In the adult mammalian brain, more than 250 protein kinases are expressed, but only a few of these kinases are currently known to enable learning and memory. Based on this information it appears that ...learning and memory-related kinases either impact on synaptic transmission by altering ion channel properties or ion channel density, or regulate gene expression and protein synthesis causing structural changes at existing synapses as well as synaptogenesis. Here, we review the roles of these kinases in short-term memory formation, memory consolidation, memory storage, retrieval, reconsolidation, and extinction. Specifically, we discuss the roles of calcium/calmodulin-dependent kinase II (CaMKII), the calcium/calmodulin kinase cascade, extracellular signal regulated kinase 1 and 2 (ERK1/2), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase G (PKG), the phosphatidylinositol 3-kinase (PI3K) pathway, and protein kinase M ? (PKM?). Although these kinases are important for learning and memory processes, much remains to be learned as to how they act. Therefore, it will be important to identify and characterize the critical phosphorylation substrates so that a sophisticated understanding of learning and memory processes will be achieved. This will also allow for a systematic analysis of dysfunctional kinase activity in mental disorders.
Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less ...than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.
Apusomonadida (apusomonads) is a group of heterotrophic biflagellates that feed on bacteria and small protists. Their diversity is not fully understood, and several major lineages remain to be ...identified in natural environments. Here, we report Podomonas kaiyoae n. sp., which was isolated from deep‐sea sediment and can be maintained as an axenic culture. While P. kaiyoae branched within one of the major unidentified lineages, the combination of the morphological characteristics is generally similar to that of Podomonas species, but can be distinguished from that of other Podomonas species based on the cell sizes.
Human induced pluripotent stem cells (hiPSCs) are considered a promising source of pancreatic β-cells for the treatment of diabetes. However, this approach is limited by issues such as low efficiency ...and high cost. Here, we have developed a new protocol to induce insulin-producing cells. To reduce costs, we decreased the number of reagents and replaced protein reagents with chemical compounds. In this method, we increased induction efficiency with ascorbic acid (vitamin C) and an ALK5 inhibitor, RepSox. In 2D culture, the majority of cells were immature β-cells with low glucose-stimulated insulin secretion. Transferring to 3D culture immediately after endocrine progenitor cell differentiation, however, improved glucose-stimulated insulin secretion. This simplified method will contribute to realizing transplantation therapy of β-cells using iPSCs.
Analysis of microRNA (miRNA) regulatory networks is useful for exploring novel biomarkers and therapeutic targets in cancer cells. The Cancer Genome Atlas dataset shows that low expression of both ...strands of pre‐miR‐101 (miR‐101‐5p and miR‐101‐3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC). The functional significance of miR‐101‐5p in cancer cells is poorly understood. Here, we focused on miR‐101‐5p to investigate the antitumor function and its regulatory networks in ccRCC cells. Ectopic expression of mature miRNAs or siRNAs was investigated in cancer cell lines to characterize cell function, ie, proliferation, apoptosis, migration, and invasion. Genome‐wide gene expression and in silico database analyses were undertaken to predict miRNA regulatory networks. Expression of miR‐101‐5p caused cell cycle arrest and apoptosis in ccRCC cells. Downstream neighbor of son (DONSON) was directly regulated by miR‐101‐5p, and its aberrant expression was significantly associated with shorter survival in propensity score‐matched analysis (P = .0001). Knockdown of DONSON attenuated ccRCC cell aggressiveness. Several replisome genes controlled by DONSON and their expression were closely associated with ccRCC pathogenesis. The antitumor miR‐101‐5p/DONSON axis and its modulated replisome genes might be a novel diagnostic and therapeutic target for ccRCC.
MicroRNA‐101‐5p expression was downregulated in clear cell renal cell carcinoma (ccRCC) tissues and functioned as tumor‐suppressive microRNA. MicroRNA‐101‐5p directly regulated DONSON, which was highly expressed in ccRCC and sunitinib‐resistant RCC tissues. DONSON and other replisome‐related genes have a potential to be diagnostic and therapeutic targets in ccRCC.
Previous research has demonstrated that sanction systems increase cooperation in social dilemma situations. However, specific literature indicates that sanctions undermine cooperation and trust in ...others. This study defined the detrimental effects of sanctions as decreasing cooperation after sanctions are removed in groups adopting sanctioning compared to a control group playing the public goods game without a punishment system. This study conducted a conceptual follow-up of previous studies and examined whether the detrimental impact of sanctions was consistent. The hypotheses, sample sizes, and analytical design of the study were pre-registered. This study’s result did not conceptually replicate the detrimental effects of sanctions. This finding suggests that the detrimental effects of sanctions, if any, were minimal in the way punishments were introduced in this study.
Our original microRNA (miRNA) expression signatures (based on RNA sequencing) revealed that both strands of the miR-145 duplex (miR-145-5p, the guide strand, and miR-145-3p, the passenger strand) ...were downregulated in several types of cancer tissues. Involvement of passenger strands of miRNAs in cancer pathogenesis is a new concept in miRNA biogenesis. In our continuing analysis of lung adenocarcinoma (LUAD) pathogenesis, we aimed here to identify important oncogenes that were controlled by miR-145-5p and miR-145-3p. Downregulation of miR-145-5p and miR-145-3p was confirmed in LUAD clinical specimens. Functional assays showed that miR-145-3p significantly blocked the malignant abilities in LUAD cells, e.g., cancer cell proliferation, migration and invasion. Thus, the data showed that expression of the passenger strand of the miR-145-duplex acted as an anti-tumor miRNA. In LUAD cells, we identified four possible target genes (LMNB2, NLN, SIX4, and DDC) that might be regulated by both strands of miR-145. Among the possible targets, high expression of LMNB2 predicted a significantly poorer prognosis of LUAD patients (disease-free survival, p = 0.0353 and overall survival, p = 0.0017). Overexpression of LMNB2 was detected in LUAD clinical specimens and its aberrant expression promoted malignant transformation of LUAD cells. Genes regulated by anti-tumor miR-145-5p and miR-145-3p are closely involved in the molecular pathogenesis of LUAD. We suggest that they are promising prognostic markers for this disease. Our approach, based on the roles of anti-tumor miRNAs, will contribute to improved understanding of the molecular pathogenesis of LUAD.
Gene sequence has been widely used in molecular ecology. For instance, the ribosomal RNA (rRNA) gene has been widely used as a biological marker to understand microbial communities. The variety of ...the detected rRNA gene sequences reflects the diversity of the microorganisms existing in the analyzed sample. Their biomass can also be estimated by applying quantitative sequencing with information on rRNA gene copy numbers in genomes; however, information on rRNA gene copy numbers is still limited. Especially, the copy number in microbial eukaryotes is much less understood than that of prokaryotes, possibly because of the large and complex structure of eukaryotic genomes. In this study, we report an alternative approach that is more appropriate than the existing method of quantitative sequencing and demonstrate that the copy number of eukaryotic rRNA can be measured efficiently and comprehensively. By applying this approach widely, information on the eukaryotic rRNA copy number can be determined, and their community structures can be depicted and compared more efficiently.
Schematic image of the experimental process to comprehensively count the copy number of the eukaryotic rRNA gene.
In spite of advances in the diagnosis and current molecular target therapies of lung cancer, this disease remains the most common cause of cancer-related death worldwide. Approximately 80% of lung ...cancers is non-small cell lung cancer (NSCLC), and 5-year survival rate of the disease is ~20%. On the other hand, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. IPF is refractory to treatment and has a very low survival rate. Moreover, IPF is frequently associated with lung cancer. However, the common mechanisms shared by these two diseases remain poorly understood. In the post-genome sequence era, the discovery of noncoding RNAs, particularly microRNAs (miRNAs), has had a major impact on most biomedical fields, and these small molecules have been shown to contribute to the pathogenesis of NSCLC and IPF. Investigation of novel RNA networks mediated by miRNAs has improved our understanding of the molecular mechanisms of these diseases. This review summarizes our current knowledge on aberrantly expressed miRNAs regulating NSCLC and IPF based on miRNA expression signatures.
Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell ...carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan-Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.
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