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BACKGROUND: Phthalates have been reported to impair fertility in various studies. However, evidence exploring the associations between phthalate metabolites in follicular fluid (FF) and reproductive outcomes is lacking. OBJECTIVES: To investigate the associations between phthalate metabolite concentrations in FF and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes among women recruited from a fertility clinic. METHODS: We included 641 women undergoing IVF/ICSI treatment from December 2018 to January 2020. The levels of eight phthalate metabolites, including monoethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono-n- butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl- 5-oxohexyl) phthalate (MEOHP), and mono(2ethyl-5-carboxypentyl) phthalate (MECPP), were quantified in FF collected on the oocyte retrieval day. Associations between quartiles of individual phthalate metabolite concentrations and nine IVF/ICSI outcomes, including oocyte yield, mature oocyte number, two distinct pronuclei (2PN) zygote number, fertilization rate, blastocyst formation rate, implantation, clinical pregnancy, miscarriage, and live birth, were estimated with generalized linear models. The effects of phthalate mixtures on IVF/ICSI outcomes were assessed using Bayesian kernel machine regression (BKMR) models. RESULTS: After adjusting for relevant confounders, elevated quartiles of MBzP, MEHHP, and MEHP in FF were inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes (all p for trends DISCUSSION: Certain phthalate metabolites in FF are inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes among women undergoing IVF/ICSI treatment. https://doi.org/10.1289/EHP11998, Introduction Infertility, defined as inability to achieve conception after 1 y of unprotected intercourse, has emerged as a prominent global concern, impacting ~15% of couples and exhibiting a consistent growth [...]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP‐43 aggregates. Recent evidence has been indicated that phosphorylated TDP‐43 (pTDP‐43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP‐43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP‐43 detectable in routine biopsied muscles? (ii) Can detection of pTDP‐43 aggregation discriminate between ALS and non‐ALS patients? (iii) Can pTDP‐43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non‐ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP‐43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP‐43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non‐ALS controls (16/54; p < 0.001). The pTDP‐43 aggregates were mainly close to the sarcolemma. Using a semi‐quantified pTDP‐43 aggregates score, we applied a cut‐off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP‐43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof‐of‐concept for the detection of pTDP‐43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS. [ABSTRACT FROM AUTHOR]

The contamination of soil with the heavy metal cadmium (Cd) is increasingly prominent and severely threatens food security in China. Owing to its low cost, suitable efficacy, and ability to address the shortcomings of plant remediation by enhancing the ability of plants to take up Cd, plant–microbe combination remediation technology has become a research hotspot in heavy metal pollution remediation. A pot experiment was performed to examine the effects of inoculation with the plant-growth-promoting bacterium Brevibacillus sp. SR-9 on the biomass, Cd accumulation, and soil nutrients of hybrid Pennisetum. The purpose of this study was to determine how Brevibacillus sp. SR-9 alleviates stress caused by heavy metal contamination. High-throughput sequencing and metabolomics were used to determine the effects of inoculation on the soil bacterial community composition and microbial metabolic functions associated with hybrid Pennisetum. The results suggest that mutation of Brevibacillus sp. SR-9 effectively alleviates Cd pollution stress, leading to increased biomass and accumulation of Cd in hybrid Pennisetum. The aboveground biomass and the root weight increased by 12.08% and 27.03%, respectively. Additionally, the accumulation of Cd in the aboveground sections and roots increased by 21.16% and 15.50%, respectively. Measurements of the physicochemical properties of the soil revealed that the strain Brevibacillus sp. SR-9 slightly increased the levels of available phosphorus, total nitrogen, total phosphorus, and available potassium. High-throughput DNA sequencing revealed that Brevibacillus sp. SR-9 implantation modified the composition of the soil bacterial community by increasing the average number of Actinobacteria and Bacillus. The total nitrogen content of the soil was positively correlated with the Actinobacteria abundance, total phosphorus level, and available phosphorus level. Metabolomic analysis revealed that inoculation affected the abundance of soil metabolites, and 59 differentially abundant metabolites were identified (p < 0.05). Among these, 14 metabolites presented increased abundance, whereas 45 metabolites presented decreased abundance. Fourteen metabolic pathways were enriched in these metabolites: the folate resistance pathway, the ABC transporter pathway, D-glutamine and D-glutamic acid metabolism, purine metabolism, and pyrimidine metabolism. The abundance of the metabolites was positively correlated with the levels of available phosphorus, total potassium, total phosphorus, and total nitrogen. According to correlation analyses, the development of hybrid Pennisetum and the accumulation of Cd are strongly associated with differentially abundant metabolites, which also impact the abundance of certain bacterial populations. This work revealed that by altering the makeup of microbial communities and their metabolic processes, bacteria that promote plant development can mitigate the stress caused by Cd. These findings reveal the microbiological mechanisms through which these bacteria increase the ability of hybrid Pennisetum to take up the Cd present in contaminated soils. [ABSTRACT FROM AUTHOR]

Objective: To explore the possible mechanism of Yi Xin Tai Formula (YXTF) in treating heart failure (HF) by network pharmacology method and to verify the related targets by western blotting. Methods: Using the traditional Chinese medicine systems pharmacology (TCMSP) database with its analysis platform for HF as a disease model, the active ingredients of YXTF were filtered according to the oral bioavailability (OB) and drug- likeness (DL), and the corresponding targets were predicted. The disease targets of HF were retrieved by Human Phenotype Ontology (HPO) database. Then, “YXTF compounds - Targets - HF” network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, the network visualized through the Cytoscape software, and the key nodes of the network achieved according to Degree (D), Closeness Centrality (CC), and Betweenness Centrality (BC). Kyoto Encyclopedia of Genes and Genomes (KEGG) gene function enrichment analysis was carried out for the key nodes with the help of GATHER database platform. The rabbit model of HF was established by coarctation of the abdominal aorta and perfusion of propylthiouracil (PTU). The pathological changes and protein expression of transforming growth factor beta (TGF-β) protein were observed by western blotting. Results: “YXTF compounds - Targets - HF” network consisted of 403 nodes, 136 key nodes and 10 related KEGG pathways that included focal adhesions, cell cycles, mitogen-activated protein kinase (MAPK) signaling pathways, Toll-like receptor signaling pathways, Cytokine-cytokine receptor interactions, Gap junctions, adherens junctions, TGF-β signaling pathways, apoptosis and Wnt signaling pathways, respectively. The expression of TGF-β protein in myocardium decreased significantly. Conclusions: According to the network pharmacology, the treatment of YXTF for HF might be related to 10 metabolic pathways. The effects of the multicompound-multitarget-multi pathways and the synergistic effect drawn from the compounds that act as the monarch, minister, adjuvant, guide medicines were revealed through this study. Keywords: Yi Xin Tai Formula (YXTF), Heart failure (HF), Network pharmacology, Western blotting, TGF-β signal pathway

Abstract: The artificial allotetraploid of Gossypium herbaceun and G. raimondii was created in the laboratory to broaden the genetic background of cotton and provide novel materials for the germplasm innovation of cotton. In this study, fiber characters, physiological and biochemical comparison, SSR markers and floral transcriptomes analysis were conducted among three generations of the artificial allotetraploid and their parents, including G. hirsutum L. acc. TM-1. The results showed that the fiber color of artificial allotetraploid, light yellow, mid-parent of G. herbaceun and G. raimondii, and the fiber length was close to TM-1. The activities of SOD, POD, CAT, and MDA content in artificial allotetraploid plants were significantly higher than parents and TM-1, indicating that the stress resistance of artificial allotetraploid was enhanced after distant hybridization and chromosome doubling. 55 polymorphic loci were detected from 11 pairs of SSR primers, with 2--10 mutation loci per primer and an average of 5. PIC ranged from 0.498 to 0.892, with an average of 0.742. The results indicated that SSR markers could reflect rich genetic diversity information among the test materials. The complementary of parents and specific bands were amplified in S2, S3, and S4, simultaneously, indicating that chromosome segment recombination occurred in the artificial allotetraploid at the molecular level. There were 37, 19, and 20 bands of S2, S3, and S4 identical with TM-1 respectively, among which 17 bands were shared with TM-1 by all generations, indicating that the artificial allotetraploid had homology in genetic background with TM-1. The floral organ transcriptome analysis showed that there were 5653 differentially expressed genes (DEGs) between artificial allotetraploid and TM-1, in which 3062 were up-regulated and 2591 were down-regulated. GO functional analysis showed that DEGs had significant differences in photosynthesis, photosystem II, RNA directed DNA polymerase activity and other pathways. KEGG enrichment analysis showed that DEGs were more active in photosynthetic-antenna proteins, photosynthesis and isoflavone biosynthesis. The enrichment analysis of fertility related DEGs between artificial allotetraploids and TM-1 revealed that most of the DEGs of artificial allotetraploids in pollen development and recognition were down-regulated, which may be the key factor leading to low seed setting percentage of artificial allotetraploid. Three G-type lectin receptor serine/threonine protein kinases (Gh_D01G067500, Gh_D05G168100, Gh_A01G062500) were obtained from Nr annotation information by clustering. The results showed that the artificial allotetraploid performed advantage in fiber color, resistance to stress and photosynthesis, combining the excellent quality of its parents. It is expected to restore its fertility by crossbreeding with G. hirsutum, and to further cultivate a valuable novel material for production. Keywords: artificial allotetraploid; physiological and biochemical detection; SSR molecular marker; transcriptome sequencing; differentially expressed gene [ABSTRACT FROM AUTHOR]

[Display omitted] • ARF1 is upregulated in both metastatic CRC and vemurafenib-resistant CRC cells. • ARF1 promotes CRC metastasis and vemurafenib resistance by interacting with IQGAP1. • ARF1-IQGAP1 interaction induces ERK pathway reactivation in vemurafenib resistance. • LY2839219 suppresses CRC metastasis by disturbing ARF1-IQGAP1 interaction. • Combination of LY2835219 and vemurafenib is a promising strategy for CRC treatment. Acquired resistance to BRAF inhibitor vemurafenib is frequently observed in metastatic colorectal cancer (CRC), and it is a thorny issue that results in treatment failure. As adaptive responses for vemurafenib treatment, a series of cellular bypasses are response for the adaptive feedback reactivation of ERK signaling, which warrant further investigation. We identified ARF1 (ADP-ribosylation factor 1) as a novel regulator of both vemurafenib resistance and cancer metastasis, its molecular mechanism and potential inhibitor were investigated in this study. DIA-based quantitative proteomics and RNA-seq were performed to systematic analyze the profiling of vemurafenib-resistant RKO cells (RKO-VR) and highly invasive RKO cells (RKO-I8), respectively. Co‑immunoprecipitation assay was performed to detect the interaction of ARF1 and IQGAP1 (IQ-domain GTPase activating protein 1). An ELISA-based drug screen system on FDA-approved drug library was established to screen the compounds against the interaction of ARF1-IQGAP1.The biological functions of ARF1 and LY2835219 were determined by transwell, western blotting, Annexin V-FITC/PI staining and in vivo experimental metastasis assays. We found that ARF1 strongly interacted with IQGAP1 to activate ERK signaling in VR and I8 CRC cells. Deletion of IQGAP1 or inactivation of ARF1 (ARF-T48S) restored the invasive ability induced by ARF1. As ARF1-IQGAP1 interaction is essential for ERK activation, we screened LY2835219 as novel inhibitor of ARF1-IQGAP1 interaction, which inactivated ERK signaling and suppressed CRC metastasis and vemurafenib-resistance in vitro and in vivo with no observed side effect. Furthermore, LY2835219 in combined treatment with vemurafenib exerted significantly inhibitory effect on ARF1-mediated cancer metastasis than used independently. This study uncovers that ARF1-IQGAP1 interaction-mediated ERK signaling reactivation is critical for vemurafenib resistance and cancer metastasis, and that LY2835219 is a promising therapeutic agent for CRC both as a single agent and in combination with vemurafenib. [ABSTRACT FROM AUTHOR]