New findings on molecular mechanisms of plant meiosis obtained through analyses of tagged mutants

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

Download Full-text

ETMR-05. SINGLE-CELL RNA-SEQ OF ETMR REVEALS CELL PROGRAMS OF DEVELOPMENTAL HIERARCHY AND CELLULAR DIVERSITY IN THE TUMOR MICROENVIRONMENT

Neuro-Oncology ◽

10.1093/neuonc/noaa222.209 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii323-iii323

Author(s):

Flavia W de Faria ◽

Marta Interlandi ◽

Natalia Moreno ◽

Monika Graf ◽

Viktoria Melcher ◽

...

Keyword(s):

Stem Cell ◽

Single Cell ◽

Molecular Mechanisms ◽

Interaction Analysis ◽

Cellular Heterogeneity ◽

Receptor Interaction ◽

Acid Oxidation ◽

Bmp Receptors ◽

New Findings ◽

Developmental Hierarchy

Abstract Embryonal tumors with multilayered rosettes (ETMR) are deadly brain malignancies affecting young children. No standard treatment is available and the median survival is less than 12 months. Molecularly, the disease is characterized by the miRNA C19MC cluster amplification, with the expression of multiples miRNAs related to a stem cell program. The discoveries on the purely molecular mechanisms of the disease did not help to create a bridge for new treatment strategies so far and the cellular diversity of ETMR remains poorly understood. In this study, we used single-cell RNA sequencing of murine and human tumors to describe ETMR cellular heterogeneity. Our findings support that intra-tumoral heterogeneity is mainly characterized by 4 cellular programs defining a developmental hierarchy related to different metabolic states: 1) Early quiescent NSC-like cells supported by fatty-acid oxidation 2) Late NSC and NP-like proliferative cells fueled by glycolytic metabolism; 3) Post-mitotic neuroblast-like cells, relying on oxidative-phosphorylation; 4) NSC-like proliferative cells, with metabolic plasticity and capable of performing the three types of metabolism. Tumor-specific ligand-receptor interaction analysis revealed that ETMR exchange with microglia and vascular mural cells (MC) signals related to extracellular matrix (ECM) organization (Cxcl12-CxCr4), stem cell signaling (BMPs-BMP receptors), anti-apoptosis and survival (Ntf3-Ntrk), not seen in the control brain. In addition, the vascular MC showed a cancer-associated fibroblast (CAF) phenotype, with potential prognostic implications, as previously demonstrated for other tumors. This study provides new findings to build up a more robust understanding of ETMR biology and opens space for further studies in the field.

Download Full-text

Integrated Physiological and Transcriptomic Analyses Responses to Altitude Stress in Oat (Avena sativa L.)

Frontiers in Genetics ◽

10.3389/fgene.2021.638683 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu Jinqiu ◽

Li Bing ◽

Song Tingting ◽

He Jinglei ◽

KongLing Zelai ◽

...

Keyword(s):

High Altitude ◽

Avena Sativa ◽

Molecular Mechanisms ◽

Rna Seq ◽

High Altitudes ◽

Genome Wide ◽

New Findings ◽

Polymerase Chain ◽

Transcriptomic Changes ◽

Stressful Environments

Oat is an annual gramineous forage grass with the remarkable ability to survive under various stressful environments. However, understanding the effects of high altitude stresses on oats is poor. Therefore, the physiological and the transcriptomic changes were analyzed at two sites with different altitudes, low (ca. 2,080 m) or high (ca. 2,918 m), respectively. Higher levels of antioxidant enzyme activity, reactive oxygen and major reductions in photosynthesis-related markers were suggested for oats at high altitudes. Furthermore, oat yields were severely suppressed at the high altitude. RNA-seq results showed that 11,639 differentially expressed genes were detected at both the low and the high altitudes in which 5,203 up-regulated and 6,436 down-regulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment tests were conducted and a group of major high altitude-responsive pigment metabolism genes, photosynthesis, hormone signaling, and cutin, suberine and wax biosynthesis were excavated. Using quantitative real-time polymerase chain response, we also confirmed expression levels of 20 DEGs (qRT-PCR). In summary, our study generated genome-wide transcript profile and may be useful for understanding the molecular mechanisms of Avena sativa L. in response to high altitude stress. These new findings contribute to our deeper relevant researches on high altitude stresses and further exploring new candidategenes for adapting plateau environment oat molecular breeding.

Download Full-text

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180523104541 ◽

2018 ◽

Vol 18 (6) ◽

pp. 484-493 ◽

Cited By ~ 29

Author(s):

Xiang Cheng ◽

Jianying Li ◽

Deliang Guo

Keyword(s):

Lipid Metabolism ◽

Cancer Therapy ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Regulatory Element ◽

Lipid Synthesis ◽

Feedback Regulation ◽

Negative Feedback Regulation ◽

Expression Of Genes ◽

New Findings

Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

Download Full-text

A20: a master regulator of arthritis

Arthritis Research & Therapy ◽

10.1186/s13075-020-02281-1 ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Yongyao Wu ◽

Xiaomin He ◽

Ning Huang ◽

Jiayun Yu ◽

Bin Shao

Keyword(s):

Cell Death ◽

Immune Responses ◽

Mouse Models ◽

Inflammatory Arthritis ◽

Molecular Mechanisms ◽

Related Research ◽

Inflammatory Protein ◽

New Findings ◽

Tnf Α

Abstract A20, also known as TNF-α-induced protein 3 (TNFAIP3), is an anti-inflammatory protein that plays an important part in both immune responses and cell death. Impaired A20 function is associated with several human inflammatory and autoimmune diseases. Although the role of A20 in mediating inflammation has been frequently discussed, its intrinsic link to arthritis awaits further explanation. Here, we review new findings that further demonstrate the molecular mechanisms through which A20 regulates inflammatory arthritis, and we discuss the regulation of A20 by many factors. We conclude by reviewing the latest A20-associated mouse models that have been applied in related research because they reflect the characteristics of arthritis, the study of which will hopefully cast new light on anti-arthritis treatments.

Download Full-text

The Developmental Phases of Zebrafish Myogenesis

Journal of Developmental Biology ◽

10.3390/jdb7020012 ◽

2019 ◽

Vol 7 (2) ◽

pp. 12 ◽

Cited By ~ 5

Author(s):

Samuel R. Keenan ◽

Peter D. Currie

Keyword(s):

Molecular Mechanisms ◽

Muscle Growth ◽

Data Sets ◽

Vertebrate Lineage ◽

New Findings ◽

Muscle Groups ◽

Teleost Muscle ◽

Axial Musculature ◽

Developmental Phases ◽

Type Specification

The development and growth of vertebrate axial muscle have been studied for decades at both the descriptive and molecular level. The zebrafish has provided an attractive model system for investigating both muscle patterning and growth due to its simple axial musculature with spatially separated fibre types, which contrasts to complex muscle groups often deployed in amniotes. In recent years, new findings have reshaped previous concepts that define how final teleost muscle form is established and maintained. Here, we summarise recent findings in zebrafish embryonic myogenesis with a focus on fibre type specification, followed by an examination of the molecular mechanisms that control muscle growth with emphasis on the role of the dermomyotome-like external cell layer. We also consider these data sets in a comparative context to gain insight into the evolution of axial myogenic patterning systems within the vertebrate lineage.

Download Full-text

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Blood ◽

10.1182/blood-2016-09-692574 ◽

2017 ◽

Vol 129 (9) ◽

pp. 1071-1081 ◽

Cited By ~ 75

Author(s):

Toshiki Watanabe

Keyword(s):

T Cells ◽

T Cell ◽

Molecular Basis ◽

Molecular Mechanisms ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

New Findings

Abstract Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

Download Full-text

Mechanisms of fibrin polymerization and clinical implications

Blood ◽

10.1182/blood-2012-09-306639 ◽

2013 ◽

Vol 121 (10) ◽

pp. 1712-1719 ◽

Cited By ~ 238

Author(s):

John W. Weisel ◽

Rustem I. Litvinov

Keyword(s):

Molecular Mechanisms ◽

Fibrin Polymerization ◽

Subsequent Formation ◽

3 Dimensional ◽

X Ray Crystallography ◽

Molecular Variants ◽

New Findings ◽

Clinical Consequences ◽

Functional Consequences ◽

Clot Structure

Abstract Research on all stages of fibrin polymerization, using a variety of approaches including naturally occurring and recombinant variants of fibrinogen, x-ray crystallography, electron and light microscopy, and other biophysical approaches, has revealed aspects of the molecular mechanisms involved. The ordered sequence of fibrinopeptide release is essential for the knob-hole interactions that initiate oligomer formation and the subsequent formation of 2-stranded protofibrils. Calcium ions bound both strongly and weakly to fibrin(ogen) have been localized, and some aspects of their roles are beginning to be discovered. Much less is known about the mechanisms of the lateral aggregation of protofibrils and the subsequent branching to yield a 3-dimensional network, although the αC region and B:b knob-hole binding seem to enhance lateral aggregation. Much information now exists about variations in clot structure and properties because of genetic and acquired molecular variants, environmental factors, effects of various intravascular and extravascular cells, hydrodynamic flow, and some functional consequences. The mechanical and chemical stability of clots and thrombi are affected by both the structure of the fibrin network and cross-linking by plasma transglutaminase. There are important clinical consequences to all of these new findings that are relevant for the pathogenesis of diseases, prophylaxis, diagnosis, and treatment.

Download Full-text

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00756.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. H482-H491 ◽

Cited By ~ 46

Author(s):

Alexey V. Glukhov ◽

Vadim V. Fedorov ◽

Mark E. Anderson ◽

Peter J. Mohler ◽

Igor R. Efimov

Keyword(s):

Molecular Mechanisms ◽

Cell Function ◽

Optical Mapping ◽

Functional Anatomy ◽

Dynamic Interaction ◽

Pacemaker Activity ◽

Intact Mouse ◽

New Findings ◽

Cardiac Automaticity ◽

Ankyrin B

The mouse is widely used as a genetic platform to investigate the molecular mechanisms of sinoatrial node (SAN) pacemaking. Recently, it has been shown that isolated SAN cells from the ankyrin-B (AnkB)-deficient mice display severe pacemaking dysfunction similar to individuals harboring ankyrin 2 allele variants. However, these results have been limited to isolated SAN cells only and thus did not evaluate the functional anatomy of the widely distributed atrial pacemaker complex (e.g., the dynamic interaction of primary and subsidiary pacemakers). We studied pacemaker function in an intact mouse atrial preparation, which included the SAN, atrioventricular junction (AVJ), and both atria, excluding most of the septum. Optical mapping with a voltage-sensitive dye and CMOS camera ULTIMA-L was used to map spontaneous pacemaker activity with or without autonomic modulation in wild-type (WT) mice ( n = 7) and in the AnkB heterozygous (AnkB+/−; n = 9) mouse model of human SAN disease. In WT mice, isoproterenol accelerated the SAN rate (for 10 μM: from 325 ± 19 to 510 ± 33 beat/min, P < 0.01) and shifted the leading pacemaker site superiorly by 0.77 ± 0.11 mm within the SAN. ACh decreased the SAN rate (from 333 ± 26 to 96 ± 22 beats/min, P < 0.01) and shifted the leading pacemaker either inferiorly within the SAN or abruptly toward the AVJ. After isoproterenol, AnkB+/− mice exhibited a larger beat-to-beat variability (SD of a cycle length: 13.4 ± 3.6 vs. 2.5 ± 0.8 ms, P < 0.01 vs. WT mice), disorganized shift of the leading pacemaker (2.04 ± 0.37 mm, P < 0.05 vs. WT mice), and competing multiple pacemakers, resulting in beat-to-beat changes of the leading pacemaker location site between the SAN and AVJ regions. Notably, AnkB+/− mice also displayed a reduced sensitivity to ACh (rate slowing by 32 ± 12% vs. 67 ± 4%, P < 0.05, AnkB+/− vs. WT mice, respectively). In conclusion, AnkB dysfunction results in SAN abnormalities in an isolated mouse atria preparation. While AnkB dysfunction dramatically alters single SAN cell function, the mechanisms underlying cardiac automaticity are clearly complex, and phenotypes may be partially compensated by the dynamic interaction of cells within the pacemaker complex. These new findings highlight the importance of the functional anatomy of the entire atrial distributed pacemaker complex, including the SAN and AVJ, and clearly demonstrate the role of AnkB in cardiac automaticity.

Download Full-text

Meeting Report on the ASM Conference on Mechanisms of Interbacterial Cooperation and Competition

Journal of Bacteriology ◽

10.1128/jb.00403-17 ◽

2017 ◽

Vol 199 (22) ◽

Cited By ~ 4

Author(s):

Bram Lories ◽

Ilse Parijs ◽

Kevin R. Foster ◽

Hans P. Steenackers

Keyword(s):

Molecular Mechanisms ◽

Meeting Report ◽

Washington Dc ◽

Social Communities ◽

Cooperation And Competition ◽

New Findings ◽

Wide Range ◽

Evolution Computation ◽

American Society ◽

American Society For Microbiology

ABSTRACT The American Society for Microbiology Conference on Mechanisms of Interbacterial Cooperation and Competition was held in Washington, DC, from 1 to 4 March 2017. The conference provided an international forum for sociomicrobiologists from different disciplines to present and discuss new findings. The meeting covered a wide range of topics, spanning molecular mechanisms, ecology, evolution, computation, and manipulation of interbacterial interactions, and encompassed social communities in medicine, the natural environment, and industry. This report summarizes the presentations and emerging themes.

Download Full-text