Upregulation of DNA repair genes and cell extrusion underpin the remarkable radiation resistance of Trichoplax adhaerens

Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic, and tissue-level mechanisms underlying cancer suppression.

The placozoan Trichoplax adhaerens is able to tolerate high levels of radiation and is resilient to DNA damage; this study reveals that exposure to X-rays triggers the extrusion of cell clusters which subsequently die, and that radiation exposure induces the overexpression of genes involved in DNA repair.     

Ensconsin-dependent changes in microtubule organization and LINC complex–dependent changes in nucleus–nucleus interactions result in quantitatively distinct myonuclear positioning defects

Nuclear movement is a fundamental process of eukaryotic cell biology. Skeletal muscle presents an intriguing model to study nuclear movement because its development requires the precise positioning of multiple nuclei within a single cytoplasm. Furthermore, there is a high correlation between aberrant nuclear positioning and poor muscle function. Although many genes that regulate nuclear movement have been identified, the mechanisms by which these genes act are not known. Using Drosophila melanogaster muscle development as a model system and a combination of live-embryo microscopy and laser ablation of nuclei, we have found that clustered nuclei encompass at least two phenotypes that are caused by distinct mechanisms. Specifically, Ensconsin is necessary for productive force production to drive any movement of nuclei, whereas Bocksbeutel and Klarsicht are necessary to form distinct populations of nuclei that move to different cellular locations. Mechanistically, Ensconsin regulates the number of growing microtubules that are used to move nuclei, whereas Bocksbeutel and Klarsicht regulate interactions between nuclei.     

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis,biological evaluation,and molecular docking study

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.     

The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q

Neuregulin-2 (NRG2) is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, neuregulin-2 induces the growth and differentiation of epithelial, neuronal, glial and other types of cells. In this study, we have cloned the human neuregulin-2 gene, and determined its genomic structure and alternative splicing patterns. By using radiation hybrid mapping panels, the human NRG2 gene was mapped to the D5S658–D5S402 region within 5q23–q33, close to an autosomal recessive form of demyelinating Charcot-Marie-Tooth (CMT) disease. The NRG2 gene was found to be on two yeast artificial chromosomes overlapping the candidate interval and was, thus, considered a good positional candidate for this form of CMT. When the entire neuregulin-2 coding sequence and splice junctions were explored, however, no mutation was identified in one CMT family linked to 5q23–q33. In addition, three intronic single nucleotide polymorphisms were identified in the NRG2 gene. Genotyping in two families localized the NRG2 gene outside of the revised candidate interval between D5S402–D5S210 and excluded NRG2 as the gene responsible for this form of CMT disease. Received: 11 December 1998 / Accepted: 19 January 1998     

Identification and characterization of a set of monocot BAHD monolignol transferases

Plant BAHD acyltransferases perform a wide range of enzymatic tasks in primary and secondary metabolism. Acyl-CoA monolignol transferases, which couple a CoA substrate to a monolignol creating an ester linkage, represent a more recent class of such acyltransferases. The resulting conjugates may be used for plant defense but are also deployed as important “monomers” for lignification, in which they are incorporated into the growing lignin polymer chain. p-Coumaroyl-CoA monolignol transferases (PMTs) increase the production of monolignol p-coumarates, and feruloyl-CoA monolignol transferases (FMTs) catalyze the production of monolignol ferulate conjugates. We identified putative FMT and PMT enzymes in sorghum (Sorghum bicolor) and switchgrass (Panicum virgatum) and have compared their activities to those of known monolignol transferases. The putative FMT enzymes produced both monolignol ferulate and monolignol p-coumarate conjugates, whereas the putative PMT enzymes produced monolignol p-coumarate conjugates. Enzyme activity measurements revealed that the putative FMT enzymes are not as efficient as the rice (Oryza sativa) control OsFMT enzyme under the conditions tested, but the SbPMT enzyme is as active as the control OsPMT enzyme. These putative FMTs and PMTs were transformed into Arabidopsis (Arabidopsis thaliana) to test their activities and abilities to biosynthesize monolignol conjugates for lignification in planta. The presence of ferulates and p-coumarates on the lignin of these transformants indicated that the putative FMTs and PMTs act as functional feruloyl-CoA and p-coumaroyl-CoA monolignol transferases within plants.

A group of identified BAHD acyltransferases function as feruloyl-CoA monolignol transferases and/or p-coumaroyl-CoA monolignol transferases in vitro and in planta.     

Chromatographic characterization of synthetic peptides: SPf66 malaria vaccine

The development and validation of a quantitative size-exclusion chromatography (SEC) method for SPf66 malaria vaccine was achieved. The results show the reliability of the analytical method for the intended use. SPf66 malaria vaccine characterization was perforrmed using both relative techniques such as the conventional SEC and absolute techniques: mass spectrometry and multi-angle laser-light scattering detection. The relative and absolute molecular masses were in the 4600-18,000 Da range. The results clearly indicate the presence of the monomer and dimer species, whereas the third species could be the trimer or tetramer.     

Mitochondrial outer-membrane permeabilization and remodelling in apoptosis

Many human pathologies are associated with defects in mitochondria such as diabetes, neurodegenerative diseases or cancer. This tiny organelle is involved in a plethora of processes in mammalian cells, including energy production, lipid metabolism and cell death. In the so-called intrinsic apoptotic pathway, the outer mitochondrial membrane (MOM) is premeabilized by the pro-apoptotic Bcl-2 members Bax and Bak, allowing the release of apoptogenic factors such as cytochrome c from the inter-membrane space into the cytosol. At the same time, mitochondria fragment in response to Drp-1 activation suggesting that mitochondrial fission could play a role in mitochondrial outer-membrane permeabilization (MOMP). In this review, we will discuss the link that could exist between mitochondrial fission and fusion machinery, Bcl-2 family members and MOMP.