Decoding of Finger Millet Genome: A Milestone of Millet Genomics

Whole genome sequencing is an important milestone of the genomics-assisted molecular biology studies. Sequencing the whole genome of plants unravels the complex molecular structure of these complex organisms. In this respect, whole genome sequencing of important small millet that is finger millet was subsequently released by 2 independent groups. This commentary outlines the major applications of these reports, which also provided some opinion about this.

Insights Into Signaling in Cell-Based Therapy for Heart Disease

Over the past several decades, stem cell therapy for heart disease has been translated from the bench to the bedside and in clinical trials improves cardiac structure and function in both ischemic and nonischemic cardiac disease. Although the regenerative effects of stem cells in cardiac disease are mediated by both paracrine and cell-to-cell contact mechanisms, many of the downstream signaling pathways remain to be fully elucidated. This review outlines what is currently known about the main signaling pathways involved in mesenchymal stem cell and cardiac stem cell survival, proliferation, and migration and mechanisms of action to repair the damaged heart.

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Supraphysiological concentrations (SPCs) of triiodo-L-thyronine (T3) have been used in the treatment of a number of nonviral diseases. However, the signaling mechanisms that regulate the function of T3 at these concentrations and their role in modulating cellular stress pathways and antiviral responses are unknown. Here, we have investigated the effects of SPCs of T3 on integrated stress response (ISR) signaling pathways and the replication of vesicular stomatitis virus (VSV). T3 amplified Poly IC-induced activation of RNA-dependent protein kinase, induced phosphorylation of eIF2α, stress granule (SG) formation, IRE1α phosphorylation, XBP1 splicing, and the expression of stress markers. T3 inhibited VSV replication by modulating SG formation and the expression of stress response markers. ISR activator guanabenz also inhibited VSV replication and amplified T3-induced anti-VSV response. To summarize, we have uncovered novel functions of T3 at SPCs as an activator of ISR signaling pathways and an inhibitor of VSV replication. This study offers a proof of principle of the concept that ISR activating agents like SPC of T3 and guanabenz can be potential antiviral agents.

Tamoxifen Action in ER-Negative Breast Cancer

Breast cancer is a highly heterogeneous disease. Tamoxifen is a selective estrogen receptor (ER) modulator and is mainly indicated for the treatment of breast cancer in postmenopausal women and postsurgery neoadjuvant therapy in ER-positive breast cancers. Interestingly, 5-10% of the ER-negative breast cancers have also shown sensitivity to tamoxifen treatment. The involvement of molecular markers and/or signaling pathways independent of ER signaling has been implicated in tamoxifen sensitivity in the ER-negative subgroup. Studies reveal that variation in the expression of estrogen-related receptor alpha, ER subtype beta, tumor microenvironment, and epigenetics affects tamoxifen sensitivity. This review discusses the background of the research on the action of tamoxifen that may inspire future studies to explore effective therapeutic strategies for the treatment of ER-negative and triple-negative breast cancers, the latter being an aggressive disease with worse clinical outcome.

Current View of microRNA Processing

Small evolutionarily conserved noncoding RNAs, microRNAs (miRNAs), regulate gene expression either by translational repression or by mRNA degradation in mammals. miRNAs play functional roles in diverse physiological and pathological processes. miRNA processing is accurately regulated through multifarious factors. The canonical miRNA processing pathway consists of four sequential steps: (a) miRNA gene is transcribed into primary miRNA (pri-miRNA) mainly by RNA polymerase II; (b) pri-miRNA is processed into precursor miRNA (pre-miRNA) through microprocessor complex; (c) pre-miRNA is exported from the nucleus to the cytoplasm with the assistance of Exportin 5 (EXP5/XP05) protein; and (d) pre-miRNA is further processed into mature miRNA via Dicer. Emerging evidence has also demonstrated that some miRNAs undergo alternative processing pathways. Dysregulation of miRNA processing is closely related to tumorigenesis. Here, we review the current advances in the knowledge of miRNA processing and briefly discuss its impact on human cancers.

Provirus Silencing in Stem Cells: The Forbidden Regulators of Cell Fate

The cryptic presence of a wide range of retroviruses with varying copy number holds biological significance for host reproduction and development. Most of the endogenous retroviruses with lost pathogenicity and replication ability still serve as transcriptional regulators of host cellular genes. These structural and functional features of proviruses present them as alternate promoters and enhancers for several host cellular genes involved in development and other biological processes. In addition, embryonic stem (ES) cells and induced pluripotent cells are known to effectively silence the expression of most of these proviruses through repressive epigenetic marks and proviral sequence heterochromatization, which is not a case for those of differentiated cells. In this review, we aim to dissect the underlying salient features of proviral silencing in embryonic stem cells and analyze the potential of these proviruses in cell fate determination.

Aberrant Expression of Cyclin D1 in Cancer

Cyclin D1 binds and activates cyclin-dependent kinases 4/6 (Cdk4/6) to phosphorylate the retinoblastoma (RB) family proteins, relieving E2F/DPs from the negative restraint of RB proteins and histone deacetylases (HDACs). The cyclin D-Cdk4/6 complexes activate cyclin E/Cdk2 through titration of the Cdk inhibitors p21Cip1/p27Kip1. Cyclin E/Cdk2 further phosphorylates RBs, thereby activating E2F/DPs, and cells enter the S-phase of the cell cycle. Cyclin D-Cdk4/6 also phosphorylates MEP50 subunit of the protein arginine methyltransferase 5 (PRMT5), which cooperates with cyclin D1 to drive lymphomagenesis in vivo. Activated PRMPT5 causes arginine methylation of p53 to suppress expression of proapoptotic and antiproliferative target genes, explaining the molecular mechanism for tumorigenesis. Cyclin D1 physically interacts with transcription factors such as estrogen receptor, androgen receptor, and Myb family proteins to regulate gene expression in Cdk-independent fashion. Dmp1 is a Myb-like protein that quenches the oncogenic signals from activated Ras or HER2 by inducing Arf/p53-dependent cell cycle arrest. Cyclin D1 binds to Dmp1 to activate both Arf and Ink4a promoters to induce cell cycle arrest or apoptosis in non-transformed cells to prevent them from neoplastic transformation. Dmp1deficiency significantly accelerates mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Cyclin D1 interferes with ligand activation of PPARγ involved in cellular differentiation; it also physically interacts with HDACs and p300 to repress gene expression. It has also been shown that cyclin D1 accelerates tumorigenesis through transcriptional activation of miR-17/20 and Dicer1 which, in turn, represses cyclin D1 expression. Identification of cyclin D1-binding proteins/promoters will be essential for further clarification of its biological activities.

Current View of miRNA with Tumor Suppressor Function, Exploring MDS and AML as Models

Since the discovery of microRNAs (miRNAs) in 1993, their role in controlling a wide variety of complex and seminal cellular functions through control of gene expression continues to be elucidated. Studies of the past decade have shown that miRNAs are able to activate or suppress target genes that are key players in the molecular pathways found to be deregulated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The ability of miRNAs to act as tumor suppressor genes has been demonstrated in a number of studies in both human samples and cell lines as well as in murine models of AML and MDS. The focus of this review will be to examine the complex interaction of specific miRNAs with genes that have been implicated in MDS/AML and which may eventually become therapeutically relevant.

Prion Protein Signaling in the Nervous System—A Review and Perspective

Prion protein (PrPC) was originally known as the causative agent of transmissible spongiform encephalopathy (TSE) but with recent research, its true function in cells is becoming clearer. It is known to act as a scaffolding protein, binding multiple ligands at the cell membrane and to be involved in signal transduction, passing information from the extracellular matrix (ECM) to the cytoplasm. Its role in the coordination of transmitters at the synapse, glyapse, and gap junction and in short- and long-range neurotrophic signaling gives PrPC a major part in neural transmission and nervous system signaling. It acts to regulate cellular function in multiple targets through its role as a controller of redox status and calcium ion flux. Given the importance of PrPC in cell physiology, this review considers its potential role in disease apart from TSE. The putative functions of PrPC point to involvement in neurodegenerative disease, neuropathic pain, chronic headache, and inflammatory disease including neuroinflammatory disease of the nervous system. Potential targets for the treatment of disease influenced by PrPC are discussed.

Network Robustness Due to Multiple Positive Feedback Loops: A Systematic Study of a Th Cell Differentiation Model

Positive feedback loops have been identified in many biological signal transduction systems. Their importance in a system's bistability has been well established by identifying multiple steady states of a network under different parameters. In this paper, we identify the contribution of positive feedback loops to network robustness by a systematic comparison between network structures and responses to perturbations at a pre-steady state. Our study is based on a T helper (Th) cell differentiation model in which positive feedback loops give rise to a subnet robustness against both positive and negative perturbations from outside the subnet. Although it is unclear whether this pre-steady state exists in vivo, the results from in silico modeling are in agreement with the reported in vivo observations. Being highly heterogeneous and rarely at a steady state, the disease cells, such as cancer cells, may gain potential resistances to certain drugs in a similar way. From the reverse engineering point of view, our results confirm that, while data from perturbation experiments are very effective in identifying causal relationships among the network components, caution should be taken, as in some circumstances, a direct interaction could be invisible due to positive feedback loops.