Mslar: Microbial synthetic lethal and rescue database.

Synthetic lethality (SL) occurs when mutations in two genes together lead to cell or organism death, while a single mutation in either gene does not have a significant impact. This concept can also be extended to three or more genes for SL. Computational and experimental methods have been developed to predict and verify SL gene pairs, especially for yeast and Escherichia coli. However, there is currently a lack of a specialized platform to collect microbial SL gene pairs. Therefore, we designed a synthetic interaction database for microbial genetics that collects 13,313 SL and 2,994 Synthetic Rescue (SR) gene pairs that are reported in the literature, as well as 86,981 putative SL pairs got through homologous transfer method in 281 bacterial genomes. Our database website provides multiple functions such as search, browse, visualization, and Blast. Based on the SL interaction data in the S. cerevisiae, we review the issue of duplications' essentiality and observed that the duplicated genes and singletons have a similar ratio of being essential when we consider both individual and SL. The Microbial Synthetic Lethal and Rescue Database (Mslar) is expected to be a useful reference resource for researchers interested in the SL and SR genes of microorganisms. Mslar is open freely to everyone and available on the web at http://guolab.whu.edu.cn/Mslar/.

[Experimental study on effects of berberine combined with 6-shogaol on intestinal inflammation and flora in mice with ulcerative colitis].

Cold-heat combination is a common method in the treatment of ulcerative colitis, which is represented by classic drug pair, Coptidis Rhizoma and Zingiberis Rhizoma.The present study explored the synergetic effects of berberine and 6-shogaol, the primary components of Coptidis Rhizoma and Zingiberis Rhizoma, respectively, on intestinal inflammation and intestinal flora in mice with ulcerative colitis to reveal the effect and mechanism of cold-heat combination in the treatment of ulcerative colitis.The ulcerative colitis model was induced by dextran sulfate sodium(DSS) in mice.The model mice were administered with berberine(100 mg·kg~(-1)), 6-shogaol(100 mg·kg~(-1)), and berberine(50 mg·kg~(-1)) combined 6-shogaol(50 mg·kg~(-1)) by gavage, once per day.After 20 days of drug administration, mouse serum, colon tissues, and feces were sampled.Hematoxylin-eosin(HE) staining was used to observe histopathological changes in colon tissues.Alcian blue/periodic acid-Schiff(AB/PAS) staining was used to observe the changes in the mucus layer of colon tissues.Enzyme-linked immunosorbent assay(ELISA) was employed to detect the serum content of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interleukin-6(IL-6).Immunohistochemical method was adopted to detect the protein expression of macrophage surface markers F4/80, mucin-2, claudin-1, and zonula occludens-1(ZO-1) in colon tissues.High-throughput Meta-amplicon library sequencing was used to detect changes in the intestinal flora of mice.The results indicated that the 6-shogaol group, the berberine group, and the combination group showed significantly relieved intestinal injury, reduced number of F4/80-labeled positive macrophages in colon tissues, increased protein expression of mucin-2, claudin-1, and ZO-1, and decreased serum le-vels of TNF-α, IL-1ß, and IL-6.Shannon, Simpson, Chao, and Ace indexes of the intestinal flora of mice in the 6-shogaol group and the combination group significantly increased, and Chao and Ace indexes in the berberine group significantly increased.As revealed by the bioinformatics analysis of intestinal flora sequencing, the relative abundance of Verrucomicrobia at the phylum, class, and order levels decreased significantly in all treatment groups after drug administration, while that of Bacillibacteria gradually increased.In the 6-shogaol group and the combination group, Akkermansia muciniphila completely disappeared, but acid-producing bacillus still existed in large quantities.As concluded, both 6-shogaol and berberine can inhibit intestinal inflammation, reduce the infiltration and activation of macrophages, relieve intestinal damage, reduce intestinal permeability, improve the structure of flora, and promote intestinal microecological balance.The combined application of berberine and 6-shogaol has a significant synergistic effect.

The combination of symphysis-fundal height and abdominal circumference as a novel predictor of macrosomia in GDM and normal pregnancy.

BACKGROUND: Macrosomia is a major adverse pregnancy outcome of gestational diabetes mellitus (GDM). Although BMI, symphysis-fundal height (SFH) and abdominal circumference (AC) are associated with foetal weight, there are some limitations to their use, especially for the prediction of macrosomia. This study aimed to identify a novel predictive methodology to improve the prediction of high-risk macrosomia. METHODS: Clinical information was collected from 3730 patients. The association between the ISFHAC (index of the SFH algorithm multiplied by the square of AC) and foetal weight was determined and validated. A new index, the ISFHAC, was evaluated by area under the curve (AUC) analysis. RESULTS: A total of 1087 GDM and 657 normal singleton pregnancies were analysed. The ISFHAC was positively correlated with foetal weight in GDM pregnancies and normal pregnancies (NPs). The AUCs of the ISFHAC were 0.815 in the GDM group and 0.804 in the NP group, which were higher than those of BMI, SFH, AC and GA. The ISFHAC cut-off points were 41.7 and 37 in the GDM and NP groups, respectively. The sensitivity values for the prediction of macrosomia with high ISFHAC values were 75.9 and 81.3% in the GDM and NP groups, respectively, which were higher than those with BMI. Regarding the validation data, the sensitivity values for prediction with high ISFHAC values were 78.9% (559 GDM pregnancies) and 78.3% (1427 NPs). CONCLUSIONS: The ISFHAC can be regarded as a new predictor of and risk factor for macrosomia in GDM pregnancy and NP.

Spectroscopic evidence for bulk-band inversion and three-dimensional massive Dirac fermions in ZrTe5.

Three-dimensional topological insulators (3D TIs) represent states of quantum matters in which surface states are protected by time-reversal symmetry and an inversion occurs between bulk conduction and valence bands. However, the bulk-band inversion, which is intimately tied to the topologically nontrivial nature of 3D Tis, has rarely been investigated by experiments. Besides, 3D massive Dirac fermions with nearly linear band dispersions were seldom observed in TIs. Recently, a van der Waals crystal, ZrTe5, was theoretically predicted to be a TI. Here, we report an infrared transmission study of a high-mobility [∼33,000 cm2/(V ⋅ s)] multilayer ZrTe5 flake at magnetic fields (B) up to 35 T. Our observation of a linear relationship between the zero-magnetic-field optical absorption and the photon energy, a bandgap of ∼10 meV and a [Formula: see text] dependence of the Landau level (LL) transition energies at low magnetic fields demonstrates 3D massive Dirac fermions with nearly linear band dispersions in this system. More importantly, the reemergence of the intra-LL transitions at magnetic fields higher than 17 T reveals the energy cross between the two zeroth LLs, which reflects the inversion between the bulk conduction and valence bands. Our results not only provide spectroscopic evidence for the TI state in ZrTe5 but also open up a new avenue for fundamental studies of Dirac fermions in van der Waals materials.

Liraglutide downregulates hepatic LDL receptor and PCSK9 expression in HepG2 cells and db/db mice through a HNF-1a dependent mechanism.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9. METHODS: At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1α) protein in HepG2 cells stimulated by liraglutide was examined using Western blot. Seven-week old db/db mice and wild type (WT) mice were administered either liraglutide (200 µg/kg) or equivoluminal saline subcutaneously, twice daily for 7 weeks. Fasting glucose level, food intake and body weight were measured every week. After the 7-week treatment, the blood was collected for lipid and PCSK9 levels detection and the liver was removed from the mice for oil red O staining, immunohistochemical analysis, immunofluorescence test and Western bolt. RESULTS: Firstly, liraglutide suppressed both PCSK9 and HNF1α expression in HepG2 cells in a time and concentration dependent manner. Secondly, liraglutide induced weight loss in WT and db/db mice, decreased serum PCSK9, glucose and lipid levels and improved hepatic accumulation in db/db but not WT mice. Thirdly, liraglutide reduced both hepatic PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1α in db/db mice but not in WT mice. CONCLUSIONS: Liraglutide suppressed PCSK9 expression through HNF1α-dependent mechanism in HepG2 cells and db/db mice, and decreased LDLR possibly via PCSK9-independent pathways in db/db mice.

Two-Dimensional Massless Dirac Fermions in Antiferromagnetic AFe_{2}As_{2} (A=Ba,Sr).

We report infrared studies of AFe_{2}As_{2} (A=Ba, Sr), two representative parent compounds of iron-arsenide superconductors, at magnetic fields (B) up to 17.5 T. Optical transitions between Landau levels (LLs) were observed in the antiferromagnetic states of these two parent compounds. Our observation of a sqrt[B] dependence of the LL transition energies, the zero-energy intercepts at B=0 T under the linear extrapolations of the transition energies and the energy ratio (∼2.4) between the observed LL transitions, combined with the linear band dispersions in two-dimensional (2D) momentum space obtained by theoretical calculations, demonstrates the existence of massless Dirac fermions in the antiferromagnet BaFe_{2}As_{2}. More importantly, the observed dominance of the zeroth-LL-related absorption features and the calculated bands with extremely weak dispersions along the momentum direction k_{z} indicate that massless Dirac fermions in BaFe_{2}As_{2} are 2D. Furthermore, we find that the total substitution of the barium atoms in BaFe_{2}As_{2} by strontium atoms not only maintains 2D massless Dirac fermions in this system, but also enhances their Fermi velocity, which supports that the Dirac points in iron-arsenide parent compounds are topologically protected.

Effect of miR-503 Down-Regulation on Growth and Invasion of Esophagus Carcinoma and Related Immune Function.

BACKGROUND MicroRNA (miR) has been proved to be an important biomarker for tumors because it can regulate occurrence, progression, invasion, and metastasis of cancer. A previous study has shown the involvement of miR-503 in multiple gastrointestinal tumors. Its detailed role and immune regulatory function in esophagus carcinoma, however, remains unknown. This study thus investigated the effect of miR-503 in regulating growth, proliferation, and invasion of esophagus cancer and its influence on cytokine secretion. MATERIAL AND METHODS Esophagus carcinoma cell line EC9706 and normal esophageal epithelial cell line HEEC were transfected with miR-503 inhibitor. MTT assay was used to quantify the cell proliferation, and a Transwell chamber was used to evaluate cell invasion. Release of cytokines, including interleukin-2 (IL-2), IL-4, IL-10, and interferon-γ (IFN-γ), was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS MiR-503 expression was significantly elevated in esophagus carcinoma cells (p<0.05). The specific inhibition of miR-503 expression remarkably suppressed proliferation and invasion of tumor cells. It can also down-regulated IL-2 and IFN-γ expression and facilitate secretion of IL-4 and IL-10 when compared to the control group (p<0.05 in all ceases). CONCLUSIONS The inhibition of miR-503 can effectively inhibit tumor progression and improve immune function, suggesting its potency as a novel drug target for esophagus cancer treatment.

ErbB4 as a potential molecular target in the treatment of esophageal squamous cell cancers.

ErbB4 is an important member of ErbB subfamily of tyrosine kinases receptor with overexpression in several tumors; however its biological role in esophageal cancer is poorly understood till date. The main objective of this study was to examine whether miRNA-140-5p could target and control ErbB4 expression at transcriptional level. The ErbB4 expressions in different cell lines were evaluated by western blotting and luciferase assay. Moreover, cell proliferation, apoptosis, and cell invasion studies were investigated using MTT, flow cytometry, and transwell assays. miRNA-140-5p remarkably downregulated the ErbB4 expression in EC9706 and TE-1A cell lines. Furthermore, miRNA-140-5p transfected cell significantly controlled the cell proliferation and enhanced the apoptosis of multiple cells. Additionally, miRNA-140-5p had marked effect on the DNA synthesis and caspase 3/7 activity in comparison to control cells. Specifically, miRNA-140-5p inhibited/repressed the cancer cell invasion and migration in a sign to have important biological role in esophageal carcinomas. Taken together, miRNA-140-5p could act as a potential molecular target in ErbB4 overexpressing ESCC cell lines paving the way for effective esophageal cancer treatment.

Human midbrain dopaminergic progenitors.

Human midbrain dopaminergic progenitors (mDAPs) are one of the most representative cell types in both basic research and clinical applications. However, there are still many challenges for the preparation and quality control of mDAPs, such as the lack of standards. Therefore, the establishment of critical quality attributes and technical specifications for mDAPs is largely needed. "Human midbrain dopaminergic progenitor" jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research, is the first guideline for human mDAPs in China. This standard specifies the technical requirements, test methods, inspection rules, instructions for usage, labelling requirements, packaging requirements, storage requirements, transportation requirements and waste disposal requirements for human mDAPs, which is applicable to the quality control for human mDAPs. It was originally released by the China Society for Cell Biology on 30 August 2022. We hope that the publication of this guideline will facilitate the institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardization of human mDAPs for clinical development and therapeutic applications.

Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer.

Accumulating evidence shows that microRNAs, functioning as either oncogenes or tumour suppressors by negatively regulating downstream target genes that are actively involved in tumour initiation and progression, may be promising biomarkers and therapy targets. Data mining through a microRNA chip database indicated that let-7c may be associated with tumour metastasis. Here, we confirmed that down-regulation of let-7c in primary cancer tissues was significantly associated with metastases, advanced TNM stages and poor survival of colorectal cancer patients. Moreover, ectopic expression of let-7c in a highly metastatic Lovo cell line remarkably suppressed cell migration and invasion in vitro by the down-regulation of K-RAS, MMP11 and PBX3, as well as tumour growth and metastases in vivo, whereas inhibition of let-7c in low-metastatic HT29 cells increased cell motility and invasion by the enhanced gene expression of K-RAS, MMP11 and PBX3. Interestingly, the luciferase reporters' activities with the 3'-UTRs of K-RAS, MMP11 and PBX3 were inhibited significantly by let-7c. Importantly, rescue experiments involving the over-expression of these genes without their 3'-UTRs completely reversed the effects of let-7c on tumour metastasis, both in vitro and in vivo. Finally, the levels of let-7c were inversely correlated with those of MMP11 and PBX3, but not with those of K-RAS. Taken together, these results demonstrate that let-7c, apart from its tumour growth suppression role, also functions as a tumour metastasis suppressor in colorectal cancer by directly destabilizing the mRNAs of MMP11 and PBX3 at least.