Application of Human‐Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders

Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human‐induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC‐derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl‐CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease‐related synaptopathy.     

Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays.     

Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.     

Porphyromonas gingivalis promotes the motility of esophageal squamous cell carcinoma by activating NF-κB signaling pathway

Esophageal carcinoma, with a increasing incidence, is one of the most aggressive carcinomas in gastrointestinal tract. Epidemiologic studies demonstrate an association of oral pathogens with multiple diseases, including rheumatoid arthritis, cardiovascular diseases, diabetes, and gastrointestinal malignancies. Nevertheless, a causal relationship between oral pathogens and esophageal squamous cell carcinoma (ESCC) has not been elucidated. Here, we found that Porphyromonas was significantly enriched in the saliva of patients with ESCC, compared with that in normal human. In vitro studies showed that Porphyromonas gingivalis (P. gingivalis) promoted the proliferation and motility of ESCC cells, as evidenced by up regulated expression of key molecules implicated in NF-κB signaling pathway. These findings, for the first time, demonstrated a role of oral pathogens in inducing ESCC tumorigenesis and metastasis, which might involve regulation of NF-κB signaling pathway.     

DHHC4 and DHHC5 Facilitate Fatty Acid Uptake by Palmitoylating and Targeting CD36 to the Plasma Membrane

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Single-Cell Heterogeneity Analysis and CRISPR Screen Identify Key β-Cell-Specific Disease Genes

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Enhancement of Ultrasonic Seed Treatment on Yield,Grain Quality Characters,and 2-Acetyl-1-Pyrroline Biosynthesis in Different Fragrant Rice Genotypes

Fragrant rice is popular for the good grain quality and special aroma. The present study conducted a field experiment to investigate the effects of ultrasonic seed treatment on grain yield, quality characters, physiological properties and aroma biosynthesis of different fragrant rice genotypes. The seeds of three fragrant rice genotypes were exposed to 1 min of ultrasonic vibration and then cultivated in paddy field. The results of present study showed that ultrasonic seed treatment increased grain yield of all fragrant rice genotypes but the responses of yield formation to ultrasonic were varied with different genotypes. Compared with control, ultrasonic seed treatment increased grain 2-acetyl-1-pyrroline (2-AP, the key component of fragrant rice aroma) content by 13.40%–44.88%. Ultrasonic seed treatment also reduced the crude protein contents in grains. The head rice rate, rice length, chalky rice rate, and chalkiness degree were influenced by ultrasonic for one or two fragrant rice genotypes. The activities of peroxidase and superoxide dismutase were also enhanced due to ultrasonic seed treatment. In conclusion, ultrasonic seed treatment increased grain, regulated grain aroma and quality, and improved stress resistance of fragrant rice varieties.     

SMYD2 facilitates cancer cell malignancy and xenograft tumor development through ERBB2-mediated FUT4 expression in colon cancer

The aim of this study is to assess the expression levels of SMYD2 in human tissue samples and cells of colon cancer, and further explore the potential mechanisms of SMYD2 in colon cancer progression. Quantitative PCR and Immunohistochemical (IHC) assays were performed to detect SMYD2 expression in 76 tissue samples of colon cancer tissues and the corresponding normal tissues. The potential correlations between SMYD2 expression levels and clinical pathological features were assessed. We further detected the effects of SMYD2 on the proliferation, invasion and apoptosis of colon cancer cells and on ERBB2/FUT4 signaling pathway through Brdu assay, transwell assay and flow cytometry assay, respectively. The potential effects of SMYD2 on tumor growth were explored using an animal model. We demonstrated the possible involvement of SMYD2 in the progression of colon cancer. We found the high expression of SMYD2 in human colon cancer tissues and cells, and found the correlations between SMYD2 expression and the clinicopathological features including vascular invasion (P?=?0.007*), TNM stage (P?=?0.016*) and lymph node metastasis (P?=?0.011*), of patients with colon cancer. Our data further confirmed that SMYD2 affects cell proliferation, invasion, and apoptosis of colon cancer cells via the regulation of ERBB2/FUT4 signaling pathway. We also demonstrated SMYD2 contributed to tumor growth of colon cancer cells in vivo. We investigated the potential involvement of SMYD2 in the progression of colon, and therefore confirmed SMYD2 as a possible therapeutic target for colon cancer.

     

Comparative analysis of complete plastid genome reveals powerful barcode regions for identifying wood of Dalbergia odorifera and D. tonkinensis (Leguminosae)

Dalbergia odorifera T. C. Chen (Leguminosae), a rare and endangered tree species endemic to Hainan Island of China, produces the most expensive and rarest wood in China. The wood characteristics of D. odorifera are remarkably similar to those of D. tonkinensis (a much less sought-after species from Vietnam), and the DNA from wood is often highly degraded, making it very difficult to identify the two species using anatomical features or DNA barcoding based on regular DNA markers. To solve the confusion of identifying wood reliably from the two species, we built and analyzed the plastome library of 26 samples from 18 Dalbergia species, of which 12 samples from eight closely related species of D. odorifera are newly sequenced in this study. Phylogenomic analysis suggested that the relationships among the 26 samples are mostly well resolved, and conspecific individuals from different populations of D. odorifera and D. tonkinensis clustered together. Between the plastid genomes of the two species, we identified 129 indels and 114 single nucleotide polymorphisms. By assessing a subset of 20 nucleotide polymorphisms and 10 indels using 37 population-level samples (20 samples of D. odorifera and 17 samples of D. tonkinensis), we recovered eight species-specific barcode regions that could be suitable for identifying the wood D. odorifera and D. tonkinensis. To examine their utility in wood identification, we amplified the eight DNA barcodes using six wood samples and recovered an amplification success rate of 83.3%, demonstrating a reliable method for precise wood identification of the two species.