Beyond genetics – The emerging role of epigenetics and its clinical aspects

Analysis of genomic sequences has clearly shown that the genomic differences among species do not explain the diversity of life. The genetic code itself serves as only a part of the dynamic complexity that results in the temporal and spatial changes in cell phenotypes during development. It has been concluded that the phenotype of a cell and of the organism as a whole is more influenced by environmentally-induced changes in gene activity than had been previously thought. The emerging field of epigenetics focuses on molecular marks on chromatin; called the epigenome, which serve as transmitters between the genome and the environment. These changes not only persist through multiple cell division cycles, but may also endure for multiple generations. Irregular alterations of the epigenome; called epimutations, may have a decisive role in the etiology of human pathologies such as malignancies and other complex human diseases. Epigenetics can provide the missing link between genetics, disease and the environment. Therefore, this field may have an increasing impact on future drug design and serve as a basis for new therapeutic/preventative approaches. Orv. Hetil., 2012, 153, 214–221.

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Surface morphology and agglutination of lectin-treated human lymphocytes and lymphoblasts

Journal of Cell Science ◽

10.1242/jcs.21.3.563 ◽

1976 ◽

Vol 21 (3) ◽

pp. 563-578

Author(s):

J.H. Temmink ◽

J.G. Collard ◽

J. Roosien ◽

J.F. Van den Bosch

Keyword(s):

Cell Surface ◽

Surface Morphology ◽

Human Lymphocytes ◽

Cell Type ◽

A Cell ◽

Human Peripheral Lymphocytes ◽

Normal Human ◽

Altered Cell ◽

Induced Changes ◽

Cell Surface Morphology

Two human lymphoblasts (Raji and EB3) and normal human peripheral lymphocytes were exposed to different concentrations of Concanavalin A and wheat germ agglutinin. The lectin-induced agglutination was determined and correlated with lectin-induced changes in the surface morphology of these cells as studied in a scanning electron microscope. Whenever the lectin induced high agglutinability in a cell type, it also invariably had a smoothing effect on the cell surface. In contrast, when cells did not agglutinate well with a certain lectin, their cell surface remained essentially rough (villous) after addition of the lectin. The correlation found between increased agglutinability and altered cell surface morphology upon treatment with certain lectins suggests that both phenomena result from one and the same process. Additional evidence for this postulate is presented.

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Stakeholder Analysis as a Tool for Systems Approach Research in HRD

10.31124/advance.7433933 ◽

2018 ◽

Author(s):

Robert Yawson ◽

Bradley Greiman

Keyword(s):

Human Resource Development ◽

Agricultural Education ◽

Systems Approach ◽

Stakeholder Analysis ◽

Collective Actions ◽

It Use ◽

Dynamic Complexity ◽

Analysis Methodology ◽

Hrd Professionals ◽

Induced Changes

<p>The world is experiencing significant, largely economic and sociotechnical, induced change. These induced changes are meaningful with a function of people taking collective actions around common beliefs. These changes are more than jargon, cliché and hyperbole, and they are effecting major transformations. These transformations will impact on how human resources are developed and we need to be able to forecast its effects. In order to produce such forecasts, HRD needs to become more predictive - to develop the ability to understand how human capital systems and organizations will behave in future. Further development of systems models is required to allow such predictions to be made. Critical to the development of such models will be to understand that linear epistemology cannot be the dominant epistemology of practice and that dynamic complexity of challenges confronted by HRD professionals in their daily research and practice requires a nonlinear epistemology of practice, rather than reductive or linear thinking or processes of normal science. Although the adoption of a systems approach to research in HRD is not novel, methodologies and conceptual approaches underlying it use are not very well developed. In this paper, a stakeholder analysis methodology that was developed as a novel method in conducting systems approach research in human resource development, public policy and agricultural education is described. </p>

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Discovery of a Novel Bat Gammaherpesvirus

mSphere ◽

10.1128/msphere.00016-16 ◽

2016 ◽

Vol 1 (1) ◽

Cited By ~ 5

Author(s):

Kurtis M. Host ◽

Blossom Damania

Keyword(s):

Phylogenetic Analysis ◽

Hybrid Label-Free Molecular Microscopies for Simultaneous Visualization of Changes in Cell Wall Polysaccharides of Peach at Single- and Multiple-Cell Levels during Postharvest Storage

Cells ◽

10.3390/cells9030761 ◽

2020 ◽

Vol 9 (3) ◽

pp. 761

Author(s):

Weinan Huang ◽

Yating Nie ◽

Nan Zhu ◽

Yifan Yang ◽

Changqing Zhu ◽

...

Keyword(s):

Cell Wall ◽

Label Free ◽

Cell Wall Polysaccharides ◽

Cell Level ◽

Postharvest Storage ◽

Peach Fruit ◽

Spatial Changes ◽

Multiple Cell ◽

Parenchymal Cells ◽

Simultaneous Visualization

Softening of fruit during the postharvest storage, which is mainly associated with both compositional and spatial changes of polysaccharides within cell wall, affects the texture and quality of fruit. Current research on the fruit softening mechanism lacks an understanding of the overall softening at the cell level. The objective of this work was to investigate the change in the spatial distribution of cell wall polysaccharides in peach flesh cells at both single- and multiple-cell levels in a label-free way during the postharvest storage. Nonmelting peaches (Prunus persica L. Batsch cv.”Zhonghuashoutao”) at commercial maturity were stored at 0 °C and 20 °C. Firmness measurement and chemical analysis were performed at each storage time. In addition, three molecular imaging techniques, namely confocal Raman microspectroscopy (CRM), Fourier transform infrared microspectroscopy (FTIRM), and stimulated Raman scattering microscopy (SRS) were used to visualize changes in the spatial distribution of cell wall polysaccharides of peach fruit in a label-free way during the postharvest storage. The combination of CRM and FTIRM provided complementary spectral information to visualize the spatial changes of cellulose, hemicellulose, and pectin in the cell wall of peach flesh during softening at the single-cell level, and found that the cell wall polysaccharides tended to be concentrated in the cell corner of parenchymal cells at the late stage. Furthermore, SRS, which is an ultrafast Raman imaging technique (approximately three or four orders of magnitude faster than CRM), was used for high-throughput cell wall phenotypes measurement. Different degradation degrees of parenchymal cells during fruit softening were found based on the gray-scale statistical analysis of SRS data. In general, cell wall polysaccharides decreased during softening and tended to be concentrated in the cell corner for most parenchymal cells at the late stage, but there were also some cells not in line with the whole softening trends. The results show that there were differences in the content and spatial changes of cell wall polysaccharides among parenchymal cells of peach fruit during the softening process, and the hybrid use of CRM, FTIRM, and SRS is a promising method for simultaneous visualization of changes in cell wall polysaccharides of peach.

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Cortical Thinning and Hydrocephalus in Mice Lacking the Immunoglobulin Superfamily Member CDO

Molecular and Cellular Biology ◽

10.1128/mcb.26.10.3764-3772.2006 ◽

2006 ◽

Vol 26 (10) ◽

pp. 3764-3772 ◽

Cited By ~ 26

Author(s):

Wei Zhang ◽

Min-Jeong Yi ◽

Xiaoping Chen ◽

Francesca Cole ◽

Robert S. Krauss ◽

...

Keyword(s):

Neuronal Differentiation ◽

Myogenic Differentiation ◽

Immunoglobulin Superfamily ◽

Cortical Thinning ◽

Helix Loop Helix ◽

Neuronal Precursor Cells ◽

A Cell ◽

Multiple Cell

ABSTRACT CDO is a cell surface immunoglobulin superfamily member that positively regulates myogenic differentiation in vitro and in vivo and signals to posttranslationally activate myogenic basic helix-loop-helix (bHLH) transcription factors. The Cdo gene is also expressed in the dorsal aspect and midline structures of the developing central nervous system, and mice lacking CDO on the C57BL/6 background display holoprosencephaly with ∼80% penetrance, resulting in perinatal lethality. We report here that a fraction of Cdo −/− mice from this background have additional defects in brain development, including hydrocephalus and cortical thinning. Primary neural progenitor cultures from E14.5 Cdo −/− mutants display reduced proliferation, which may underlie the thinning. The cortical preplate and cortices of mutant animals also show reduced staining for β-tubulin III, indicating defective neuronal differentiation. CDO levels are strongly increased in cultured C17.2 neuronal precursor cells stimulated to differentiate; modulation of CDO levels in these cells by overexpression or interfering RNA approaches enhances or diminishes differentiation, respectively. Cotransfection of CDO enhances the activity of the neurogenic bHLH factor, neurogenin1, in reporter assays and enhances heterodimerization of neurogenin1 and E47. These results indicate that CDO promotes neuronal differentiation and support the hypothesis that CDO coordinates differentiation of multiple cell lineages by regulating the activity of tissue-specific bHLH factors.

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In vivo support for the new concept of pulmonary blood flow-mediated CO2 gas excretion in the lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00205.2014 ◽

2015 ◽

Vol 308 (12) ◽

pp. L1224-L1236 ◽

Cited By ~ 1

Author(s):

Yoshiko Kawai ◽

Kumiko Ajima ◽

Maki Kaidoh ◽

Masao Sakaguchi ◽

Satoshi Tanaka ◽

...

Keyword(s):

Blood Flow ◽

Pulmonary Artery ◽

Pulmonary Blood Flow ◽

Pulmonary Arteries ◽

Systemic Arterial Pressure ◽

Maximal Velocity ◽

Clinical Models ◽

A Cell ◽

Induced Changes

To further examine the validity of the proposed concept of pulmonary blood flow-dependent CO2 gas excretion in the lungs, we investigated the effects of intramediastinal balloon catheterization-, pulmonary artery catheterization-, or isoprenaline (ISP)-induced changes in pulmonary blood flow on the end-expiratory CO2 gas pressure (PeCO2), the maximal velocity of the pulmonary artery (Max Vp), systemic arterial pressure, and heart rate of anesthetized rabbits. We also evaluated the changes in the PeCO2 in clinical models of anemia or pulmonary embolism. An almost linear relationship was detected between the PeCO2 and Max Vp. In an experiment in which small pulmonary arteries were subjected to stenosis, the PeCO2 fell rapidly, and the speed of the reduction was dependent on the degree of stenosis. ISP produced significant increases in the PeCO2 of the anesthetized rabbits. Conversely, treatment with piceatannol or acetazolamide induced significant reductions in the PeCO2. Treatment with a cell surface F1/FO ATP synthase antibody caused significant reductions in the PeCO2 itself and the ISP-induced increase in the PeCO2. Neither the PeCO2 nor SAP was significantly influenced by marked anemia [%hematocrit (Ht), 70∼47%]. On the other hand, in the presence of less severe anemia (%Ht: 100∼70%) both the PeCO2 and SAP fell significantly when the rabbits' blood viscosity was decreased. The rabbits in which pulmonary embolisms were induced demonstrated significantly reduced PeCO2 values, which was compatible with the lowering of their Max Vp. In conclusion, we reaffirm the validity of the proposed concept of CO2 gas exchange in the lungs.

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A Cell Profiling Framework for Modeling Drug Responses from HCS Imaging

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057110372256 ◽

2010 ◽

Vol 15 (7) ◽

pp. 858-868 ◽

Cited By ~ 12

Author(s):

Alvin Y. J. Ng ◽

Jagath C. Rajapakse ◽

Roy E. Welsch ◽

Paul T. Matsudaira ◽

Victor Horodincu ◽

...

Keyword(s):

Similar Drug ◽

Chi Squared ◽

A Cell ◽

Clustering Approach ◽

Cell Phenotypes ◽

Cluster Profiles ◽

Treatment Concentration ◽

Fold Cross Validation ◽

Cell Profile ◽

Cytoskeletal Drugs

The authors present an unsupervised, scalable, and interpretable cell profiling framework that is compatible with data gathered from high-content screening. They demonstrate the effectiveness of their framework by modeling drug differential effects of IC-21 macrophages treated with microtubule and actin disrupting drugs. They identify significant features of cell phenotypes for unsupervised learning based on maximum relevancy and minimum redundancy criteria. A 2-stage clustering approach annotates, clusters cells, and then merges them together to form super-clusters. An interpretable cell profile consisting of super-cluster proportions profiled at each drug treatment, concentration, or duration is obtained. Differential changes in super-cluster profiles are the basis for understanding the drug’s differential effect and biology. The authors’ method is validated by significant chi-squared statistics obtained from similar drug-treated super-cluster profiles from a 5-fold cross-validation. In addition, drug profiles of 2 microtubule drugs with equivalent mechanisms of action are statistically similar. Several distinct trends are identified for the 5 cytoskeletal drugs profiled under different conditions.

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Characterizing Cannabinoid CB2 Receptor Ligands Using DiscoveRx PathHunter™ β-Arrestin Assay

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057108327329 ◽

2008 ◽

Vol 14 (1) ◽

pp. 49-58 ◽

Cited By ~ 45

Author(s):

Debra Mcguinness ◽

Asra Malikzay ◽

Richard Visconti ◽

Karen Lin ◽

Marvin Bayne ◽

...

Keyword(s):

Cb2 Receptor ◽

Receptor Ligands ◽

Camp Assay ◽

Cryopreserved Cell ◽

Random Library ◽

A Cell ◽

Multiple Cell ◽

Screening Platform ◽

Protein Complementation ◽

Camp Levels

The authors have characterized a set of cannabinoid CB2 receptor ligands, including triaryl bis sulfone inverse agonists, in a cell-based receptor/β-arrestin interaction assay (DiscoveRx PathHunter™). The results were compared with results using a competitive ligand binding assay, and with effects on forskolin-stimulated cAMP levels (PerkinElmer LANCE™). The authors show good correlation between the 3 assay systems tested, with the β-arrestin protein complementation assay exhibiting a more robust signal than the cAMP assay for cannabinoid CB2 agonists. Further assay validation shows that DiscoveRx PathHunter™ HEK293 CB2 β-arrestin assay can be carried out from cryopreserved cell suspensions, eliminating variations caused by the need for multiple cell pools during live cell screening campaigns. These results, and the authors' results evaluating a test set of random library compounds, validate the use of ligand-induced interaction between the human cannabinoid CB2 receptor and β-arrestin as an appropriate and valuable screening platform for compounds specific for the cannabinoid CB2 receptor. ( Journal of Biomolecular Screening 2009:49-58)

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ICELLNET: a transcriptome-based framework to dissect intercellular communication

10.1101/2020.03.05.976878 ◽

2020 ◽

Cited By ~ 5

Author(s):

Floriane Noël ◽

Lucile Massenet-Regad ◽

Irit Carmi-Levy ◽

Antonio Cappuccio ◽

Maximilien Grandclaudon ◽

...

Keyword(s):

Cell Population ◽

Cell Communication ◽

Cell Types ◽

Receptor Expression ◽

Global Integration ◽

Cancer Associated Fibroblast ◽

Receptor Interactions ◽

Biological Interpretation ◽

A Cell ◽

Multiple Cell

AbstractCell-to-cell communication can be inferred from ligand-receptor expression in cell transcriptomic datasets. However, important challenges remain: 1) global integration of cell-to-cell communication, 2) biological interpretation, and 3) application to individual cell population transcriptomic profiles. We developed ICELLNET, a transcriptomic-based framework integrating: 1) an original expert-curated database of ligand-receptor interactions accounting for multiple subunits expression, 2) quantification of communication scores, 3) the possibility to connect a cell population of interest with 31 reference human cell types (BioGPS), and 4) three visualization modes to facilitate biological interpretation. We applied ICELLNET to uncover different communication in breast cancer associated fibroblast (CAF) subsets. ICELLNET also revealed autocrine IL-10 as a switch to control human dendritic cell communication with up to 12 other cell types, four of which were experimentally validated. In summary, ICELLNET is a global, versatile, biologically validated, and easy-to-use framework to dissect cell communication from single or multiple cell-based transcriptomic profile(s).

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Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons

eLife ◽

10.7554/elife.62911 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Claudia Scheckel ◽

Marigona Imeri ◽

Petra Schwarz ◽

Adriano Aguzzi

Keyword(s):

Prion Disease ◽

Prion Diseases ◽

Affinity Purification ◽

Ribosome Profiling ◽

Neurological Symptoms ◽

Disease Manifestation ◽

Biologically Relevant ◽

Primary Driver ◽

A Cell ◽

Induced Changes

Prion diseases are caused by PrPSc, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrPSc causes a robust, reproducible and specific disease manifestation. Here, we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type-specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.

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