[Driving Factors Analyze of Phytoplankton Community by Comparison of Population and Functional Groups and Water Quality Evaluation in Dongting Lake].

Phytoplankton is the most important component of water ecosystems, which could indicate the state of the water environment owing to its sensitivity to water environment variation. However, its response to the environment is influenced by classification methods. To understand the phytoplankton population(phyla and genera) and functional groups(FG) for driving response characteristics and applicability to the environment in Dongting Lake, a total of four samples were collected from the lake from March to December 2019, and the distribution characteristics of the phytoplankton population and functional groups and their responses to environmental factors were compared and analyzed. Meanwhile, the applicability of the TLI index, Shannon-Wiener index, and Q index was compared in Dongting Lake. The results showed that a total of 61 genera belonging to six phyla of phytoplankton were detected in Dongting Lake, which could be divided into 23 functional groups and nine dominant functional groups. The succession trend of functional groups was P/MP/D(March)→MP/P/J(June)→MP/H1(September)→Y/P/MP(December). The results of hierarchical segmentation showed that the population distribution and change in phytoplankton were driven by environmental factors more than the area in Dongting Lake. The main environmental factors affecting phytoplankton population and functional groups were water temperature(WT), permanganate index, dissolved oxygen(DO), conductivity(Cond), water level(WL), and total phosphorus(TP). RDA analysis showed that phytoplankton functional groups identified phytoplankton response to environmental factors better than phytoplankton population. It was shown that using the Q index to evaluate water quality had better applicability in Dongting Lake.

Identification of Mixtures of Two Types of Body Fluids Using the Multiplex Methylation System and Random Forest Models.

OBJECTIVE: Body fluid mixtures are complex biological samples that frequently occur in crime scenes, and can provide important clues for criminal case analysis. DNA methylation assay has been applied in the identification of human body fluids, and has exhibited excellent performance in predicting single-source body fluids. The present study aims to develop a methylation SNaPshot multiplex system for body fluid identification, and accurately predict the mixture samples. In addition, the value of DNA methylation in the prediction of body fluid mixtures was further explored. METHODS: In the present study, 420 samples of body fluid mixtures and 250 samples of single body fluids were tested using an optimized multiplex methylation system. Each kind of body fluid sample presented the specific methylation profiles of the 10 markers. RESULTS: Significant differences in methylation levels were observed between the mixtures and single body fluids. For all kinds of mixtures, the Spearman's correlation analysis revealed a significantly strong correlation between the methylation levels and component proportions (1:20, 1:10, 1:5, 1:1, 5:1, 10:1 and 20:1). Two random forest classification models were trained for the prediction of mixture types and the prediction of the mixture proportion of 2 components, based on the methylation levels of 10 markers. For the mixture prediction, Model-1 presented outstanding prediction accuracy, which reached up to 99.3% in 427 training samples, and had a remarkable accuracy of 100% in 243 independent test samples. For the mixture proportion prediction, Model-2 demonstrated an excellent accuracy of 98.8% in 252 training samples, and 98.2% in 168 independent test samples. The total prediction accuracy reached 99.3% for body fluid mixtures and 98.6% for the mixture proportions. CONCLUSION: These results indicate the excellent capability and powerful value of the multiplex methylation system in the identification of forensic body fluid mixtures.

General Formulas for Calculating Commonly Used Kinship Index.

OBJECTIVES: To derive general formulas for calculating commonly used kinship index (KI). METHODS: By introducing the Kronecker symbol, the formulas used to calculate the same KI under different genotype combinations were summarized into a unified expression. RESULTS: The general formulas were successfully derived for KI in various case situations, including the paternity index, full sibling index, half sibling index, avuncular index, grandpaternity index, first-cousin index, and second-cousin index between two individuals without or with the mother being involved; grandpaternity index between grandparents and a grandchild without or with the mother being involved; half sibling index between two children with two mothers being involved; full sibling index among three children; and half sibling index among three children with no, one, or two mothers being involved. CONCLUSIONS: The general formulas given in this study simplify the calculation of KIs and facilitate fast and accurate calculation through programming.

Preclinical study of LMP1-RNAi-based anti-tumor therapy in EBV-positive nasopharyngeal carcinoma.

RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.

The therapeutic effect of transcranial direct current stimulation combined with cognitive training on patients with unilateral neglect after stroke.

BACKGROUND: Unilateral neglect (UN) is a frequent cognitive disability following a stroke. Additional research is needed to determine the most effective cognitive rehabilitation techniques. OBJECTIVE: Based on the unilateral neglect neural network, we aim to explore the effect of a new model of transcranial direct current stimulation (tDCS) combined with cognitive training on stroke patients with unilateral neglect. METHODS: Thirty stroke patients with UN after stroke were randomly divided into three groups. All patients received cognitive training for UN and transcranial direct current stimulation with an anode placed on the corresponding part of the right hemisphere for 2 weeks. Treatment group A received multi-site tDCS from the inferior parietal lobule, middle temporal gyrus to prefrontal lobe. Group B received single-site tDCS of the inferior parietal lobule. The improvement of UN symptoms was evaluated by the scores of the Deviation index and Behavioral Inattention Test conventional tests. RESULTS: All groups showed improvements in all tests, and the scores of the treatment groups were statistically significant compared with the control group. CONCLUSION: Both single-site tDCS and multi-site tDCS have therapeutic effects on UN after stroke, and the difference in the therapeutic effects of the two modes still needs to be further explored.

Discovery of Novel Benzoxaborole-Containing Streptochlorin Derivatives as Potential Antifungal Agents.

Streptochlorin is a kind of indole alkaloid derived from marine microorganisms. It is a promising lead compound due to its potent bioactivity in preventing many phytopathogens, as shown in our previous study. To explore the potential applications of this natural product, a series of novel benzoxaborole-containing streptochlorin derivatives were designed and synthesized through a one-step and catalyst-free reaction in water at room temperature. All target compounds were first screened for their antifungal profiles in vitro against six common phytopathogenic fungi. The results of bioassay revealed that most of the designed compounds exhibited more significant antifungal activities against Botrytis cinrea, Gibberella zeae, Rhizoctorzia solani, Colletotrichum lagenarium, and alternaria leaf spot under the concentration of 50 µg/mL, and this is highlighted by compounds 4i and 5f, which demonstrated impressive antifungal effects against G. zeae and R. solani, with their corresponding EC50 values 0.2983 and 0.2657 µg/mL, which are obviously better than positive control flutriafol and boscalid (5.2606 and 1.2048 µg/mL, respectively). Scanning electron microscopy on the hyphae morphology showed that compound 5b might cause mycelial abnormalities of G. zeae. 3D-QSAR studies of CoMFA and CoMSIA were carried out on 29 target compounds with antifungal activity against B. cinrea. The analysis results indicated that introducing appropriate electronegative groups at the 5-position of benzoxaborole and the 4,5-positions of the indole ring could effectively improve the anti-B. cinrea activity. Moreover, compound 5b showed good antifungal activities in vivo against Phytophthora capsici. Molecular docking was further explored to ascertain the practical value of the active compound as a potential inhibitor of LeuRS. The abovementioned results indicate that the designed benzoxaborole-containing streptochlorin derivatives could be further studied as template molecules of novel antifungal agents.

Galectin-9 Facilitates Epstein-Barr Virus Latent Infection and Lymphomagenesis in Human B Cells.

The immune regulator galectin-9 (Gal-9) is commonly involved in the regulation of cell proliferation, but with various impacts depending on the cell type. Here, we revealed that Gal-9 expression was persistently increased in Epstein-Barr virus (EBV)-infected primary B cells from the stage of early infection to the stage of mature lymphoblastoid cell lines (LCLs). This sustained upregulation paralleled that of gene sets related to cell proliferation, such as oxidative phosphorylation, cell cycle activation, and DNA replication. Knocking down or blocking Gal-9 expression obstructed the establishment of latent infection and outgrowth of EBV-infected B cells, while exogenous Gal-9 protein promoted EBV acute and latent infection and outgrowth of EBV-infected B cells at the early infection stage. Mechanically, stimulator of interferon gene (STING) activation or signal transducer and activator of transcription 3 (STAT3) inhibition impeded the outgrowth of EBV-infected B cells and promotion of Gal-9-induced lymphoblastoid cell line (LCL) transformation. Accordingly, Gal-9 expression was upregulated by forced EBV nuclear antigen 1 (EBNA1) expression in 293T cells in vitro. Clinical data showed that Gal-9 expression in B-cell lymphomas (BCLs) correlated positively with EBNA1 and disease stage. Targeting Gal-9 slowed LCL tumor growth and metastasis in xenografted immunodeficient mice. These findings highlight an oncogenic role of Gal-9 in EBV-associated BCLs, indicating that Gal-9 boosts the transformation of EBV-infected B cells. IMPORTANCE The cross talk between Epstein-Barr virus (EBV) and the host cell transcriptome assumes important roles in the oncogenesis of EBV-associated malignancies. Here, we first observed that endogenous Gal-9 expression was persistently increased along with an overturned V-type change in antivirus signaling during the immortalization of EBV-transformed B cells. Upregulation of Gal-9 promoted the outgrowth and latent infection of EBV-infected B cells, which was linked to B-cell-origin tumors by suppressing STING signaling and subsequently promoting STAT3 phosphorylation. EBV nuclear antigen EBNA1 induced Gal-9 expression and formed a positive feedback loop with Gal-9 in EBV-infected B cells. Tumor Gal-9 levels were positively correlated with disease stage and EBNA1 expression in patients with B-cell lymphomas (BCLs). Targeting Gal-9 slowed the growth and metastases of LCL tumors in immunodeficient mice. Altogether, our findings indicate that Gal-9 is involved in the lymphomagenesis of EBV-positive BCLs through cross talk with EBNA1 and STING signals.

Stamen curvature and temporal flower closure assure reproductive success in an early-spring-flowering perennial in the cold desert of Middle Asia.

Floral organ movements that ensure autonomous selfing are likely to occur in species that grow in habitats with pollinator scarcity and/or an unpredictable environment. Stamen curvature and temporal flower closure are two important floral behaviors that can influence plant pollination mode and reproductive success. However, both behaviors are rarely reported within a species, and little is known about how these two movements of floral organs ensure reproductive success in an unpredictable early spring environment with few pollinators. The aim of this study was to assess whether stamen curvature and temporal flower closure ensure successful reproduction of Leontice incerta in its cold desert habitat. Flowering phenology, floral traits, stamen curvature patterns and flower visitors were surveyed. The breeding system, capacity and timing for autonomous selfing were estimated by pollination manipulations. The timing of floral opening and closure, and benefits of temporal flower closure were determined. We found that flowering of L. incerta began in late March to early April in two populations in two years, and the yellow flowers had neither nectar nor scent. Floral visitation occurred very rarely, but bees (Colletes sp.) were potential pollinators. Fruit and seed set of open and bagged flowers did not differ significantly from that of self-pollinated or cross-pollinated flowers. However, removal of stamens significantly decreased seed set. Self-pollination occurs when the stamens curve and anthers touch the stigma autonomously, suggesting autonomous selfing assurance of seed production in this self-compatible species. Both fruit and seed set of flowers that were prevented from closing were significantly lower than those of control flowers and closed flowers treated with simulated rain treatment. Therefore, stamen curvature and temporal floral closure can ensure successful sexual reproduction of L. incerta in early spring in the cold desert, where lack of pollinators otherwise may lead to pollination failure.

Preclinical study of LMP1-RNAi-based anti-tumor therapy in EBV-positive nasopharyngeal carcinoma

RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.

miRNA-29 aggravates myocardial infarction via inhibiting the PI3K/mTOR/HIF1α/VEGF pathway.

INTRODUCTION: MI is defined by the presence of myocardial necrosis, which is caused by acute and persistent ischemia and hypoxia of the coronary artery. In recent years, its incidence rate has been on the rise in China. METHODS: GSE34198, GSE97320 and GSE141512 datasets were download for DEG analysis. KEGG pathway analysis, GO analysis, GSEA and PPI network construction were performed. Later, target genes of candidate miRNAs were predicted. Next, echocardiography was conducted to detect the effects of miR-29 on left ventricular structure and cardiac function in vivo, and H&E staining was adopted to study the effects of miR-29 on angiogenesis and fibrosis in vivo. Furthermore, Western blotting was employed to investigate the effects of miR-29 inhibition on the expressions of proteins related to the PI3K\mTOR\ HIF-1α\VEGF pathway. RESULTS: There were 162 DEGs involved in MI. GO analysis revealed that inflammatory responses, negative regulation of apoptosis and innate immune response were the main enriched biological processes. KEGG analysis manifested that DEGs were mainly enriched in the PI3K/Akt signaling pathway, and GSEA demonstrated that they were mainly enriched in the PI3K/Akt/mTOR, HIF and VEGF pathways. Moreover, target gene prediction showed that miR-29 was lowly expressed in MI. According to Masson's trichrome staining, miR-29 inhibition promoted angiogenesis, reduced fibrosis, and increased the protein expressions of p-PI3K, p-mTOR, HIF-1α, and VEGF. CONCLUSIONS: MiR-29 may play an important role in the growth and development of MI. After inhibition of miR-29, the PI3K/mTOR/HIF-1α/VEGF pathway is activated to alleviate MI.

miRNA-29a inhibits atherosclerotic plaque formation by mediating macrophage autophagy via PI3K/AKT/mTOR pathway.

BACKGROUND: miR-29a plays a vital role in AS, but the relationship between the miR-29a-targeted PI3K signaling pathway and AS remains unclear. Therefore, this study was carried out. METHODS: Gene expression profiles from the GEO database containing AS samples were analyzed. ApoE-/- mice and RAW264.7 cells were treated with miR-29a negative control (NC), miR-29a mimic and miR-29a inhibitor to establish the AS model. Then MOVAT staining, TEM, Western blotting, and immunofluorescence staining were adopted for testing target proteins. RESULTS: DEGs were identified from GSE137578, GSE132651, GSE113969, GSE43292, and GSE97210 datasets. It was found that there were targeted binding sites between miR-29a and PIK3CA. Besides, GO and KEGG analysis demonstrated that autophagy was an enriched pathway in AS. Later, PPI network was depicted, and hub genes were then determined. The results revealed that miR-29a suppressed the areas of plaques and lesional macrophages, but had no impact on VSMCs. TEM results showed the organelles pyknosis of lesional macrophages damaged morphological changes. Furthermore, miR-29a amplified the M2-like macrophages but suppressed the polarization of M1-like macrophages in atherosclerotic plaques. According to mouse and RAW 264.7 cell experiments, miR-29a significantly inhibited the protein expressions of PI3K, p-PI3K, p-AKT, and p-mTOR, which were consistent with the increased expressions of autophagy-related proteins, Beclin 1 and LC3II. However, the miR-29a suppression exhibited the contrary results. CONCLUSION: MiR-29a elevation induces the increase of autophagy by down-regulating the PI3K/AKT/mTOR pathway in the progression of AS, indicating that miR-29a is a novel therapeutic strategy for AS.

Inhibiting effect of miR-29 on proliferation and migration of uterine leiomyoma via the STAT3 signaling pathway.

AIM: Uterine leiomyoma is the most common benign tumor of female genitalia, and the incidence is rising gradually. This study explores the mechanism of miR-29 and STAT3 signaling pathways on uterine leiomyoma. METHODS: GSE64763 and GSE5244 datasets were downloaded. Enrichment analyses were performed in GSE64763. PPI network was constructed, and the significant module was identified. Uterine leiomyoma cell lines were divided into NC, miR-29 mimic, anti-NC, and miR-29 inhibitor groups. Plate clone formation and Transwell assays detected the proliferation, invasion, and migration of cells. The expression levels of STAT3, proliferation, EMT, invasion-associated proteins were determined by Western blotting. RESULTS: Differently expressed genes were mainly enriched in positive regulation of cell migration and gene expression, cell proliferation. Through GSEA, JAK-STAT is a significantly correlated enrichment pathway. A Venn diagram was drawn to identify the common miRNA (miR-29-3p). miR-29 inhibitors promoted protein expression of STAT-3, Cyclin D1, and c-Myc compared with the anti-NC control (P < 0.01), and miR-29 inhibitors promoted cell proliferation in uterine leiomyoma cells (P < 0.05). Furthermore, miR-29 inhibitors promoted the protein expression of MMP-2 and MMP-9 (P < 0.01), and EMT promoting proteins N-cadherin, snail, vimentin, and Transwell assay showed that miR-29 inhibitors promoted cell migration in uterine leiomyoma (P < 0.01). CONCLUSIONS: High expression of miR-29 could inhibit cell proliferation, invasion, and metastasis in uterine leiomyoma, which might be related to the inhibition of the STAT3 signaling pathway, and could provide a novel target for the treatment of uterine leiomyoma.

Suppression of ADAM8 attenuates angiotensin II-induced cardiac fibrosis and endothelial-mesenchymal transition via inhibiting TGF-ß1/Smad2/Smad3 pathways.

Endothelial-to-mesenchymal transition (EndMT) is involved in cardiac fibrosis induced by angiotensin II (Ang II). A disintegrin and metalloproteinase 8 (ADAM8), a member of ADAMs family, participates in cell adhesion, proteolysis and various signaling. However, its effects on the development of cardiac fibrosis remain completely unknown. This study aimed to reveal whether ADAM8 aggravates cardiac fibrosis induced by Ang II in vivo and in vitro. The C57BL/6J mice or cardiac endothelial cells were subjected to Ang II infusion to induce fibrosis. The results showed that systolic blood pressure and diastolic blood pressure were significantly increased under Ang II infusion, and ADAM8 was up-regulated. ADAM8 inhibition attenuated Ang II-induced cardiac dysfunction. ADAM8 knockdown suppressed Ang II-induced cardiac fibrosis as evidenced by the down-regulation of CTGF, collagen I, and collagen III. In addition, the endothelial marker (VE-cadherin) was decreased, whilst mesenchymal markers (α-SMA and FSP1) were increased following Ang II infusion. However, ADAM8 repression inhibited Ang II-induced EndMT. Moreover, ADAM8 silencing repressed the activation of TGF-ß1/Smad2/Smad3 pathways. Consistent with the results in vivo, we also found the inhibitory effects of ADAM8 inhibition on EndMT in vitro. All data suggest that ADAM8 promotes Ang II-induced cardiac fibrosis and EndMT via activating TGF-ß1/Smad2/Smad3 pathways.

The impact of the COVID-19 preventive measures on influenza transmission: molecular and epidemiological evidence.

OBJECTIVE: We quantify the impact of COVID-19-related control measures on the spread of human influenza virus H1N1 and H3N2. METHODS: We analyzed case numbers to estimate the end of the 2019-2020 influenza season and compared it with the median of the previous 9 seasons. In addition, we used influenza molecular data to compare within-region and between-region genetic diversity and effective population size from 2019 to 2020. Finally, we analyzed personal behavior and policy stringency data for each region. RESULTS: The 2019-2020 influenza season ended earlier than the median of the previous 9 seasons in all regions. For H1N1 and H3N2, there was an increase in between-region genetic diversity in most pairs of regions between 2019 and 2020. There was a decrease in within-region genetic diversity for 12 of 14 regions for H1N1 and 9 of 12 regions for H3N2. There was a decrease in effective population size for 10 of 13 regions for H1N1 and 3 of 7 regions for H3N2. CONCLUSIONS: We found consistent evidence of a decrease in influenza incidence after the introduction of preventive measures due to COVID-19 emergence.

Occupational Radiation Exposure and Changes in Thyroid Hormones in a Cohort of Chinese Medical Radiation Workers.

OBJECTIVE: This study aimed to evaluate the association between occupational radiation exposure and changes in thyroid hormone levels among medical radiation workers. METHODS: This retrospective cohort study included 2,946 radiation workers from 20 Guangzhou hospitals. Data on general characteristics, participant radiation dosimetry, and thyroid function test results [thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroid hormone (T4)] were extracted from dosimetry and medical records. The generalized estimating equation was used to evaluate the trend of changes in thyroid hormone levels over time and was adjusted for age, gender, and occupation. RESULTS: The average annual effective dose was very low and showed a general downward trend. During the follow-up period, changes in T3 and T4 levels among radiation workers were -0.015 [95% confidence interval ( CI) -0.018 to -0.012] nmol/L per year and -2.294 (95% CI -2.426 to -2.162) nmol/L per year, respectively. Thyroid hormone levels were significantly different between males and females. T3 levels in the group of upper quartile of dose were significantly higher than in the lower quartile group ( P = 0.006). No significant decreased trend in thyroid hormone levels was observed with increasing average effective doses. CONCLUSION: Thyroid hormone secretion might be affected even in low-dose radiation exposure environments.

Streptochlorin analogues as potential antifungal agents: Design, synthesis, antifungal activity and molecular docking study.

Streptochlorin is a small molecule of indole alkaloid isolated from marine Streptomyces sp., it is a promising lead compound due to its potent bioactivity in preventing many phytopathogens in our previous study, but further structural modifications are required to improve its antifungal activity. Our work in this paper focused on the replacement of oxazole ring in streptochlorin with the imidazole ring, to discover novel analogues. Based on this design strategy, three series of streptochlorin analogues were efficiently synthesized through sequential Vilsmeier-Haack reaction, Van Leusen imidazole synthesis and halogenation reaction. Some of the analogues displayed excellent activity in the primary assays, and this is highlighted by compounds 4g and 4i, the growth inhibition against Alternaria Leaf Spot and Rhizoctorzia solani under 50 µg/mL are 97.5% and 90.3%, respectively, even more active than those of streptochlorin, pimprinine and Osthole. Molecular docking models indicated that streptochlorin binds with Thermus thermophiles Leucyl-tRNA Synthetase in a similar mode to AN2690, offering a perspective on the mode of action study for antifungal activities of streptochlorin derivatives. Further study is still ongoing with the aim of discovering synthetic analogues, with improved antifungal activity and clear mode of action.

GPR39 promotes cardiac hypertrophy by regulating the AMPK-mTOR pathway and protein synthesis.

Hypertrophic growth of the cardiomyocytes is one of the core mechanisms underlying cardiac hypertrophy. However, the mechanism underlying cardiac hypertrophy remains not fully understood. Here we provided evidence that G protein-coupled receptor 39 (GPR39) promotes cardiac hypertrophy via inhibiting AMP-activated protein kinase (AMPK) signaling. GRP39 expression is overexpressed in hypertrophic hearts of humans and transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice. In neonatal cardiomyocytes, adenovirus-mediated overexpression of GPR39 promoted angiotensin II-induced cardiac hypertrophy, while GPR39 knockdown repressed hypertrophic response. Adeno-associated virus 9-mediated knockdown of GPR39 suppressed TAC-induced decline in fraction shortening and ejection fraction, increase in heart weight and cardiomyocyte size, as well as overexpression of hypertrophic fetal genes. A mechanism study demonstrated that GPR39 repressed the activation of AMPK to activate the mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase ß-1 (S6K1), subsequently promoted de novo protein synthesis. Inhibition of mTOR with rapamycin blocked the effects of GPR39 overexpression on protein synthesis and repressed cardiac hypertrophy. Collectively, our findings demonstrated that GPR39 promoted cardiac hypertrophy via regulating the AMPK-mTOR-S6K1 signaling pathway, and GRP39 can be targeted for the treatment of cardiac hypertrophy.

Apert syndrome: A case report of prenatal ultrasound, postmortem cranial CT, and molecular genetic analysis.

Apert syndrome is characterized by craniosynostosis, mid-facial hypoplasia, and symmetric syndactyly. Prenatal diagnosis is challenging until the skull and facial anomalies become more pronounced during the third trimester. We present a case in which typical sonographic signs of Apert syndrome were observed after 23 weeks of gestation. Following termination of the pregnancy, both clinical features such as craniofacial abnormalities and syndactyly and cranial 3D-CT images showed high correlation with the previous sonographic findings. Furthermore, genetic analysis revealed a spontaneous mutation, c.755C≥G (p.S252W), in the FGFR2 gene, with this mutation implicated in the etiology of Apert syndrome.

Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways.

T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (TExh) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a TExh phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The TExh phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genes MYC and fibroblast growth factor 11 (FGF11). Downregulation of MYC and FGF11 induces TExh differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription of FGF11 and MFN1. In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy.