MicroRNA-19b downregulates insulin 1 through targeting transcription factor NeuroD1

AbstractMiR-17-92 cluster miRNAs are disclosed to contribute to the development of multiple organs and tumorigenesis, but their roles in pancreas development remains unclear. In this study, we found that miR-19b, a member of miR-17-92, was highly expressed in the pancreatic progenitor cells, and miR-19b could target the 3′ UTR of NeuroD1 mRNA to decrease its protein and mRNA levels. Functional analysis showed that miR-19b exerted little effect on the proliferation of pancreatic progenitors, whereas it inhibited the expression of insulin 1, but not insulin 2 in MIN6 cells. These results suggest that miR-19b can downregulate insulin 1 expression through targeting transcription factor NeuroD1, and thus regulate the differentiation and function of β-cells

New Results on the SymSum Distinguisher on Round-Reduced SHA3

In ToSC 2017 Saha et al. demonstrated an interesting property of SHA3 based on higher-order vectorial derivatives which led to self-symmetry based distinguishers referred to as SymSum and bettered the complexity w.r.t the well-studied ZeroSum distinguisher by a factor of 4. This work attempts to take a fresh look at this distinguisher in the light of the linearization technique developed by Guo et al. in Asiacrypt 2016. It is observed that the efficiency of SymSum against ZeroSum drops from 4 to 2 for any number of rounds linearized. This is supported by theoretical proofs. SymSum augmented with linearization can penetrate up to two more rounds as against the classical version. In addition to that, one more round is extended by inversion technique on the final hash values. The combined approach leads to distinguishers up to 9 rounds of SHA3 variants with a complexity of only 264 which is better than the equivalent ZeroSum distinguisher by the factor of 2. To the best of our knowledge this is the best distinguisher available on this many rounds of SHA3

Deregulation of CREB Signaling Pathway Induced by Chronic Hyperglycemia Downregulates NeuroD Transcription

CREB mediates the transcriptional effects of glucose and incretin hormones in insulin-target cells and insulin-producing β-cells. Although the inhibition of CREB activity is known to decrease the β-cell mass, it is still unknown what factors inversely alter the CREB signaling pathway in β-cells. Here, we show that β-cell dysfunctions occurring in chronic hyperglycemia are not caused by simple inhibition of CREB activity but rather by the persistent activation of CREB due to decreases in protein phophatase PP2A. When freshly isolated rat pancreatic islets were chronically exposed to 25 mM (high) glucose, the PP2A activity was reduced with a concomitant increase in active pCREB. Brief challenges with 15 mM glucose or 30 µM forskolin after 2 hour fasting further increased the level of pCREB and consequently induced the persistent expression of ICER. The excessively produced ICER was sufficient to repress the transcription of NeuroD, insulin, and SUR1 genes. In contrast, when islets were grown in 5 mM (low) glucose, CREB was transiently activated in response to glucose or forskolin stimuli. Thus, ICER expression was transient and insufficient to repress those target genes. Importantly, overexpression of PP2A reversed the adverse effects of chronic hyperglycemia and successfully restored the transient activation of CREB and ICER. Conversely, depletion of PP2A with siRNA was sufficient to disrupt the negative feedback regulation of CREB and induce hyperglycemic phenotypes even under low glucose conditions. Our findings suggest that the failure of the negative feedback regulation of CREB is the primary cause for β-cell dysfunctions under conditions of pathogenic hyperglycemia, and PP2A can be a novel target for future therapies aiming to protect β-cells mass in the late transitional phase of non-insulin dependent type 2 diabetes (NIDDM)

Preimage Attacks on Round-reduced Keccak-224/256 via an Allocating Approach

We present new preimage attacks on standard Keccak-224 and Keccak-256 that are reduced to 3 and 4 rounds. An allocating approach is used in the attacks, and the whole complexity is allocated to two stages, such that fewer constraints are considered and the complexity is lowered in each stage. Specifically, we are trying to find a 2-block preimage, instead of a 1-block one, for a given hash value, and the first and second message blocks are found in two stages, respectively. Both the message blocks are constrained by a set of newly proposed conditions on the middle state, which are weaker than those brought by the initial values and the hash values. Thus, the complexities in the two stages are both lower than that of finding a 1-block preimage directly. Together with the basic allocating approach, an improved method is given to balance the complexities of two stages, and hence, obtains the optimal attacks. As a result, we present the best theoretical preimage attacks on Keccak-224 and Keccak-256 that are reduced to 3 and 4 rounds. Moreover, we practically found a (second) preimage for 3-round Keccak-224 with a complexity of 2^{39.39}

Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/β gene expression via acetylation of nuclear factor of activated T cells c1

The nuclear factor of activated T-cells (NFAT) c1 has been shown to be essential for Ca2+-dependent upregulation of myosin heavy chain (MyHC) I/β expression during skeletal muscle fiber type transformation. Here, we report activation of extracellular signal-regulated kinase (ERK) 1/2 in Ca2+-ionophore-treated C2C12 myotubes and electrostimulated soleus muscle. Activated ERK1/2 enhanced NFATc1-dependent upregulation of a −2.4 kb MyHCI/β promoter construct without affecting subcellular localization of endogenous NFATc1. Instead, ERK1/2-augmented phosphorylation of transcriptional coactivator p300, promoted its recruitment to NFATc1 and increased NFATc1–DNA binding to a NFAT site of the MyHCI/β promoter. In line, inhibition of ERK1/2 signaling abolished the effects of p300. Comparison between wild-type p300 and an acetyltransferase-deficient mutant (p300DY) indicated increased NFATc1–DNA binding as a consequence of p300-mediated acetylation of NFATc1. Activation of the MyHCI/β promoter by p300 depends on two conserved acetylation sites in NFATc1, which affect DNA binding and transcriptional stimulation. NFATc1 acetylation occurred in Ca2+-ionophore treated C2C12 myotubes or electrostimulated soleus. Finally, endogenous MyHCI/β gene expression in C2C12 myotubes was strongly inhibited by p300DY and a mutant deficient in ERK phosphorylation sites. In conclusion, ERK1/2-mediated phosphorylation of p300 is crucial for enhancing NFATc1 transactivation function by acetylation, which is essential for Ca2+-induced MyHCI/β expression

MicroRNA expression profiles during cotton (Gossypium hirsutum L) fiber early development

The role of microRNAs (miRNAs) during cotton fiber development remains unclear. Here, a total of 54 miRNAs belonging to 39 families were selected to characterize miRNA regulatory mechanism in eight different fiber development stages in upland cotton cv BM-1. Among 54 miRNAs, 18 miRNAs were involved in cotton fiber initiation and eight miRNAs were related to fiber elongation and secondary wall biosynthesis. Additionally, 3,576 protein-coding genes were candidate target genes of these miRNAs, which are potentially involved in cotton fiber development. We also investigated the regulatory network of miRNAs and corresponding targets in fiber initiation and elongation, and secondary wall formation. Our Gene Ontology-based term classification and KEGG-based pathway enrichment analyses showed that the miRNA targets covered 220 biological processes, 67 molecular functions, 45 cellular components, and 10 KEGG pathways. Three of ten KEGG pathways were involved in lignan synthesis, cell elongation, and fatty acid biosynthesis, all of which have important roles in fiber development. Overall, our study shows the potential regulatory roles of miRNAs in cotton fiber development and the importance of miRNAs in regulating different cell types. This is helpful to design miRNA-based biotechnology for improving fiber quality and yield

Vertebrate Paralogous MEF2 Genes: Origin, Conservation, and Evolution

BACKGROUND: The myocyte enhancer factor 2 (MEF2) gene family is broadly expressed during the development and maintenance of muscle cells. Although a great deal has been elucidated concerning MEF2 transcription factors' regulation of specific gene expression in diverse programs and adaptive responses, little is known about the origin and evolution of the four members of the MEF2 gene family in vertebrates. METHODOLOGY/PRINCIPAL FINDINGS: By phylogenetic analyses, we investigated the origin, conservation, and evolution of the four MEF2 genes. First, among the four MEF2 paralogous branches, MEF2B is clearly distant from the other three branches in vertebrates, mainly because it lacks the HJURP_C (Holliday junction recognition protein C-terminal) region. Second, three duplication events might have occurred to produce the four MEF2 paralogous genes and the latest duplication event occurred near the origin of vertebrates producing MEF2A and MEF2C. Third, the ratio (K(a)/K(s)) of non-synonymous to synonymous nucleotide substitution rates showed that MEF2B evolves faster than the other three MEF2 proteins despite purifying selection on all of the four MEF2 branches. Moreover, a pair model of M0 versus M3 showed that variable selection exists among MEF2 proteins, and branch-site analysis presented that sites 53 and 64 along the MEF2B branch are under positive selection. Finally, and interestingly, substitution rates showed that type II MADS genes (i.e., MEF2-like genes) evolve as slowly as type I MADS genes (i.e., SRF-like genes) in animals, which is inconsistent with the fact that type II MADS genes evolve much slower than type I MADS genes in plants. CONCLUSION: Our findings shed light on the relationship of MEF2A, B, C, and D with functional conservation and evolution in vertebrates. This study provides a rationale for future experimental design to investigate distinct but overlapping regulatory roles of the four MEF2 genes in various tissues