therefore, there is an urgent need to identify alternatives to control pathogens and reduce antibiotic usage. In this study, we assessed the protective effect of a novel probiotic in a weaned piglet model infected with ETEC and analyzed its mechanisms both in vivo and in vitro. The study results provide theoretical support and reference for implementing interventions in the gut microbiota to alleviate early weaned piglet diarrhea and improve intestinal health.

This work reports a simple method for manufacturing heterogeneous structured Al–Mg–Si–Cu alloy profile modified by TiB2–TiC particles using conventional hot extrusion and solution heat treatment. The heterogeneous structures containing different proportions of coarse grains and fine grains can be regulated by the solution treatment time, and their relationships with the mechanical properties are studied. The results show that the formation of the heterogeneous structure in the alloy is attributed to the non-uniform distribution of the TiB2–TiC particles, which have strong inhibition effects on the recrystallization in the particle-rich zone. When the proportion of coarse/fine grains in the heterostructure is about 2:1, the mechanical properties of the solution-treated alloy profile achieved a high level: tensile strength and yield strength are 345 MPa and 227 MPa, respectively, which are 35% and 53% higher than those of the as-extruded alloy with almost no loss of elongation. This work provides a strategy to advance the scalable manufacturing of heterogeneous structured Al alloy profile for various applications.

Arundo donax is widely used as an ornamental plant in landscape gardening because of its adaptability to varying degrees of waterlogged conditions. However, to date, little information is available about the adaptive mechanism of A. donax under waterlogging stress. The results showed that long-term mild waterlogging efficiently induced the formation of adventitious roots (ARs) and further promoted root aerenchyma development, and that the activity of antioxidant enzymes (SOD, POD, and CAT) in Ars also was greatly enhanced after waterlogging. At the transcriptomic level, the expression of genes related to apoptosis, the regulation of cell division, ethylene biosynthesis, alginate synthesis, auxin signaling pathways, and anaerobic respiration was mostly up-regulated after the occurrence of waterlogging stress but genes involved in the abscisic acid signaling pathways were partly down-regulated, which indicated a preferential and favorable transcriptional response in regulating adventitious root development. Taken together, this study definitely advances our knowledge of the morphological, physiological, and transcriptomic responses of A. donax under waterlogging stress and sheds new lights on its adaptive mechanisms.

Abstract Context Naru 3 pill is a traditional Mongolian medicine for the treatment of intervertebral disc degeneration (IDD), but the mechanism is not yet clear. Objective This study investigated the mechanism of Naru 3 pill in the treatment of IDD. Materials and methods Active ingredients and related targets of Naru 3 pill, as well as IDD-related genes, were collected from public databases. The analysis was performed by protein‒protein interaction network analysis, gene ontology and Kyoto Gene and Genome Encyclopedia (KEGG) functional enrichment analysis, molecular docking and molecular dynamics simulations. Finally, the network pharmacology results were validated by in vitro experiments. Results Network analysis showed that sesamin, piperine and ellagic acid were potential key components and CASP3, BAX and BCL2 were key targets. KEGG analysis indicated the apoptotic pathway as a potential pathway. Molecular docking showed that sesamin interacted better with the targets than the other components. The results of molecular dynamics simulations indicated that the three systems BAX-sesamin, BCL2-sesamin and CASP3-sesamin were stable and reasonable during the simulation. In vitro experiments showed that sesamin had the least effect on cell growth and the most pronounced proliferation-promoting effect, and so sesamin was considered the key component. The experiments confirmed that sesamin had antiapoptotic effects and reversed the expression of CASP3, BAX and BCL2 in degeneration models, which was consistent with the network pharmacology results. Furthermore, sesamin alleviated extracellular matrix (ECM) degeneration and promoted cell proliferation in the IDD model. Conclusion The present study suggested that Naru 3 pill might exert its therapeutic and antiapoptotic effects on IDD by delaying ECM degradation and promoting cell proliferation, which provides a new strategy for the treatment of IDD.

Abstract The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single‐cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)‐induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier‐related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early‐stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post‐Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2‐specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.

Severe acute pancreatitis (SAP) is a critical illness characterized by a severe systemic inflammatory response resulting in persistent multiple organ failure and sepsis. The intestinal microbiome is increasingly appreciated to play a crucial role in modulation of AP disease outcome, but limited information is available about the identity and mechanism of action for specific commensal bacteria involved in AP-associated inflammation. Here we show that Bifidobacteria, particularly B. animalis, can protect against AP by regulating pancreatic and systemic inflammation in germ-free (GF) and oral antibiotic-treated (Abx) mouse models. Colonization by B. animalis and administration of its metabolite lactate protected Abx and GF mice from AP by reducing serum amylase concentration, ameliorating pancreatic lesions and improving survival rate after retrograde injection of sodium taurocholate. B. animalis relieved macrophage-associated local and systemic inflammation of AP in a TLR4/MyD88- and NLRP3/Caspase1-dependent manner through its metabolite lactate. Supporting our findings from the mouse study, clinical AP patients exhibited a decreased fecal abundance of Bifidobacteria that was inversely correlated with the severity of systemic inflammatory responses. These results may shed light on the heterogeneity of clinical outcomes and drive the development of more efficacious therapeutic interventions for AP, and potentially for other inflammatory disorders.

Flame recognition is of great significance in fire prevention. However, current algorithms for flame detection have some problems, such as missing detection and false detection, and the detection accuracy cannot satisfy the requirements for fire prevention. In order to further the above problems, we propose a flame detection algorithm based on an improved YOLOv7 network. In our algorithm, we replace a convolution of the MP-1 module with a SimAM structure, which is a parameter-free attention mechanism. In this way, the missing detection problem can be improved. Furthermore, we use a ConvNeXt-based CNeB module to replace a convolution of the ELAN-W module for increasing detection accuracy and the false detection problem in complex environments. Finally, we evaluate the performance of our algorithm through a large number of test cases, and the data set used in our experiments was constructed by combining several publicly available data sets for various application scenarios. The experimental results indicate that compared with the original YOLOv7 algorithm, our proposed algorithm can achieve a 7% increase in the aspect of mAP_0.5 and a 4.1% increase in the aspect of F1 score.

COPD is predicted to become the third leading cause of morbidity and mortality worldwide by 2030. Cigarette smoking (active or passive) is one of its chief causes, with about 20% of cigarette smokers developing COPD from cigarette smoke (CS)-induced irreversible damage and sustained inflammation of the airway epithelium. Inflammasome activation leads to the cleavage of pro-interleukin (IL)-1β and pro-IL-18, along with the release of pro-inflammatory cytokines via gasdermin D N-terminal fragment membrane pores, which further triggers acute phase pro-inflammatory responses and concurrent pyroptosis. There is currently intense interest in the role of nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein-3 inflammasomes in chronic inflammatory lung diseases such as COPD and their potential for therapeutic targeting. Phytochemicals including polyphenols and flavonoids have phyto-medicinal benefits in CS-COPD. Here, we review published articles from the last decade regarding the known associations between inflammasome-mediated responses and ameliorations in pre-clinical manifestations of CS-COPD via polyphenol and flavonoid treatment, with a focus on the underlying mechanistic insights. This article will potentially assist the development of drugs for the prevention and therapy of COPD, particularly in cigarette smokers.

The accumulation of pollutants on the surface of a Concentrating Solar Power (CSP) station reduces the power generation efficiency of the whole power plant, affects electricity output, and decreases sales income; therefore, it is particularly important to develop a reasonable and effective cleaning process. Surface pollutants which have a strong interaction with the cleaning process of power stations can determine the quality of cleaning to a certain extent. In this paper, the pollutants on the surface of a trough CSP station with different usage times were collected and characterized using a scanning electron microscope (SEM), a particle size analyzer (PSA), and a transmission electron microscope (TEM). It was found that most of the surface pollutants were of a fine size and included amorphous particles which mainly resulted from the sedimentation of particles suspended for a short time or particles in the process of atmospheric circulation for a long time. Considering the service life of the mirror and the scarcity of water resources in the area where the trough CSP power station is located, a brush-based dry cleaning process with different cleaning times was developed. By comparing the changes in the reflectivity and micro-morphology of the mirror surface before and after cleaning, the feasibility and superiority of the brush-based dry cleaning process were fully confirmed.

With the continuous development of agricultural product e-commerce platforms and the rapid growth of trading volume, conducting in-depth mining and analysis of online review data to improve consumer satisfaction is of considerable importance. This paper uses JingDong’s self-run online reviews of rice agricultural products as the research object and analyzes the logistics factors that affect consumer satisfaction through text mining technology. A multi-objective model for logistics center distribution path optimization under a soft time window was constructed. The model used the results of online review analysis, namely, packaging integrity, delivery timeliness, and logistics cost, as the goals, and the model used ant colony algorithm (ACO) and genetic algorithm (GA) to solve the optimal distribution solution to minimize the penalty cost and transportation cost. Through examples to solve the optimal distribution vehicle number and shipping routes, in addition, a comparison of the two types of algorithm performance of the model under different node number indicated that the number of nodes affects algorithm performance. With a node number below 50, the ant ACO has high precision and a better distribution path. With a node number above 50, GA has more comprehensive performance. The average efficiency of the GA is 12.28% higher than that of ACO.

The television ratings provide an effective way to analyze the popularity of TV programs and audiences’ watching habits. Most previous studies have analyzed the ratings from a single perspective. Few efforts have integrated analysis from different perspectives and explored the reasons for changes in ratings. In this paper, we design a visual analysis system called TVseer to analyze audience ratings from three perspectives: TV channels, TV programs, and audiences. The system can help users explore the factors that affect ratings, and assist them in decisions about program productions and schedules. There are six linked views in TVseer: the channel ratings view and program ratings view show ratings change information from the perspective of TV channels and programs respectively; the overlapping program competition view and the same-type program competition view indicate the competitive relationships among programs; the audience transfer view shows how audiences are moving among different channels; the audience group view displays audience groups based on their watching behavior. Besides, we also construct case studies and expert interviews to prove our system is useful and effective.

Background: Dual antiplatelet therapy combining aspirin with a P2Y12 adenosine diphosphate receptor inhibitor is a therapeutic mainstay for acute coronary syndrome (ACS). However, the optimal choice of P2Y12 adenosine diphosphate receptor inhibitor in elderly (aged ≥65 years) patients remains controversial. We conducted a meta-analysis to compare the efficacy and safety of ticagrelor and clopidogrel in elderly patients with ACS. Methods: We comprehensively searched in Web of Science, EMBASE, PubMed, and Cochrane databases through 29th March, 2021 for eligible randomized controlled trials (RCTs) comparing the efficacy and safety of ticagrelor or clopidogrel plus aspirin in elderly patients with ACS. Four studies were included in the final analysis. A fixed effects model or random effects model was applied to analyze risk ratios (RRs) and hazard ratios (HRs) across studies, and I2 to assess heterogeneity.Results: A total number of 4429 elderly patients with ACS were included in this analysis, of whom 2170 (49.0%) patients received aspirin plus ticagrelor and 2259 (51.0%) received aspirin plus clopidogrel. The ticagrelor group showed a significant advantage over the clopidogrel group concerning all-cause mortality (HR 0.78, 95% CI 0.63–0.96, I2 = 0%; RR 0.79, 95% CI 0.66–0.95, I2 = 0%) and cardiovascular death (HR 0.71, 95% CI 0.56–0.91, I2 = 0%; RR 0.76, 95% CI 0.62–0.94, I2 = 5%) but owned a higher risk of PLATO major or minor bleeding (HR 1.46, 95% CI 1.13–1.89, I2 = 0%; RR 1.40, 95% CI 1.11–1.76, I2 = 0%). Both the groups showed no significant difference regarding major adverse cardiovascular events (MACEs) (HR 1.06, 95% CI 0.68–1.65, I2 = 77%; RR 1.04, 95% CI 0.69–1.58, I2 = 77%).Conclusion: For elderly ACS patients, aspirin plus ticagrelor reduces cardiovascular death and all-cause mortality but increases the risk of bleeding. Herein, aspirin plus ticagrelor may extend lifetime for elderly ACS patients compared with aspirin plus clopidogrel. The optimal DAPT for elderly ACS patients may be a valuable direction for future research studies.

The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease, cancer, and Alzheimer disease, among others. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models, in which AKI was induced by either the contrast agent iohexol or renal ischemia/reperfusion, KO, activation/overexpression of ALDH2 were associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation, and eliminated ROS. In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2-mediated renoprotection. In mice with iohexol-induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. In summary, our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.

Abstract Background DUOII is a multi-ovary wheat (Triticum aestivum L.) line with two or three pistils and three stamens in each floret. The multi-ovary trait of DUOII is controlled by a dominant gene, whose expression can be suppressed by the heterogeneous cytoplasm of TeZhiI (TZI), a line with the nucleus of common wheat and the cytoplasm of Aegilops. Crosses between female DUOII plants and male TZI plants resulted in multi-ovary F1s; whereas, the reciprocal crosses resulted in mono-ovary F1s. Although the multi-ovary trait is inherited as single trait controlled by a dominant allele in lines with a Triticum cytoplasm, the mechanism by which the special heterogeneous cytoplasm suppresses the expression of multi-ovary is not well understood. Results Observing the developmental process, we found that the critical stage of additional pistil primordium development was when the young spikes were 2–6 mm long. Then, we compared the quantitative proteomic profiles of 2–6 mm long young spikes obtained from the reciprocal crosses between DUOII and TZI. A total of 90 differentially expressed proteins were identified and analyzed based on their biological functions. These proteins had obvious functional pathways mainly implicated in chloroplast metabolism, nuclear and cell division, plant respiration, protein metabolism, and flower development. Importantly, we identified two key proteins, Flowering Locus K Homology Domain and PEPPER, which are known to play an essential role in the specification of pistil organ identity. By drawing relationships between the 90 differentially expressed proteins, we found that these proteins revealed a complex network which is associated with multi-ovary gene expression under heterogeneous cytoplasmic suppression. Conclusions Our proteomic analysis has identified certain differentially expressed proteins in 2–6 mm long young spikes, which was the critical stage of additional primordium development. This paper provided a universal proteomic profiling involved in the cytoplasmic suppression of wheat floral meristems; and our findings have laid a solid foundation for further mechanistic studies on the underlying mechanisms that control the heterogeneous cytoplasm-induced suppression of the nuclear multi-ovary gene in wheat.

In this article, a comprehensive parameter analysis for the polling-based medium access control protocol is executed. The theoretical expressions of the relationship between network parameters and performance including delay and energy consumption are given for the first time. The specific conclusions in this article are as follows: (1) awake duration is the parameter that has the greatest impact on delay and energy consumption. Increasing the duty cycle (awake duration) will effectively reduce the delay, but will also increase the energy consumption within a certain range; (2) increasing polling duration can reduce the delay, but it will also increase the energy consumption; and (3) more forwarding nodes cause a smaller delay, and it can save the energy with modest increase of delay by reducing the polling duration. An adaptive parameter optimization polling-based medium access control protocol is proposed to optimize network performance. In this protocol, the residual energy gets fully used to increase awake duration and polling duration, which makes the delay smaller, and the network maintains a long lifetime meanwhile. Based on the results of the analysis, the adaptive parameter optimization polling-based medium access control protocol proposed in this article reduces the delay by 22.40% and increases the energy efficiency by 23.25%.

Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using α-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and 7a and its stereoisomer 13a exhibited excellent activities against Hela cells with IC50 = 0.31 µM and IC50 = 5.19 µM, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of 7a, a small-scale virtual screen using reverse docking for HDAC isoforms (1–10) was performed and the results showed that HDAC6 was the best receptor for 7a, suggesting that HDAC6 may be a potential target for 7a. The interaction pattern analysis showed that the α-amino amide moiety of 7a coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex’s conformational stability. In this work, we identified 7a as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors.

Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds 19c (∆P50 = 45.50 mmHg) and 19t (∆P50 = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P50 = 36.40 mmHg). Preliminary safety evaluation revealed that 19c exhibited no cytotoxicity towards HEK293 and U87MG cells, while 19t was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that 19c exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that 19c was orally available.

Cytoplasmic male sterility (CMS) is a complex phenomenon in plants, rendering them unable to produce functional pollen. In general, this is caused by an abnormal or dysfunctional mitochondrial genome. In wheat, however, the systematic structural characteristics of the mitochondrial genome from the CMS line, vis-à-vis its maintainer line, are rarely reported. Here, we identified the morphological characteristics, sequenced, assembled, and characterized the complete mitogenomes of the wheat B-type CMS line (B) and its maintainer line (YS9). The morphological results indicated that the B likely undergoes binucleate microspore abortion. The B and YS9 genomes were assembled into a typical circular molecule 452,794 and 452,453 bp in length, respectively, comprising 34 protein-coding genes (PCGs), 3 ribosomal RNA genes (rRNAs), and 16 transfer RNA genes (tRNAs). The codon usage analysis revealed leucine (Leu) and serine (Ser) as the most frequently used amino acid residues in the B and YS9 mitochondrial proteins. In particular, we uncovered a specific ORF2718, whose length of 501 bp was more 30 bp than that of the atp8 gene in the B genome, which perhaps could affect normal function of ATP8. Further, the existence of SNPs at the atp6 gene is probably associated with the CMS mechanism. This study suggests that sequencing and comparing the genomic features of the B and YS9 mitogenomes provides not only an important opportunity to conduct further genomic breeding studies, but also valuable information for future evolutionary and molecular studies of CMS in wheat.

The multi-ovary trait of wheat inbred line DUOII is controlled by a dominant gene whose expression can be suppressed by the heterogeneous cytoplasm of TeZhiI (TZI), another inbred line with the nucleus of common wheat and the cytoplasm of Aegilops. DUOII (♀) × TZI (♂) shows multi-ovary trait, while TZI (♀) × DUOII (♂) shows mono-ovary. To elucidate the molecular mechanism regulating heterogeneous cytoplasmic suppression of the multi-ovary gene, we performed an untargeted metabolomic analysis of 2–6 mm young spikes of reciprocal crosses between DUOII and TZI at the critical stage of additional pistil primordium development. We identified 198 annotated differentially expressed metabolites and analyzed them according to their biological functions. The results showed that these metabolites had obvious functional pathways mainly implicated in amino acid, carbohydrate, nicotinate and nicotinamide, and purine metabolism and isoquinoline alkaloid biosynthesis. We also found that shikimate, phosphoglycolic acid, nicotinamide, guanine, and xanthine might play essential roles in cytoplasmic suppression of multi-ovary trait. Chloroplast metabolism was also implicated in the nuclear-cytoplasmic effect of the multi-ovary gene. The findings provide solid theoretical and empirical foundations for future studies elucidating the mechanisms controlling heterogeneous cytoplasmic suppression of the nuclear multi-ovary gene in wheat.

The vertical surface is a common and typical characteristic structure among Nomex honeycomb core components. However, the conventional high-speed milling and ultrasonic cutting struggle to meet the high-quality machining requirements of a vertical surface. In this study, an ultrasonic trepanning method is proposed and a special ultrasonic trepanning tool is developed, aiming to improve the machining quality of the vertical surface. The trepanning quality of the vertical surface is further studied from the aspects of dimensional error and trepanning incision quality. Based on the kinematic characteristics of ultrasonic trepanning, a theoretical model of dimensional error in trepanning is established. Meanwhile, the influence of ultrasonic vibration on the trepanning process is analyzed, and the result shows that ultrasonic vibration significantly improves the equivalent elastic constant of the honeycomb core material. The theoretical model is proposed to predict the trepanning dimensional error, which is verified by experiment. The effectiveness of the ultrasonic vibration on the incision quality is verified by several experiments, and the quantitative analysis results demonstrate that ultrasonic vibration significantly improves the trepanning quality of the vertical surface.

Chemical hybridization agent (CHA)-induced male sterility is an important tool in crop heterosis. To demonstrate that CHA-SQ-1-induced male sterility is associated with abnormal tapetal and microspore development, the cytology of CHA-SQ-1-treated plant anthers at various developmental stages was studied by light microscopy, scanning and transmission electron microscopy, in situ terminal deoxynucleotidyl transferasemediated dUTP nick end-labelling (TUNEL) assay and DAPI staining. The results indicated that the SQ-1-treated plants underwent premature tapetal programmed cell death (PCD), which was initiated at the early-uninucleate stage of microspore development and continued until the tapetal cells were completely degraded; the process of microspore development was then blocked. Microspores with low-viability (fluorescein diacetate staining) were aborted. The study suggests that premature tapetal PCD is the main cause of pollen abortion. Furthermore, it determines the starting period and a key factor in CHA-SQ-1-induced male sterility at the cell level, and provides cytological evidence to further study the mechanism between PCD and male sterility.

Objectives This study aimed to explore the cognitive development of low-risk children during early childhood for early-term births at 37 and 38 weeks of gestation compared with full term births at 39-41 weeks of gestation. Setting and participants We conducted a cross-sectional study in Shanghai, one of the largest cities in China. A total of 1444 children from singleton pregnancies born at term gestation were included in the study. Measures The cognitive outcomes of the subjects were measured using the cognitive subtest of Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) across three cities in China. We analysed the association between gestational age and cognitive development during infancy and toddler stages using multivariate linear modelling. Results The cognitive development scores for infants born at 37 gestational weeks were significantly lower than those born at 39-41 gestational weeks (β=-2.257, 95% CI -4.280 to -0.235; p<0.05) after adjusting for children's and maternal characteristics, as well as socio-economic factors. However, there were no significant differences in cognitive ability between infants born at 38 gestational weeks compared with their full-term counterparts (p>0.05). Moreover, these effects were not found in toddlers (between 17 and 48 months of age) after adjusting for the possible confounders (p>0.05). Conclusions Infants born at 37 weeks of gestation exhibited weaker cognitive ability compared with those born at 39-41 weeks of gestation. Our findings provide evidences for the close monitoring of potential developmental problems in early-term children, especially those born at 37 gestational weeks. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a global health problem characterized by excessive accumulation of fat in the liver without effect of other pathological factors including hepatitis infection and alcohol abuse. Current studies indicate that gene factors play important roles in the development of NAFLD. However, the molecular characteristics of differentially expressed genes (DEGs) and associated mechanisms with NAFLD have not been well elucidated. Using two microarray data associated with the gene expression profiling in liver tissues of NAFLD mice models, we identified and selected several common key DEGs that contributed to NAFLD. Based on bioinformatics analysis, we discovered that the DEGs were associated with a variety of biological processes, cellular components, and molecular functions and were also related to several significant pathways. Via pathway crosstalk analysis based on overlapping DEGs, we observed that the identified pathways could form large and complex crosstalk networks. Besides, large and complex protein interaction networks of DEGs were further constructed. In addition, many hub host factors with a high degree of connectivity were identified based on interaction networks. Furthermore, significant modules in interaction networks were found, and the DEGs in the identified modules were found to be enriched with distinct pathways. Taken together, these results suggest that the key DEGs, associated pathways, and modules contribute to the development of NAFLD and might be used as novel molecular targets for the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Generally, there is only one seed in each floret of the common wheat (Triticum aestivum L.). However, DUOII is a multi-ovary variety that has 2–3 pistils and 3 stamens. The genetics of DUOII are very stable; and it can set 2–3 seeds similar to mono-ovary wheat. Previously, we found that special heterogeneous cytoplasm influenced the expression of the multi-ovary gene. To study the genetics governing DUOII under the influence of special heterogeneous cytoplasm, we made a reciprocal cross between DUOII and TeZhiI, which has the nucleus of common wheat with the cytoplasm of Aegilops. By investigating the multi-ovary trait in the reciprocal cross and the F2, F3, BC1, and BC1F1 offspring, we found that the DUOII multi-ovary trait was controlled by a dominant gene, and that the special heterogeneous cytoplasm of TeZhiI suppressed the expression of this gene. In addition, the special heterogeneous cytoplasm could only suppress the expression of the heterozygous, but not homozygous, dominant multi-ovary gene, which resulted in the heterozygous dominant multi-ovary plant producing a mono-ovary phenotype, and the homozygous dominant plant producing the multi-ovary trait. The multi-ovary trait of DUOII was determined by nuclear-cytoplasm interactions and that the special heterogeneous cytoplasm of TZI could suppress the expression of the multi-ovary gene in a new particular way. Hence, the DUOII is an ideal model for further research into nuclear-cytoplasm interactions, and the genetic basis of DUOII provides a theoretical foundation for the practical application of the multi-ovary trait in hybrid wheat. [ABSTRACT FROM AUTHOR]

The present study was conducted to investigate novel methylated targets in colorectal cancer (CRC). The mRNA expression profiles of GSE32323 in 17 cancer and non-cancerous tissues from CRC patients, as well as expression profiles of 5 CRC cell lines prior and subsequent to 5-aza-2'-deoxycytidine (5-aza-dC) treatment, were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) in 5 CRC cell lines prior and subsequent to 5-aza-dC treatment were combined with the CRC-specific gene expression profiling array data. Context likelihood of relatedness algorithm was used to construct the co-expression network of CRC-specific gene expression profile. A sub-network of identified reverse-overlapped DEGs was selected and underwent Kyoto Encyclopedia of Genes and Genomes Pathway Analysis. A total of 6 reverse-overlapped DEGs were identified. This present study verified fibulin 2 (FBLN2) and protein phosphatase 1 regulatory inhibitor subunit 14A (PPP1R14A) to be downregulated in the CRC tissue sample but upregulated in CRC cell lines following 5-aza-dC treatment. The identified reverse-overlapped DEGs were enriched in tumor-associated signaling pathways, including cellular tumor antigen p53, cell cycle and NOD-like receptor (NLR) signaling pathway. A total of 2 silenced genes with abnormal methylation in CRC were identified, including FBLN2 and PPP1R14A. The reverse-overlapped DEGs were enriched in p53, cell cycle and NLR signaling pathways, indicating that reverse-overlapped DEGs, particularly FBLN2 and PPP1R14A, may be important tumor suppressors and that these reverse-overlapped DEGs are inactivated by methylation in CRC. [ABSTRACT FROM AUTHOR]

Plant male sterility has often been associated with mitochondrial dysfunction; however, the mechanism in wheat (Triticum aestivum L.) has not been elucidated. This study set out to probe the mechanism of physiological male sterility (PHYMS) induced by the chemical hybridizing agent (CHA)-SQ-1, and cytoplasmic male sterility (CMS) of wheat at the proteomic level. A total of 71 differentially expressed mitochondrial proteins were found to be involved in pollen abortion and further identified by MALDI-TOF/TOF MS (matrix-assisted laser desorption/ionization-time of light/time of light mass spectrometry). These proteins were implicated in different cellular responses and metabolic processes, with obvious functional tendencies toward the tricarboxylic acid cycle, the mitochondrial electron transport chain, protein synthesis and degradation, oxidation stress, the cell division cycle, and epigenetics. Interactions between identified proteins were demonstrated by bioinformatics analysis, enabling a more complete insight into biological pathways involved in anther abortion and pollen defects. Accordingly, a mitochondria-mediated male sterility protein network in wheat is proposed; this network was further confirmed by physiological data, RT-PCR (real-time PCR), and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assay. The results provide intriguing insights into the metabolic pathway of anther abortion induced by CHA-SQ-1 and also give useful clues to identify the crucial proteins of PHYMS and CMS in wheat. [ABSTRACT FROM AUTHOR]

The induction of wheat male fertile lines by using the chemical hybridizing agent SQ-1 (CHA-SQ-1) is an effective approach in the utilization of heterosis; however, the molecular basis of male fertility remains unknown. Wheat flag leaves are the initial receptors of CHA-SQ-1 and their membrane structure plays a vital role in response to CHA-SQ-1 stress. To investigate the response of wheat flag leaves to CHA-SQ-1 stress, we compared their quantitative proteomic profiles in the absence and presence of CHA-SQ-1. Our results indicated that wheat flag leaves suffered oxidative stress during CHA-SQ-1 treatments. Leaf O2-, H2O2, and malonaldehyde levels were significantly increased within 10 h after CHA-SQ-1 treatment, while the activities of major antioxidant enzymes such as superoxide dismutase, catalase, and guaiacol peroxidase were significantly reduced. Proteome profiles of membrane-enriched fraction showed a change in the abundance of a battery of membrane proteins involved in multiple biological processes. These variable proteins mainly impaired photosynthesis, ATP synthesis protein mechanisms and were involved in the response to stress. These results provide an explanation of the relationships between membrane proteomes and anther abortion and the practical application of CHA for hybrid breeding. [ABSTRACT FROM AUTHOR]