Calcium-sensing receptor and NF-κB pathways in TN breast cancer contribute to cancer-induced cardiomyocyte damage via activating neutrophil extracellular traps formation.

Cardiovascular disorders are commonly prevalent in cancer patients, yet the mechanistic link between them remains poorly understood. Because neutrophil extracellular traps (NETs) have implications not just in cardiovascular diseases (CVD), but also in breast cancer (BC), it was hypothesized to contribute to CVD in the context of oncogenesis. We established a mouse model using nude mice to simulate liver metastasis of triple-negative BC (TNBC) through the injection of MDA-MB-231 cells. Multiple imaging and analysis techniques were employed to assess the cardiac function and structure, including echocardiography, HE staining, Masson staining, and transmission electron microscopy (TEM). MDA-MB-231 cells underwent treatment with a CaSR inhibitor, CaSR agonist, and NF-κB channel blocker. The phosphorylation of NF-κB channel protein p65 and the expression and secretion of IL-8 were assessed using qRT-PCR, Western Blot, and ELISA, respectively. In addition, MDA-MB-231 cells were co-cultured with polymorphonuclear neutrophils (PMN) under varying conditions. The co-localization of PMN extracellular myeloperoxidase (MPO) and DNA were observed by cellular immunofluorescence staining to identify the formation of NETs. Then, the cardiomyocytes were co-cultured with the above medium that contains NETs or not, respectively; the effects of NETs on cardiomyocytes apoptosis were perceived by flow cytometry. The ultrastructural changes of myocardial cells were perceived by TEM, and ELISA detected the levels of myocardial enzyme (LDH, MDA and SOD). Overall, according to our research, CaSR has been found to have a regulatory role in IL-8 secretion in MDA-MB-231 cells, as well as in the formation of NETs by PMN cells. These findings suggest CaSR-mediated stimulation in PMN can lead to increased NETs formation and subsequently to cytotoxicity in cardiomyocytes, which potentially via activation of the NF-κB signaling cascade of BC cell.

Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis.

p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other's expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2-p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2-p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.

Polarization-mismatching transmissive metasurface for independent amplitude and phase control of circular polarization.

This work presents a strategy for independent control of the amplitude and phase of transmissive circular-polarization (CP) waves. The designed meta-atom consists of an elliptical-polarization receiver and a CP transmitter. By changing the axial ratio (AR) and polarization of the receiver, amplitude modulation can be realized based on polarization mismatching theory, with negligible cumbrous components. While by rotating the element, a full phase coverage enabled by the geometric phase is achieved. Subsequently, a CP transmitarray antenna (TA) with high gain and low side-lobe level (SLL) is implemented to experimentally validate our strategy, and the tested results match well with the simulated ones. During the operating band from 9.6 to 10.4 GHz, the proposed TA obtains an average SLL of -24.5 dB, a lowest SLL of -27.7 dB at 9.9 GHz, and a maximum gain of 19 dBi at 10.3 GHz, with the measured AR lower than 1 dB, which mainly benefits from high polarization purity (HPP) of the proposed elements. The proposed strategy for full amplitude-phase manipulation of CP waves together with HPP paves a way for complicated field manipulations and indicates a promising candidate in antenna applications, such as anti-jamming systems and wireless communications.

Combining genome-wide association study based on low-coverage whole genome sequencing and transcriptome analysis to reveal the key candidate genes affecting meat color in pigs.

Meat color is an attractive trait that influences consumers' purchase decisions at the point of sale. To decipher the genetic basis of meat color traits, we performed a genome-wide association study based on low-coverage whole-genome sequencing. In total, 669 (Pietrain × Duroc) × (Landrace × Yorkshire) pigs were genotyped using low-coverage whole-genome sequencing. Single nucleotide polymorphism (SNP) calling and genotype imputation were performed using the BaseVar + STITCH channel. Six individuals with an average depth of 12.05× whole-genome resequencing were randomly selected to assess the accuracy of imputation. Heritability evaluation and genome-wide association study for meat color traits were conducted. Functional enrichment analysis of the candidate genes from genome-wide association study and integration analysis with our previous transcriptome data were conducted. The imputation accuracy parameters, allele frequency R2 , concordance rate, and dosage R2 were 0.959, 0.952, and 0.933, respectively. The heritability values of a*45 min , b*45 min , L*45 min , C*, and H0 were 0.19, 0.11, 0.06, 0.16, and 0.26, respectively. In total, 3884 significant SNPs and 15 QTL, corresponding to 382 genes, were associated with meat color traits. Functional enrichment analysis revealed that 10 genes were the potential candidates for regulating meat color. Moreover, integration analysis revealed that DMRT2, EFNA5, FGF10, and COL11A2 were the most promising candidates affecting meat color. In summary, this study provides new insights into the molecular basis of meat color traits, and provides a new theoretical basis for the molecular breeding of meat color traits in pigs.

Genome-wide association study reveals new QTL and functional candidate genes for the number of ribs and carcass length in pigs.

The number of ribs (NR) and carcass length (CL) are important economic traits in pig breeding programs. Pigs with a higher NR and longer CL produce greater pork yields. In the present study, Suhuai pigs with NR and CL phenotypes were genotyped using the Neogen® GGP Porcine 80 K SNP array to identify the QTL affecting NR and CL and dissect the candidate genes for the two traits. The SNP-chip data was imputed to the whole-genome sequence (iWGS) to increase the probability of identifying causal variants. Through genome-wide association studies (GWAS) based on both chip and iWGS data, significant SNPs were detected on Sus scrofa chromosome (SSC) 1, SSC4 and SSC7 for NR and on SSC5, SSC16 and SSC17 for CL. Moreover, two SNPs (H3GA0022644 and WU_10.2_7_103460706) on SSC7 detected in chip-based GWAS were significantly associated with both NR and CL. Through Bayes fine mapping, one reported QTL for NR on SSC7 and two reported QTL for CL on SSC17 were verified, and two new QTL (SSC1: 14.05-15.84 Mb and SSC4: 64.83-66.59 Mb) affecting NR and two new QTL (SSC5: 58.31-59.84 Mb and SSC16: 22.98-23.43 Mb) affecting CL were detected. According to the biological functions of genes, MTHFD1L on SSC1 and SULF1 on SSC4 are novel functional candidate genes for NR, and EMP1 on SSC5 and EGFLAM on SSC16 are novel functional candidate genes for CL. Overall, our findings provide a basis for identifying new causal genes and mutations affecting NR and CL.

The protective role of HMGB1 in affecting the balance between autophagy and pyroptosis to maintain neutrophils homeostasis during ß-glucan-induced mice lung inflammation.

Fungal contamination is omnipresent, and inhalation of fungi-contaminated organic dust leads to hypersensitivity pneumonitis (HP), in which neutrophils played a pivotal role. Existing studies have suggested that cell homeostasis is crucial for the pathogenesis of the inflammatory disease. Although HMGB1 has been shown to contribute to suppressing HP, there is a lack of studies on its mechanisms, especially the regulation of neutrophil homeostasis. This study aims to investigate how HMGB1 regulates neutrophil function by affecting neutrophil homeostasis, and then affects lung inflammation induced by ß-glucan, the exposure marker of fungi. Our results showed that deficient HMGB1 led to neutrophil death by disrupting the balance between autophagy and pyroptosis after ß-glucan treatment. And HMGB1 deficiency exacerbated the ß-glucan-induced lung inflammation and neutrophil dysfunction both in vivo and in vitro. Furthermore, HMGB1 contributed to remodeling neutrophil function by restricting autophagy and aggravating pyroptosis ß-glucan exposure. Our funding suggested that HMGB1 deficiency could break the balance between autophagy and pyroptosis towards pyroptosis to cause neutrophil dysfunction during the exacerbated inflammatory response, which provides insights into the pathogenesis of HP and the potential biological targets for its treatment. DATA AVAILABILITY: The datasets used during the current study are available from the corresponding author on reasonable request.

Protective Effect of Baicalin on Chlorpyrifos-Induced Liver Injury and Its Mechanism.

Chlorpyrifos (CPF) plays a vital role in the control of various pests in agriculture and household life, even though some studies have indicated that CPF residues pose a significant risk to human health. Baicalin (BA) is a flavonoid drug with an obvious effect on the prevention and treatment of liver diseases. In this study, the protective effect of BA in vitro and in vivo was investigated by establishing a CPF-induced AML12 cell damage model and a CPF-induced Kunming female mouse liver injury model. The AML12 cell damage model indicated that BA had a good positive regulatory effect on various inflammatory factors, redox indexes, and abnormal apoptosis factors induced by CPF. The liver injury model of female mice in Kunming showed that BA significantly improved the liver function indexes, inflammatory response, and fibrosis of mice. In addition, BA alleviated CPF-induced AML12 cell damage and Kunming female mouse liver injury by enhancing autophagy and regulating apoptosis pathways through Western blotting. Collectively, these data suggest that the potential mechanism of BA is a multi-target and multi-channel treatment for chlorpyrifos-induced liver injury.

WDR63 inhibits Arp2/3-dependent actin polymerization and mediates the function of p53 in suppressing metastasis.

Accumulating evidence suggests that p53 plays a suppressive role in cancer metastasis, yet the underlying mechanism remains largely unclear. Regulation of actin dynamics is essential for the control of cell migration, which is an important step in metastasis. The Arp2/3 complex is a major nucleation factor to initiate branched actin polymerization that drives cell migration. However, it is unknown whether p53 could suppress metastasis through modulating Arp2/3 function. Here, we report that WDR63 is transcriptionally upregulated by p53. We show with migration assays and mouse xenograft models that WDR63 negatively regulates cell migration, invasion, and metastasis downstream of p53. Mechanistically, WDR63 interacts with the Arp2/3 complex and inhibits Arp2/3-mediated actin polymerization. Furthermore, WDR63 overexpression is sufficient to dampen the increase in cell migration, invasion, and metastasis induced by p53 depletion. Together, these findings suggest that WDR63 is an important player in the regulation of Arp2/3 function and also implicate WDR63 as a critical mediator of p53 in suppressing metastasis.

Discovery of 3, 6-disubstituted isobenzofuran-1(3H)-ones as novel inhibitors of monoamine oxidases.

Monoamine oxidases A and B (MAO-A and MAO-B) play important roles in biogenic amine metabolism, oxidative stress, and chronic inflammation. Particularly, MAO-B selective inhibitors are promising therapeutic choices for the treatment of neurodegenerative diseases, such as Pakinson's disease and Alzheimer's disease. Herein, novel 3,6-disubstituted isobenzofuran-1(3H)-ones were designed, synthesized and evaluated in vitro as inhibitors of monoamine oxidases A and B. Structure-activity relationships were investigated, and all of the compounds with (R)-3-hydroxy pyrrolidine moiety on the 6-position displayed preferable inhibition toward the MAO-B isoform. Among them, compounds 6c with a 4'-fluorobenzyl ring and 6m bearing a 3',4'-difluorobenzyl ring on the 3-position were the most potent MAO-B inhibitors with IC50 values of 0.35 µM and 0.32 µM, respectively. The binding mode of compound 6m in MAO-B was predicted by CDOCKER program, revealing that (R)-3-hydroxypyrrolidine moiety is a critical structural feature for this series of MAO-B inhibitors. Compound 6m could serve as a new template structure for developing potent and selective MAO-B inhibitors.

Phylogeny of the HO family in cyprinus carpio and the response of the HO-1 gene to adding Bacillus coagulans in feed under Cd2+ stress.

The heavy metal cadmium (Cd2+) is an environmental pollutant that poses serious health hazards. Due to the increasing contamination of aquatic systems with Cd2+, the increased accumulation of Cd2+ in fish has become a food safety and public health concern. Heme oxygenase (HO) is an important antioxidant enzyme that plays a key role in defending the body against oxidative damage, but little research has been done in common carp. In this study, 6 HO genes were identified in the common carp genome database. Comparative genomics analysis showed considerable expansion of the HO genes and verified the four-round whole genome duplication (WGD) event in common carp. Phylogenetic analysis revealed that all HO genes of common carp were clustered into orthologous groups, indicating high conservation during evolution. In addition, the tissue distribution results showed that most HO genes had extensive tissue distribution and showed tissue-specific expression patterns. Exposure to 0.5 mg/L Cd2+ significantly reduced the expression of TGF-ß and IL-10 in common carp, which may indicate that Cd2+ exposure can destroy the physical barrier function of the intestine, inhibit intestinal immune defense and induce intestinal inflammation. To find a suitable concentration of Bacillus coagulans that could activate HO-1 genes and the immunity of the organism, we investigated the changes in HO-1 gene expression levels in the intestinal tract of common carp under Cd2+ stress at 30 days and 60 days by adding different concentrations of B. coagulans to the feed. Compared with the Cd2+ stress group without supplementation, the expression levels of the HO-1 gene in the gut of three different concentrations of B. coagulans were almost increased. And B. coagulans with L2 concentrations had better activation effect on the HO-1 gene. Similarly, compared to the Cd2+ stressed group, adding B. coagulans to the diet can almost cause the early upregulation of IL-10 and TGF-ß genes. Therefore, the addition of appropriate concentrations of B. coagulans may be a good way to activate HO-1, IL-10, and TGF-ß genes, reduce oxidative damage, and encourage the immune.

Correction: Eight RGS and RGS-like Proteins Orchestrate Growth, Differentiation, and Pathogenicity of Magnaporthe oryzae.

[This corrects the article DOI: 10.1371/journal.ppat.1002450.].

Ultra-broadband transmissive gradient metasurface based on the topologically coding optimization method.

Metasurfaces have provided a novel way on modulating the wavefront of electromagnetic (EM) waves, where phase modulating is an important method to control EM waves. Normally, phase can be continuously modulated by changing the size of a meta-atom. For a broadband device, it is essential that phase changes linearly varying against frequency within a wide frequency interval, which is quite difficult to design, especially for the transmissive scheme. In this paper, we propose a 0-1 coding method by using genetic algorithm (GA) to realize broadband linear transmission phase and high transmission amplitude against frequency. To verify the method, a beam bending metasurface is designed based on array of six meta-atoms with step gap of 60°. Simulation and experimental results show that the metasurface deflector achieves perfect beam refraction from 8 to 12 GHz, which is consistent with theoretical calculations. Moreover, the working efficiency is kept at about 75%, with the variation of the frequency, which demonstrates the good stability of the metasurface. This method offers a new insight into the designing of broadband devices.

HMGB1 could restrict 1,3-ß-glucan induced mice lung inflammation by affecting Beclin1 and Bcl2 interaction and promoting the autophagy of epithelial cells.

Fungi were microorganisms that are ubiquitous in a variety of environments. Inhalation of fungi-contaminated organic dust led to hypersensitivity pneumonitis and might eventually cause irreversible pulmonary fibrosis. Studies showed that maintaining the homeostasis of epithelial cells was vital for defending the exogenous fungi invasion. HMGB1-dependent autophagy played a critical role in maintaining cell homeostasis in multiple inflammatory diseases. However, the actual role of HMGB1-dependent autophagy in hypersensitivity pneumonitis was unclear. In our study, mice were exposed to 0.3 mg/50 µL 1,3-ß-glucan solution by intratracheal instillation to set up the lung inflammation model. To investigate the role of HMGB1-dependent autophagy in 1,3-ß-glucan induced lung inflammation, AAV-sh-HMGB1 was intratracheally injected to silence HMGB1 in the lung. Our finding suggested that silencing HMGB1 could aggravate the 1,3-ß-glucan induced lung inflammation by inhibiting the autophagy of epithelial cells. And ubiquitination of Beclin1 contributed to decreasing the interaction of Beclin1 and Bcl2, which might be a key regulatory mechanism of HMGB1 on 1,3-ß-glucan induced autophagy.

Organocatalytic Asymmetric [2 + 4] Cycloadditions of 3-Vinylindoles with ortho-Quinone Methides.

Catalytic asymmetric [2 + 4] cycloadditions of 3-vinylindoles with ortho-quinone methides and their precursors were carried out in the presence of chiral phosphoric acid to afford a series of indole-containing chroman derivatives with structural diversity in overall high yields (up to 98%), good diastereoselectivities (up to 93:7 dr) and moderate to excellent enantioselectivities (up to 98% ee). This approach not only enriches the chemistry of catalytic asymmetric cycloadditions involving 3-vinylindoles but is also useful for synthesizing chiral chroman derivatives.

The genetic architecture of heterochrony as a quantitative trait: lessons from a computational model.

Heterochrony is known as a developmental change in the timing or rate of ontogenetic events across phylogenetic lineages. It is a key concept synthesizing development into ecology and evolution to explore the mechanisms of how developmental processes impact on phenotypic novelties. A number of molecular experiments using contrasting organisms in developmental timing have identified specific genes involved in heterochronic variation. Beyond these classic approaches that can only identify single genes or pathways, quantitative models derived from current next-generation sequencing data serve as a more powerful tool to precisely capture heterochronic variation and systematically map a complete set of genes that contribute to heterochronic processes. In this opinion note, we discuss a computational framework of genetic mapping that can characterize heterochronic quantitative trait loci that determine the pattern and process of development. We propose a unifying model that charts the genetic architecture of heterochrony that perceives and responds to environmental perturbations and evolves over geologic time. The new model may potentially enhance our understanding of the adaptive value of heterochrony and its evolutionary origins, providing a useful context for designing new organisms that can best use future resources.

Ultra-thin and high-efficiency full-space Pancharatnam-Berry metasurface.

Full-space metasurfaces (MSs) attract significant attention in the field of electromagnetic (EM) wave manipulation due to their advantages of functionality integration, spatial integration and wide applications in modern communication systems. However, almost all reported full-space metasurfaces are realized by multilayer dielectric cascaded structures, which not only has the disadvantages of high cost and complex fabrication but also is inconvenient to device integration. Thus, it is of great interest to achieve high-efficiency full-space metasurfaces through simple design and easy fabrication procedures. Here, we propose a full-space MS that can efficiently manipulate the circularly polarized (CP) waves in dual frequency bands by only using a single substrate layer, the reflection and transmission properties can be independently controlled by rotating the optimized meta-structures on the metasurface. Our full-space metasurface has the potential to design multifunctional devices. To prove the concept, we fabricate the device and measured it in microwave chamber. For the reflection mode, our metasurface can behave as a CP beam splitter at the frequency of f1 = 8.3 GHz and exhibit high efficiencies in the range of 84.1%-84.9%. For the transmission mode, our metasurface acts as a meta-lens at the frequency of f2 = 12.8 GHz for the LCP incidence, and the measured relative efficiency of the meta-lens reaches about 82.7%. Our findings provide an alternative way to design full-space metasurfaces and yield many applications in EM integration systems.

Dual-band transmissive circular polarization generator with high angular stability.

Metasurfaces (MSs) offer us an efficient way to control electromagnetic wave polarization due to its capability of flexible wave manipulation and compact configurations. However, the design of dual-band polarization conversion MS with high angular stability is still a challenge, especially in transmission geometry. Here, we propose a dual-band linear-to-circular (LTC) polarization conversion MS with high angular stability by using an array of multi-resonance meta-atoms. The meta-atom consists of two outer double split-ring layers and a central bar layer with circle-slot and can realize circular polarization at two bands with high efficiency and angular stability. The MS can transform the x-polarized wave into right-hand circular polarization (RHCP) at lower band and left-hand circular polarization (LHCP) at higher band and an opposite role for the y-polarized wave. The results show that the MS operates with insertion loss less than 0.5 dB and 0.3 dB and axial ratio below 3 dB in the frequency range of 9.05-9.65 GHz and 12.55-13.1 GHz, respectively. Moreover, our MS is insensitive to the oblique incident waves and can operate at high performance with the incident angle less than 55°. The proposed MS provides a new avenue to design meta-devices with dual frequency property and also high angular stability.

ARTP mutation and adaptive laboratory evolution improve probiotic performance of Bacillus coagulans.

Bacillus coagulans is a thermophilic, facultative anaerobic, spore-forming Gram-positive bacterium, which is used as a probiotic in animal feed and human dietary supplements. In the present study, a bile-resistant thermophilic B. coagulans WT-03 strain was isolated and genetically identified. Atmospheric pressure room temperature plasma (ARTP)-induced mutation combined with adaptive laboratory evolution (ALE) was used to improve the probiotic performance of B. coagulans WT-03. After 15 s of ARTP mutation and 40 days of ALE culture, a mutant artp-aleBC15 was obtained and showed the improved tolerance to pH 2.5 and 0.3% bile salt with a survival rate of 22.4%. Further studies showed that the artp-aleBC15 mutant exhibited a relatively stable morphology, lower permeability, and higher hydrophobicity of cell membrane compared with the parent strain of B. coagulans. Additionally, artp-aleBC15 could maintain homeostasis with an intracellular pH of over 4.5 and had the altered contents of saturated fatty acids/unsaturated fatty acids in the cell membrane at pH 2.5. Our study proved that ARTP mutation combined with ALE is an efficient mutagenesis strategy to improve the probiotic performance of B. coagulans for potential industrial use.Key Points• A B. coagulans strain that can grow at 80 °C and 0.3% bile salt was screened.• ARTP combined with ALE effectively mutated B. coagulans WT-03.• B. coagulans artp-aleBC15 mutant showed an improved probiotic performance.• The mutant exhibited the lower permeability and altered fatty acid contents in the cell membrane.

Research on the Forward and Reverse Calculation Based on the Adaptive Zero-Velocity Interval Adjustment for the Foot-Mounted Inertial Pedestrian-Positioning System.

Pedestrian-positioning technology based on the foot-mounted micro inertial measurement unit (MIMU) plays an important role in the field of indoor navigation and has received extensive attention in recent years. However, the positioning accuracy of the inertial-based pedestrian-positioning method is rapidly reduced because of the relatively low measurement accuracy of the measurement sensor. The zero-velocity update (ZUPT) is an error correction method which was proposed to solve the cumulative error because, on a regular basis, the foot is stationary during the ordinary gait; this is intended to reduce the position error growth of the system. However, the traditional ZUPT has poor performance because the time of foot touchdown is short when the pedestrians move faster, which decreases the positioning accuracy. Considering these problems, a forward and reverse calculation method based on the adaptive zero-velocity interval adjustment for the foot-mounted MIMU location method is proposed in this paper. To solve the inaccuracy of the zero-velocity interval detector during fast pedestrian movement where the contact time of the foot on the ground is short, an adaptive zero-velocity interval detection algorithm based on fuzzy logic reasoning is presented in this paper. In addition, to improve the effectiveness of the ZUPT algorithm, forward and reverse multiple solutions are presented. Finally, with the basic principles and derivation process of this method, the MTi-G710 produced by the XSENS company is used to complete the test. The experimental results verify the correctness and applicability of the proposed method.