FoxO induces pupal diapause by decreasing TGFß signaling.

Diapause is a form of dormancy used widely by insects to survive adverse seasons. Previous studies have demonstrated that forkhead box O (FoxO) is activated during pupal diapause initiation in the moth Helicoverpa armigera. However, it is unclear how FoxO induces diapause. Here, we show that knockout of FoxO causes H. armigera diapause-destined pupae to channel into nondiapause, indicating that FoxO is a master regulator that induces insect diapause. FoxO activates the ubiquitin-proteasome system (UPS) by promoting ubiquitin c (Ubc) expression via directly binding to the Ubc promoter. Activated UPS decreases transforming growth factor beta (TGFß) receptor signaling via ubiquitination to block developmental signaling to induce diapause. This study significantly advances the understanding of insect diapause by uncovering the detailed molecular mechanism of FoxO.

Activation of protein arginine methyltransferase 1 and subsequent extension of moth lifespan is effected by the ROS/JNK/CREB signaling axis.

Previous studies have demonstrated that high physiological levels of reactive oxygen species induce pupal diapause and extend lifespan in the moth Helicoverpa armigera. This has been shown to occur via protein arginine methyltransferase 1 (PRMT1) blockade of Akt-mediated phosphorylation of the transcription factor FoxO, after which activated FoxO promotes the initiation of diapause. However, it is unclear how PRMT1 is activated upstream of FoxO activity. Here, we show that high reactive oxygen species levels in the brains of H. armigera diapause-destined pupae activate the expression of c-Jun N-terminal kinase, which subsequently activates the transcription factor cAMP-response element binding protein. We show that cAMP-response element binding protein then directly binds to the PRMT1 promoter and upregulates its expression to prevent Akt-mediated FoxO phosphorylation and downstream FoxO nuclear localization. This novel finding that c-Jun N-terminal kinase promotes FoxO nuclear localization in a PRMT1-dependent manner to regulate pupal diapause reveals a complex regulatory mechanism in extending the healthspan of H. armigera.

Visible-Light-Promoted Radical Cascade Cyclization of 2-Vinyl Benzimidazoles: Access to Benzo[4,5]imidazo[1,2-b]isoquinolin- 11(6H)-ones.

A visible-light-enabled photoredox radical cascade cyclization of 2-vinyl benzimidazole derivatives is developed. This chemistry is applicable to a wide range of N-aroyl 2-vinyl benzimidazoles as acceptors, and halo compounds, including alkyl halides, acyl chlorides and sulfonyl chlorides, as radical precursors. The Langlois reagent also serves as an effective partner in this photocatalytic oxidative cascade process. This protocol provides a robust alternative for rendering highly functionalized benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones.

Enantioselective Benzylation and Allylation of a Crucial Synthon of 3-Amino Oxindole Schiff Base Promoted by a Cinchonidinium Phase Transfer Catalyst to Enable the Effective Preparation of Chiral Quaternary 3-Amino Oxindoles.

3-Amino oxindole Schiff base has been used as an efficient and crucial synthon for highly enantioselective benzylation and allylation with benzyl bromides and allyl bromides in the presence of a 1,3-bis[O(9)-allylcinchonidinium-N-methyl]-2-fluorobenzene dibromide phase transfer catalyst under mild reaction conditions. A broad series of chiral quaternary 3-amino oxindoles were smoothly obtained in good to excellent yields with excellent enantioselectivities (up to 98% ee) with broad substrate generality. A typical scale-up preparation and subsequent Ullman coupling reaction were also smoothly performed, and a special and important chiral spirooxindole benzofuzed pyrrol scaffold with potential pharmaceutical and organocatalytic activities was successfully obtained.

Organocatalytic enantioselective aza-Friedel-Crafts reaction between benzothiazolimines and 2-naphthols for the preparation of chiral 2'-aminobenzothiazolomethyl naphthols.

A bifunctional cinchona squaramide catalyzed enantioselective aza-Friedel-Crafts reaction between 2-naphthols and benzothiazolimines has been developed, and a series of chiral 2'-aminobenzothiazolomethyl naphthols with potential antiproliferative and anthelmintic activities have been successfully and effectively prepared in good to excellent yields (up to 98%) with excellent enantioselectivities (up to >99% ee) even in a scale-up preparation under mild conditions.

The association of baseline N-terminal pro-B-type natriuretic peptide with short and long-term prognosis following percutaneous coronary intervention in non-ST segment elevation acute coronary syndrome with multivessel coronary artery disease: a retrospective cohort study.

BACKGROUND: Several studies have shown that N-terminal pro-B-type natriuretic peptide (NT-proBNP) is strongly correlated with the complexity of coronary artery disease and the prognosis of patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS), However, it remains unclear about the prognostic value of NT-proBNP in patients with NSTE-ACS and multivessel coronary artery disease (MCAD) undergoing percutaneous coronary intervention (PCI). Therefore, this study aimed to reveal the relationship between NT-proBNP levels and the prognosis for NSTE-ACS patients with MCAD undergoing successful PCI. METHODS: This study enrolled 1022 consecutive NSTE-ACS patients with MCAD from January 2010 to December 2014. The information of NT-proBNP levels was available from these patients. The primary outcome was in-hospital all-cause death. In addition, the 3-year follow-up all-cause death was also ascertained. RESULTS: A total of 12 (1.2%) deaths were reported during hospitalization. The 4th quartile group of NT-proBNP (> 1287 pg/ml) showed the highest in-hospital all-cause death rate (4.3%) (P < 0.001). Besides, logistic analyses revealed that the increasing NT-proBNP level was robustly associated with an increased risk of in-hospital all-cause death (adjusted odds ratio (OR): 2.86, 95% confidence interval (CI) = 1.16-7.03, P = 0.022). NT-proBNP was able to predict the in-hospital all-cause death (area under the curve (AUC) = 0.888, 95% CI = 0.834-0.941, P < 0.001; cutoff: 1568 pg/ml). Moreover, as revealed by cumulative event analyses, a higher NT-proBNP level was significantly related to a higher long-term all-cause death rate compared with a lower NT-proBNP level (P < 0.0001). CONCLUSIONS: The increasing NT-proBNP level is significantly associated with the increased risks of in-hospital and long-term all-cause deaths among NSTE-ACS patients with MCAD undergoing PCI. Typically, NT-proBN P > 1568 pg/ml is related to the all-cause and in-hospital deaths.

NF-κB induces miR-148a to sustain TGF-ß/Smad signaling activation in glioblastoma.

BACKGROUND: Inflammatory cytokines and transforming growth factor-ß (TGF-ß) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-ß signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-ß signaling. METHODS: We determined NF-κB and TGF-ß/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase-associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice. RESULTS: QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-ß/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-ß/Smad signaling in a cohort of human glioblastoma specimens. CONCLUSIONS: These findings uncover a plausible mechanism for NF-κB-sustained TGF-ß/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer.

Esophageal intraepithelial invasion of Helicobacter pylori correlates with atypical hyperplasia.

Helicobacter pylori (H. pylori), a common pathogen residing in the gastrointestinal tract, has been well characterized in stomach cancer,while its correlation with esophageal cancer remains poorly understood. In this study, we aim to assess the relationship between esophageal intraepithelial H. pylori invasion and inflammation as well as atypical hyperplasia in esophageal squamous epithelial tissues. Esophageal squamous cell carcinoma (ESCC) tissue samples from 196 individuals from both southern and northern esophageal carcinoma high-risk areas in China were examined (125 from northern high-risk areas, 71 from southern high-risk area), while additional 30 samples were collected adjacent to the esophageal squamous cell carcinoma (A-ESCC). H. pylori infection was identified by Giemsa staining, immuno-histochemical staining, and H. pylori 16S rRNA-based PCR. A significant increase of H. pylori infection was found in tumor tissues (including ESCC and A-ESCC samples) compared to that of non-tumor tissues (p < 0.05). The positive rate of H. pylori 16S rRNA in ESCC, A-ESCC, and normal groups were 62.5, 74.1, and 26.7%, respectively. The PCR results showed that the positive incidence of the H. pylori virulence factor CagA gene in tumor (ESCC and A-ESCC) and normal groups was 54.9 and 20%, respectively (p < 0.05). To explore the possible causes of CagA+ H. pylori infection leading to carcinogenesis, we found that CagA+ H. pylori filtrate induced DNA strand breaks in esophageal epithelial NE3 cells, suggesting that H. pylori infection may be an original cause leading to atypical hyperplasia of esophageal squamous epithelial tissues and contributed to pathological carcinogenesis of ESCC.

[Correlation of methylation of CpG island in cystathionine beta synthase promoter and clinicopathological features in colorectal cancer].

OBJECTIVE: To explore the association between methylation of cystathionine-beta-synthase (CBS) promoter and clinicopathological features in colorectal cancer. METHODS: Bisulfate sequencing PCR, real-time RT-PCR, and immunohistochemistry were used to investigate the methylation of CpG island in CBS promoter of 95 sporadic colorectal cancers. Software SPSS PASW Statistics was used to analyze the data of the hypermethylation levels in the malignant tissues and the correlation with pathological parameters and clinical outcome. RESULTS: Methylation levels in tumor tissue of patients [(64.9 ± 14.3)%]with colorectal cancer were significantly higher than that in normal tissues[(27.5 ± 13.1)%, P < 0.001]. The CBS mRNA levels in the hypomethylation group (7.22 ± 1.91) were significantly higher than that in the hypermethylation group (2.78 ± 1.12, P < 0.01). Univariate analysis showed that age, pT stage, pN stage, liver metastases, pTNM stage, and CBS hypermethylation level significantly correlated with the survival and recurrence rates of colorectal cancer patients (All P < 0.05). Multivariate analysis showed that CBS hypermethylation level and liver metastasis were independent factors significantly correlated with the recurrence rate and overall survival of the patients (All P < 0.05). CONCLUSIONS: Our study indicates that methylation of CpG island in CBS promoter is correlated with the occurrence and progression of colorectal cancer and plays a role in its tumorigenesis. It might serve as a useful marker for early diagnosis, targeted therapy and prediction of prognosis in colorectal cancer.

[An epidemiological study of food intolerance in 2434 children].

OBJECTIVE: To investigate the epidemiological characteristics of intolerance to 14 foods in children and the relationship between food intolerance and disease of various systems. METHODS: Serum samples of 2434 children with diseases were collected for food intolerance testing between January 2009 and October 2012. Allergen-specific IgG antibodies to 14 foods were detected using enzyme-linked immunosorbent assay. The children's intolerance to different foods and its relationship with age, sex and disease of various systems were analyzed. RESULTS: Among these children, positive rates of intolerance to milk and eggs were as high as 74.16% and 66.47% respectively, while positive rates of intolerance to chicken and pork were relatively low (0.29% and 0.21% respectively). The overall positive rates of food intolerance were 12.579% and 12.470% in males and females respectively. For infants, the highest intolerance rate was to milk; for preschool and school-age children, the highest intolerance rates were to milk and eggs respectively; for children in adolescence, the highest intolerance rate was to eggs. Among children with food intolerance involving single system, those with developmental abnormality or immune system disease had the highest overall positive rate of food intolerance. Children with double-system diseases had an overall positive rate of food intolerance as high as 13.393%. Among the children involving various systems, the positive rate of intolerance to milk and eggs were higher than other food. CONCLUSIONS: Factors influencing food intolerance in children include food categories and age. There may be a relationship between food intolerance and disease of various systems, and this is significant to the growth and development of children.

Different approaches for treating myopic choroidal neovascularization: a network Meta-analysis.

AIM: To evaluate the efficacy of intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF), photodynamic therapy (PDT), and laser treatment (LT) for anatomical and functional improvement in myopic choroidal neovascularization (mCNV) patients. METHODS: Two researchers independently searched PubMed, Cochrane Library, Web of Science, and other databases to screen studies comparing best-corrected vision acuity (BCVA) and foveal center thickness (FCT) changes after mCNV treatment. Post-treatment chorioretinal atrophy (CRA) is a secondary outcome indicator. The retrieval time limit is from the database construction to January 30, 2023. RESULTS: A total of 1072 eyes in 16 articles were included. In the RCTs, intravitreal bevacizumab (IVB) and intravitreal ranibizumab (IVR) were superior to PDT (MD=0.18, 95%CI: 0.02, 0.40, MD=0.18, 95%CI: 0.01, 0.42) in improving BCVA of mCNV patients (P<0.05). The relative effectiveness in improving BCVA, from high to low, appeared to be IVR, intravitreal aflibercept (IVA), IVB, LT, PDT, and sham first followed by IVA (Sham/IVA). While improving the FCT from high to low was IVA, IVR, IVB, PDT. In retrospective studies, the results of BCVA after long-term treatment showed that all the therapeutic effects from high to low was IVA, intravitreal conbercept (IVC), IVR, IVB, IVB/IVR, PDT with IVB/IVR, PDT. The effect of improving FCT was IVA, IVR, IVC, PDT, and IVB from high to low. And in the effects of improving CRA, the IVB appeared to be higher than IVR, while the PDT was the smallest, but none of the differences in the results were statistically significant. CONCLUSION: Anti-VEGF has the best effect on long-term vision improvement in mCNV patients, using IVB or IVR alone to treat mCNV may be better than IVB or IVR combined with PDT. There is no significant difference in the improvement of visual acuity, macular edema, and CRA in mCNV patients treated with any different anti-VEGF drugs.

Evaluation of renal cortical echogenicity in healthy cats using anisotropic backscatter artifacts and echogenicity differences among internal organs.

BACKGROUND: Renal cortical anisotropic backscatter artifact (CABA) is a hyperechoic region of the renal poles where the insonation of sound beams is perpendicular to the renal tubules within the renal cortex. AIMS: To determine whether renal CABA can be observed in healthy cats and to compare the echogenicity of renal CABA with that of the spleen and liver. MATERIAL AND METHODS: Images of the spleen, liver, kidneys, and urinary bladder were acquired from 30 clinically healthy cats with renal CABA. Echogenicity differences among organs and echo scores within urine were recorded and analyzed. All ultrasound images were acquired using a 7.2-14-MHz linear transducer. Univariate logistic regression was used to assess the associations between the presence of renal CABA and various variables. RESULTS: The prevalence of the renal CABA was 86.7% (26/30) and 93.3% (28/30) according to different observers. The reproducibility of renal CABA is substantial to excellent. The renal CABA echogenicity was greater or equal to the spleen and greater than the hepatic echogenicity in 90.0% of cats (27/30). For comparison with the spleen and liver, there were three and six combinations of echogenicity differences using the CABA and non-CABA regions, respectively. The renal cortical echogenicity in the CABA region was higher than the liver in all subjects. Renal CABA was not associated with age, body weight, gender, body condition score, or lipid droplets in the urinary bladder. CONCLUSION: Renal CABA was present in most healthy cats and could be used for echogenicity comparisons with the liver and spleen.

Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment.

OBJECTIVE: Schizophrenia (SZ) is associated with cognitive impairment, and it is known that the activity of cAMP response element binding protein (CREB) decreases in the brain of SZ patients. The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit. The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment. METHODS: MK-801 was used to induce SZ in rats. Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats. The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment, respectively. RESULTS: The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats. Interestingly, among the upstream kinases of CREB, merely ERK1/2 was downregulated, while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats. The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133, and induced synaptic dysfunction in primary hippocampal neurons. Conversely, the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment. CONCLUSION: These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment. The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.

[Current studies on induced pluripotent stem cells in retinal degenerative diseases].

Retinal degeneration diseases are a group of severe eye diseases that can lead to blindness. They are characterized by degeneration and apoptosis of photoreceptor cells and still lacking effective therapeutic procedures. Pluripotent stem cells (induced pluripotent stem cells, iPS cells) obtained from somatic cell reprogramming are similar to the embryonic stem cells (embryonic stem cells, ES cells), which have unlimited proliferation, differentiation and memory characteristics. Retinal cells from iPS cells have been used in cell transplantation for the treatment of retinal diseases, for the study of pathogenesis and drug toxicity evaluation in retinal degenerative diseases. This may provide new ideas and novel procedures for the treatment of retinal degenerative diseases in the future.

What Is Your Diagnosis?

In collaboration with the American College of Veterinary Radiology.

4-Dimethyl-amino-N'-(2-hy-droxy-3,5-diiodo-benzyl-idene)benzohydrazide.

The title mol-ecule, C(16)H(15)I(2)N(3)O(2), adopts an E configuration about the C=N bond. The dihedral angle between the two benzene rings is 6.4 (2)°. An intra-molecular O-H⋯N hydrogen bond occurs. In the crystal, mol-ecules are linked through inter-molecular N-H⋯O hydrogen bonds, forming chains propagating in the c-axis direction.

[Quantitative trait locus analysis of standard length, body depth and body thickness in mirror carp (Cyprinus carpio L.)].

Based on a full-sib family, the genetic linkage map was constructed with 246 microsatellite and 306 SNP markers, which was used to detect the QTLs for standard length (SL), body depth (H), body thickness (BT), and the ratio of standard length and body depth (SLH) in mirror carp by GridQTL software. The results indicated that a total of 14 related QTLs distributed on the 7 linkage groups were obtained. Seven QTLs were related to standard length, of which the linkage groups of LG6, LG17, LG21, LG23, and LG35 were at 5% significant level, and linkage group LG1 and LG28 were at 1% significant level, which explained 6.6%-12.6% of the phenotypic variance. Three QTLs were identified for body depth on the linkage groups of LG17, LG23 and LG28 (P amp; 0.01), accounting for 11.6%, 12.7%, and 15.6% of the phenotypic variance, respectively. Two QTLs were associated with body thickness on the linkage of LG23 and LG28 (P amp; 0.05), which explained 8.6% and 7.2% of the phenotypic variation, respectively. Two QTLs were responsible for the ratio of standard length and body depth on the linkage of LG21 and LG35 (P amp; 0.05), both of which explained 8.2% of the phenotypic variance. The results provide a useful reference for further candidate gene research and molecular marker assisted selection in mirror carp.

[Mapping and genetic effect analysis of quantitative trait loci related to body length in mirror carp (Cyprinus carpio L.)].

A group of F2 hybrids of mirror carp including 68 individuals was used to construct a linkage map using JoinMap4.0 software. Of 560 markers genotyped, 507 markers (143 SSR markers, 33 EST-SSR markers, and 321 SNP markers) were assigned to the map, which comprised of 62 linkage groups. Quantitative traits loci (QTLs) associated with body length were identified by interval mapping of the software MapQTL 5.0. A linkage group wide permutation test (1 000 replicates) determined the significance of the maximum LOD value over the various intervals analyzed for each linkage group. Twelve QTLs were identified for body length on the linkage groups of BL-1-1 (SNP0137-SNP1481), BL-4-1 (SNP0092-HLJ797), BL-5-1 (SNP1268-HLJ423), BL-7-1 (HLJ870-SNP0702), BL-12-1 (SNP0922-HLJ639), BL-16-1 (HLJE351-SNP0674), BL-25-1 (SNP0394-SNP0862), BL-35-1 (HLJ668-SNP0832), BL-43-1 (SNP0389-SNP1425), BL-47-1 (HLJ057-HLJ1113), BL-47-2 (HLJ1439-HLJ14180), which explained 13.8% to 64.9% of the total variation of body length. Eight major QTLs explained over 20% of the phenotypic variation, which were major QTLs associated with the body length of mirror carp.

[Progress in gene therapy study of Leber congenital amaurosis].

Leber congenital amaurosis (LCA) is an early onset retinal dystrophy that causes severe visual impairment. With the development of molecular genetics and the therapeutic gene replacement technology, the adeno-associated viral (AAV) vector-mediated gene therapy for LCA achieved encouraging progress in the past decade. The success of the Phase I clinical trials of human RPE65 gene therapy for LCA II patients makes it a pioneer in the field of retinal gene therapy and brings light to the cure of other hereditary retinopathy. This article briefly reviews the recent developments in the preclinical animal experiments and Phase I clinical trials for LCA.

[Differential expression and significance of complement C4b and transthyretin in proliferative vitreoretinopathy].

OBJECTIVE: To investigate the differential expression of complement C4b and transthyretin in proliferative vitreoretinopathy (PVR). METHODS: It was a controlled experimental study. Human vitreous samples of 5 patients with PVR were analyzed by using two-dimensional gel electrophoresis and mass spectrometry, and the results were compared with those from normal control vitreous obtained from donor eyes. An in vivo model of PVR was created by intravitreous injection of cultured rabbit retinal pigment epithelial (RPE) cells. The vitreous of PVR models were analyzed by enzyme linked immunosorbent assay (ELISA) to confirm the proteomic results from the PVR patients. RESULTS: Seventy nine various proteins were expressed differently between PVR and normal vitreous, among which nine up-regulated proteins including complement C4b, transthyretin (TTR), and 7 albumins were identified by mass spectrometry. The up-regulation of complement C4b and TTR in PVR patients was also confirmed by ELISA. The concentration of complement C4b and TTR in normal vitreous were (20.18 ± 1.97) mg/L and (88.58 ± 8.84) mg/L respectively, in PVR patients were (38.1 ± 5.79) mg/L and (112.57 ± 6.89) mg/L respectively, difference significantly between these two groups (C4b: t = 11.54, TTR:t = 9.24; P < 0.05). CONCLUSIONS: Differences of complement C4b and TTR expression were observed between PVR and normal vitreous. These results have lead to the assumption that there is a connection between elevated concentrations of both complement C4b and TTR and the pathogenesis of PVR and further studies on the functions of these proteins are required.