Gene regulatory networks involved in flowering time and photoperiodic responses in legumes remain unknown. Although the major maturity gene E1 has been successfully deciphered in soybean, knowledge on the functional conservation of this gene is limited to a certain extent to E1 homologs in legumes. The ectopic expression of Phvul.009G204600 (PvE1L), an E1 homolog from common bean, delayed the onset of flowering in soybean. By contrast, the ectopic expression of Medtr2g058520 (MtE1L) from Medicago truncatula did not affect the flowering of soybean. Characterization of the late-flowering mte1l mutant indicated that MtE1L promoted flowering in Medicago truncatula. Moreover, all transgenic E1, PvE1L and MtE1L soybean lines exhibited phenotypic changes in terms of plant height. Transgenic E1 or PvE1L plants were taller than the wild-type, whereas transgenic MtE1L plants produced dwarf phenotype with few nodes and short internode. Thus, functional conservation and diversification of E1 family genes from legumes in the regulation of flowering and plant growth may be associated with lineage specification and genomic duplication.

α-Farnesene is a volatile sesquiterpene synthesized by the plant mevalonate (MVA) pathway through the action of α-farnesene synthase. The α-farnesene synthase 1 (MdAFS1) gene was isolated from apple peel (var. white winter pearmain), and transformed into tobacco (Nicotiana tabacum NC89). The transgenic plants had faster stem elongation during vegetative growth and earlier flowering than wild type (WT). Our studies focused on the transgenic tobacco phenotype.

The spore germination rate and growth characteristics were compared between the citric acid high-yield strain Aspergillus niger CGMCC 5751 and A. niger ATCC 1015 in media containing antimycin A or DNP. We inferred that differences in citric acid yield might be due to differences in energy metabolism between these strains. To explore the impact of energy metabolism on citric acid production, the changes in intracellular ATP, NADH and NADH/NAD+ were measured at various fermentation stages. In addition, the effects of antimycin A or DNP on energy metabolism and citric acid production was investigated by CGMCC 5751.

A major function of T helper (Th) 17 cells is to induce the production of factors that activate and mobilize neutrophils. Although Th17 cells have been implicated in the pathogenesis of multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE), little attention has been focused on the role of granulocytes in those disorders. We show that neutrophils, as well as monocytes, expand in the bone marrow and accumulate in the circulation before the clinical onset of EAE, in response to systemic up-regulation of granulocyte colony-stimulating factor (G-CSF) and the ELR(+) CXC chemokine CXCL1. Neutrophils comprised a relatively high percentage of leukocytes infiltrating the central nervous system (CNS) early in disease development. G-CSF receptor deficiency and CXCL1 blockade suppressed myeloid cell accumulation in the blood and ameliorated the clinical course of mice that were injected with myelin-reactive Th17 cells. In relapsing MS patients, plasma levels of CXCL5, another ELR(+) CXC chemokine, were elevated during acute lesion formation. Systemic expression of CXCL1, CXCL5, and neutrophil elastase correlated with measures of MS lesion burden and clinical disability. Based on these results, we advocate that neutrophil-related molecules be further investigated as novel biomarkers and therapeutic targets in MS.

Adhesion is an important virulence factor of Vibrio alginolyticus. This factor may be affected by environmental conditions; however, its molecular mechanism remains unclear. In our previous research, adhesion deficient strains were obtained by culturing V. alginolyticus under stresses including Cu, Pb, Hg, and low pH. With RNA-seq and bioinformatics analysis, we found that all of these stress treatments significantly affected the flagellar assembly pathway, which may play an important role in V. alginolyticus adhesion. Therefore, we hypothesized that the environmental stresses of the flagellar assembly pathway may be one way in which environmental conditions affect adhesion. To verify our hypothesis, a bioinformatics analysis, QPCR, RNAi, in vitro adhesion assay and motility assay were performed. Our results indicated that (1) the flagellar assembly pathway was sensitive to environmental stresses, (2) the flagellar assembly pathway played an important role in V. alginolyticus adhesion, and (3) motility is not the only way in which the flagellar assembly pathway affects adhesion.

The silk gland of Bombyx mori (BmSG) has gained significant attention by dint of superior synthesis and secretion of proteins. However, the application of BmSG bioreactor is still a controversial issue because of low yields of recombinant proteins. Here, a 3057 bp full-length coding sequence of Hpl was designed and transformed into the silkworm genome, and then the mutant (Hpl/Hpl) with specific expression of Hpl in posterior BmSG (BmPSG) was obtained. In the mutants, the transcription level of Fib-L and P25, and corresponding encoding proteins, did not decrease. However, the mRNA level of Fib-H was reduced by 71.1%, and Fib-H protein in the secreted fibroin was decreased from 91.86% to 71.01%. The mRNA level of Hpl was 0.73% and 0.74% of Fib-H and Fib-L, respectively, while HPL protein accounted for 18.85% of fibroin and 15.46% of the total amount of secreted silk protein. The exogenous protein was therefore very efficiently translated and secreted. Further analysis of differentially expressed gene (DEG) was carried out in the BmPSG cells and 891 DEGs were detected, of which 208 genes were related to protein metabolism. Reduced expression of endogenous silk proteins in the BmPSG could effectively improve the production efficiency of recombinant exogenous proteins.

Certain probiotic bacteria have been shown to reduce distension-dependent gut pain, but the mechanisms involved remain obscure. Live luminal Lactobacillus reuteri (DSM 17938) and its conditioned medium dose dependently reduced jejunal spinal nerve firing evoked by distension or capsaicin, and 80% of this response was blocked by a specific TRPV1 channel antagonist or in TRPV1 knockout mice. The specificity of DSM action on TRPV1 was further confirmed by its inhibition of capsaicin-induced intracellular calcium increases in dorsal root ganglion neurons. Another lactobacillus with ability to reduce gut pain did not modify this response. Prior feeding of rats with DSM inhibited the bradycardia induced by painful gastric distension. These results offer a system for the screening of new and improved candidate bacteria that may be useful as novel therapeutic adjuncts in gut pain. Certain bacteria exert visceral antinociceptive activity, but the mechanisms involved are not determined. Lactobacillus reuteri DSM 17938 was examined since it may be antinociceptive in children. Since transient receptor potential vanilloid 1 (TRPV1) channel activity may mediate nociceptive signals, we hypothesized that TRPV1 current is inhibited by DSM. We tested this by examining the effect of DSM on the firing frequency of spinal nerve fibres in murine jejunal mesenteric nerve bundles following serosal application of capsaicin. We also measured the effects of DSM on capsaicin-evoked increase in intracellular Ca(2+) or ionic current in dorsal root ganglion (DRG) neurons. Furthermore, we tested the in vivo antinociceptive effects of oral DSM on gastric distension in rats. Live DSM reduced the response of capsaicin- and distension-evoked firing of spinal nerve action potentials (238 ± 27.5% vs. 129 ± 17%). DSM also reduced the capsaicin-evoked TRPV1 ionic current in DRG neuronal primary culture from 83 ± 11% to 41 ± 8% of the initial response to capsaicin only. Another lactobacillus (Lactobacillus rhamnosus JB-1) with known visceral anti-nociceptive activity did not have these effects. DSM also inhibited capsaicin-evoked Ca(2+) increase in DRG neurons; an increase in Ca(2+) fluorescence intensity ratio of 2.36 ± 0.31 evoked by capsaicin was reduced to 1.25 ± 0.04. DSM releasable products (conditioned medium) mimicked DSM inhibition of capsaicin-evoked excitability. The TRPV1 antagonist 6-iodonordihydrocapsaicin or the use of TRPV1 knock-out mice revealed that TRPV1 channels mediate about 80% of the inhibitory effect of DSM on mesenteric nerve response to high intensity gut distension. Finally, feeding with DSM inhibited perception in rats of painful gastric distension. Our results identify a specific target channel for a probiotic with potential therapeutic properties.

Tumor cell mediated immune-suppression remains a question of interest in tumor biology. In this study, we focused on the metabolites that are released by prostate cancer cells (PCC), which could potentially attenuate T cell immunity.

Modern Latin American populations were formed via genetic admixture among ancestral source populations from Africa, the Americas and Europe. We are interested in studying how combinations of genetic ancestry in admixed Latin American populations may impact genomic determinants of health and disease. For this study, we characterized the impact of ancestry and admixture on genetic variants that underlie health- and disease-related phenotypes in population genomic samples from Colombia, Mexico, Peru, and Puerto Rico.

Despite several studies being conducted to examine the associations between the NUDT15 R139C polymorphism and thiopurine-induced leukopenia in the Asian population, the results remain inconsistent. This meta-analysis determined the risk of thiopurine-induced leukopenia conferred by the NUDT15 R139C polymorphism.

Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown.

Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor-β1 (TGF-β1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF-β1 signalling is a promising therapeutic strategy for muscle-wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane-bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF-β subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF-β1 signalling.

Periodontitis is the most prevalent inflammatory disease of the periodontium, and is related to oral and systemic health. Exosomes are emerging as non-invasive biomarker for liquid biopsy. We here evaluated the levels of programmed death-ligand 1 (PD-L1) mRNA in salivary exosomes from patients with periodontitis and non-periodontitis controls. The purposes of this study were to establish a procedure for isolation and detection of mRNA in exosomes from saliva of periodontitis patients, to characterize the level of salivary exosomal PD-L1, and to illustrate its clinical relevance. Bioinformatics analysis suggested that periodontitis was associated with an inflammation gene expression signature, that PD-L1 expression positively correlated with inflammation in periodontitis based on gene set enrichment analysis (GSEA) and that PD-L1 expression was remarkably elevated in periodontitis patients versus control subjects. Exosomal RNAs were successfully isolated from saliva of 61 patients and 30 controls and were subjected to qRT-PCR. Levels of PD-L1 mRNA in salivary exosomes were higher in periodontitis patients than controls (P < 0.01). Salivary exosomal PD-L1 mRNA showed significant difference between the stages of periodontitis. In summary, the protocols for isolating and detecting exosomal RNA from saliva of periodontitis patients were, for the first time, characterized. The current study suggests that assay of exosomes-based PD-L1 mRNA in saliva has potential to distinguish periodontitis from the healthy, and the levels correlate with the severity/stage of periodontitis.

Protein S-glutathionylation is an important reversible post-translational modification implicated in redox signaling. Oxidative modifications to protein thiols can alter the activity of metabolic enzymes, transcription factors, kinases, phosphatases, and the function of contractile proteins. However, the extent to which muscle contraction induces oxidative modifications in redox sensitive thiols is not known. The purpose of this study was to determine the targets of S-glutathionylation redox signaling following fatiguing contractions. Anesthetized adult male CB6F1 (BALB/cBy × C57BL/6) mice were subjected to acute fatiguing contractions for 15 min using in vivo stimulations. The right (stimulated) and left (unstimulated) gastrocnemius muscleswere collected 60 min after the last stimulation and processed for redox proteomics assay of S-glutathionylation. Using selective reduction with a glutaredoxin enzyme cocktail and resin-assisted enrichment technique, we quantified the levels of site-specific protein S-glutathionylation at rest and following fatiguing contractions. Redox proteomics revealed over 2200 sites of S-glutathionylation modifications, of which 1290 were significantly increased after fatiguing contractions. Muscle contraction leads to the greatest increase in S-glutathionylation in the mitochondria (1.03%) and the smallest increase in the nucleus (0.47%). Regulatory cysteines were significantly S-glutathionylated on mitochondrial complex I and II, GAPDH, MDH1, ACO2, and mitochondrial complex V among others. Similarly, S-glutathionylation of RYR1, SERCA1, titin, and troponin I2 are known to regulate muscle contractility and were significantly S-glutathionylated after just 15 min of fatiguing contractions. The largest fold changes (> 1.6) in the S-glutathionylated proteome after fatigue occurred on signaling proteins such as 14-3-3 protein gamma and MAP2K4, as well as proteins like SERCA1, and NDUV2 of mitochondrial complex I, at previously unknown glutathionylation sites. These findings highlight the important role of redox control over muscle physiology, metabolism, and the exercise adaptive response. This study lays the groundwork for future investigation into the altered exercise adaptation associated with chronic conditions, such as sarcopenia.

BACKGROUND The Notch signaling pathway has been reported to play a pivotal role in tumorigenesis. Emerging evidence has demonstrated that the Notch signaling pathway regulates several cellular processes. The present study investigated the effect of the Notch signaling pathway on cell growth, invasiveness, and drug resistance, as well as epithelial-mesenchymal transition (EMT), of cervical cancer cells. MATERIAL AND METHODS We used quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis to measure the expression level of Notch2. CCK-8, clonality, wound healing, and Transwell assays were used to evaluate the effect of γ-secretase inhibitor (GSI) RO4929097 on cervical cancer cell lines HeLa and Caski. To explore the role of the Notch signaling pathway in EMT, the epithelial and mesenchymal markers were detected by qRT-PCR and Western blot after cervical cancer cell lines were treated with GSI RO4929097. RESULTS The expression of Notch2 was found to increase in cervical cancer cell lines compared with the normal immortalized human cervical epithelial cells. GSI RO4929097 was confirmed to inhibit the Notch signaling pathway and impaired the proliferation, drug resistance, migration, and invasion abilities of cervical cancer cells. The protein expression levels of the mesenchymal biomarkers Snail, Twist, and neural cadherin (N-cadherin) decreased; however, the expression of the epithelial biomarker epithelial cadherin (E-cadherin) increased in the cervical cancer cells treated with GSI RO4929097. CONCLUSIONS Notch signaling pathway plays an important role in the development and progression of cervical cancer. Blockade of the Notch pathway using GSI RO4929097 inhibited cell growth and reduced chemoresistance, invasion, metastasis, and EMT in cervical cancer cells.

MicroRNAs (miRNAs) are important regulators of tumor formation, progression and metastasis. The present study characterized a novel miRNA (miR)-888, as a potent oncomiR in human colorectal cancer (CRC). The clinicopathological investigation on 126 cases of CRC patients demonstrated that the expression level of miR-888 was significantly upregulated in tumors compared with adjacent healthy tissue, and was associated with tumor stage and histological differentiation. A Kaplan-Meier analysis and log-rank test demonstrated that CRC patients with increased miR-888 expression exhibited a decreased overall survival (OS) and disease-free survival (DFS) compared with patients with low miR-888 expression. Further univariate and multivariate analyses identified miR-888 as an independent prognostic factor for poor survival outcome in CRC patients. To determine the biological role of miR-888 in human CRC, in vitro Cell Counting kit-8, wound healing and transwell assays were performed and demonstrated that miR-888 contributed greatly to CRC cell proliferation, invasion and metastasis. Furthermore, potential targets of miR-888 were investigated using a luciferase reporter assay, followed by polymerase chain reaction and western blot analysis. The findings revealed that miR-888 directly bound to the 3'-untranslated region of mothers against decapentaplegic-4 and thus inhibited its expression and promoted the tumor growth factor-1-induced cancer metastasis signaling. The results of the present study identified miR-888 as an oncogenic miRNA in CRC and provide a foundation for promising research in the future regarding this predictive and prognostic biomarker.

Monoacylglycerol lipase (MAGL), a critical lipolytic enzyme, has emerged as a key regulator of tumor progression, yet its biological function and clinical significance in hepatocellular carcinoma (HCC) is still unknown.

Generating functional hepatocyte-like cells (HLCs) from mesenchymal stem cells (MSCs) is of great urgency for bio-artificial liver support system (BALSS). Previously, we obtained HLCs from human umbilical cord-derived MSCs by overexpressing seven microRNAs (HLC-7) and characterized their liver functions in vitro and in vivo. Here, we aimed to screen out the optimal miRNA candidates for hepatic differentiation. We sequentially removed individual miRNAs from the pool and examined the effect of transfection with remainder using RT-PCR, periodic acid-Schiff (PAS) staining and low-density lipoprotein (LDL) uptake assays and by assessing their function in liver injury models. Surprisingly, miR-30a and miR-1290 were dispensable for hepatic differentiation. The remaining five miRNAs (miR-122, miR-148a, miR-424, miR-542-5p and miR-1246) are essential for this process, because omitting any one from the five-miRNA combination prevented hepatic trans-differentiation. We found that HLCs trans-differentiated from five microRNAs (HLC-5) expressed high level of hepatic markers and functioned similar to hepatocytes. Intravenous transplantation of HLC-5 into nude mice with CCl4 -induced fulminant liver failure and acute liver injury not only improved serum parameters and their liver histology, but also improved survival rate of mice in severe hepatic failure. These data indicated that HLC-5 functioned similar to HLC-7 in vitro and in vivo, which have been shown to resemble hepatocytes. Instead of using seven-miRNA combination, a simplified five-miRNA combination can be used to obtain functional HLCs in only 7 days. Our study demonstrated an optimized and efficient method for generating functional MSC-derived HLCs that may serve as an attractive cell alternative for BALSS.

Objectives: Binocular rivalry is a typical example of bistable perception that arises when two monocular images are simultaneously presented to each eye. Binocular rivalry is a heritable perceptual cognitive function that is impaired in patients with schizophrenia (SZ). Despite its potential suitability as a visual endophenotype, binocular rivalry has hardly been studied in the unaffected siblings of schizophrenia (SIB). There is also little research about whether binocular rivalry is a potential visual endophenotype between SZ and SIB. Methods: In our cross-sectional study, we included 40 SZ and their unaffected SIBs, as well as 40 age- and sex-matched healthy controls (HC). All subjects underwent the binocular rivalry test, the Positive and Negative Syndrome Scale (PANSS) and a battery of cognitive neuropsychological assessments evaluating attention, memory and executive function domains. Results: Our results demonstrate that the switching rate in SZ was significantly slower than in HC (p < 0.001), and compared to the SIB, the mean alternation rates were significantly different (p < 0.01). Moreover, there was a significant difference in mean switching rate between the SIB and the HC (p < 0.001). There was no significant correlation between the alternation rate of binocular rivalry and these cognitive tasks and the PANSS scores. Conclusion: The present study shows that SZ and SIB both exhibit changes in binocular rivalry, with SIB exhibiting intermediate performance compared with that of SZ and the HC. This supports the claim that the switching rate for SZ differs from that of SIB and suggests that binocular rivalry may qualify as a visual endophenotype for SZ.

Triple‑negative breast cancer (TNBC) is a type of breast cancer that is characterized by the lack of expression of estrogen and progesterone receptors, and epidermal growth factor receptor 2. Therefore, there is an absence of a specific target for effective therapy in TNBC. Cisplatin is usually employed as a first‑line chemotherapy agent for patients with TNBC. However, resistance remains an obstacle for cisplatin‑based chemotherapy, due to its elusive underlying mechanism. Previously, abnormal expression of Islet 1 (ISL1) was demonstrated to be closely associated with cancer development and progression. The present study revealed that (ISL1) was significantly upregulated in TNBC tissues in comparison with adjacent normal tissues. Overexpression of ISL1 markedly promoted the proliferation and invasion of the TNBC MDA‑MB‑231 and MDA‑MB‑468 cell lines, while knockdown of ISL1 inhibited cell invasion and proliferation in these cell lines. In addition, overexpression of ISL1 reversed cisplatin‑induced cell apoptosis, while knockdown of ISL1 enhanced apoptosis following cisplatin treatment in MDA‑MB‑231 and MDA‑MB‑468 cells. Furthermore, the levels of the anti‑apoptotic proteins, phosphorylated‑protein kinase B and B‑cell lymphoma‑2 (Bcl‑2), were significantly decreased, while the levels of the pro‑apoptotic protein Bcl‑2‑associated X protein were remarkably increased in response to cisplatin treatment. The present study revealed that ISL1 overexpression reversed the protein expression profile of p‑Akt, Bcl‑2 and Bax, while ISL1 knockdown promoted cell apoptosis. Therefore, the data of the present study demonstrated that ISL1 contributes to TNBC progression and reverses cell sensitivity towards cisplatin in TNBC cells, suggesting that ISL1 is a potential therapeutic target for the treatment of TNBC.