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PubMed2001

Protein kinase C phosphorylates nonmuscle myosin-II heavy chain from Drosophila but regulation of myosin function by this enzyme is not required for viability in flies.

Conventional myosins (myosin-IIs) generate forces for cell shape change and cell motility. Myosin heavy chain phosphorylation regulates myosin function in simple eukaryotes and may also be important in metazoans. To investigate this regulation in a complex eukaryote, we purified the Drosophila myosin-II tail expressed in Escherichia coli and showed that it was phosphorylated in vitro by protein kinase C(PKC) at serines 1936 and 1944, which are located in the nonhelical globular tail piece. These sites are close to a conserved serine that is phosphorylated in vertebrate, nonmuscle myosin-IIs. If the two serines are mutagenized to alanine or aspartic acid, phosphorylation no longer occurs. Using a 341 amino acid tail fragment, we show that there is no difference in the salt-dependent assembly of wild-type phosphorylated and mutagenized polypeptides. Thus, the nonmuscle myosin heavy chain in Drosophila, which is encoded by the zipper gene, appears to be similar to rabbit nonmuscle myosin-IIA. In vivo, we generated transgenic flies that expressed the various myosin heavy chain variants in a zipper null or near-null genetic background. Like their wild-type counterparts, such variants are able to completely rescue the lethal phenotype due to severe zipper mutations. These results suggest that while the myosin-II heavy chain can be phosphorylated by PKC, regulation by this enzyme is not required for viability in Drosophila. Conservation during 530-1000 million years of evolution suggests that regulation by heavy chain phosphorylation may contribute to nonmuscle myosin-II function in some real, but minor, way.

Amino Acid Sequence↗
PubMed2006

Anatomy of the avian hippocampal formation.

Increasing knowledge of the avian hippocampal formation (hippocampus and parahippocampal area) suggests that it plays a role in a variety of behaviors, such as homing, cache retrieving, visual discrimination, imprinting, and sexual behavior. Knowledge of the neural circuits in the hippocampal formation and its related areas or nuclei is important for the understanding of these functions. This review therefore describes the functional neuroanatomy of the avian hippocampal formations, i.e., its subdivisions, cytoarchitecture, and afferent and efferent connections. Evidence obtained by a combination of Nissl staining and tract-tracing shows that the pigeon hippocampal formation can be divided into seven subdivisions: dorsolateral (DL), dorsomedial (DM), triangular (Tr), V-shaped (V), magnocellular (Ma), parvocellular, and cell-poor regions. DL and DM can be further divided into dorsal and ventral, and lateral and medial portions, respectively. In the hippocampal formation, reciprocal connections are found between DL-DM, DL-Tr, DL-Ma, DM-Ma, DM-V, and Tr-V. Neurons in the V-shaped layer appear to be intrinsic neurons. Sensory inputs from higher order visual and olfactory stations enter DL and DM, are modified or integrated by intrinsic hippocampal circuitry, and the outputs are sent, via DL and DM, to various telencephalic nuclei, septum, and hypothalamus. The neural pathways indicate that the hippocampal formation plays a central role in the limbic system, which also includes the dorsolateral corticoid area, nucleus taeniae of the amygdala, posterior pallial amygdala, septum, medial part of the anterior dorsolateral nucleus of the thalamus, and the lateral mammillary nucleus. Connectional and comparative studies, including the use of kainic acid excitotoxicity, suggest that the V-shaped layer is comparable to the dentate gyrus of the mammalian hippocampal formation and DM to Ammon's horn and subiculum.

Animals↗
PubMed2003

Evolutionary convergence in Otx expression in the pentameral adult rudiment in direct-developing sea urchins.

Convergence is a significant evolutionary phenomenon. Arrival at similar morphologies from different starting points indicates a strong role for natural selection in shaping morphological phenotypes. There is no evidence yet of convergence in the developmental mechanisms that underlie the evolution of convergent developmental phenotypes. Here we report the expression domains in sea urchins of two important developmental regulatory genes ( Orthodenticle and Runt), and show evidence of molecular convergence in the evolution of direct-developing sea urchins. Indirect development is ancestral in sea urchins. Evolutionary loss of the feeding pluteus stage and precocious formation of the radially symmetric juvenile has evolved independently in numerous sea urchin lineages, thus direct development is an evolutionary convergence. Indirect-developing species do not express Otx during the formation of their five primordial tube feet, the ancestral condition. However, each direct-developing urchin examined does express Otx in the tube feet. Otx expression in the radial arms of direct-developing sea urchins is thus convergent, and may indicate a specific need for Otx use in direct development, a constraint that would make direct development less able to evolve than if there were multiple molecular means for it to evolve. In contrast, Runt is expressed in tube feet in both direct- and indirect-developing species. Because echinoderms are closely related to chordates and postdate the protostome/deuterostome divergence, they must have evolved from bilaterally symmetrical ancestors. Arthropods and chordates use Otx in patterning their anterior axis, and Runt has multiple roles including embryonic patterning in arthropods, and blood and bone cell differentiation in vertebrates. Runt has apparently been co-opted in echinoderms for patterning of pentamery, and Otx in pentameral patterning among direct-developing echinoids. The surprisingly dynamic nature of Otx evolution reinvigorates debate on the role of natural selection vs shared ancestry in the evolution of novel features.

Animals↗
PubMed2002

Cell volume homeostasis: ionic and nonionic mechanisms. The sodium pump in the emergence of animal cells.

Plant cells and bacterial cells are surrounded by a massive polysaccharide wall, which constrains their high internal osmotic pressure (tens of atmospheres). Animal cells, in contrast, are in osmotic equilibrium with their environment, have no restraining surround, and can take on a variety of shapes and can change these from moment to moment. This osmotic balance is achieved, in the first place, by the action of the energy-consuming sodium pump, one of the P-type ATPase transport protein family, members of which are found also in bacteria. The pump's action brings about a transmembranal electrochemical gradient of sodium ions, harnessed in a range of transport systems which couple the dissipation of this gradient to establishing a gradient of the coupled substrate. These transport systems include many which are responsible for short-term regulation of the cell's volume in response to acute changes of their osmotic balance. Thus, the primary role of the sodium pump as a regulator of cell volume has been built upon to provide the basis for an enormous variety of physiological functions.

Animals↗
PubMed1975

A light- and electron-microscope study of the oocyte nucleus during development of the antral follicle in the prepubertal mouse.

The ordered changes which occur in the structural organization of the mouse oocyte nucelus during the preparatory, the maturative and the preovulatory stages of antral follicle development, have been studied under both light and electron microscopy. All observations have been made on those antral follicles whose development is initiated on postnatal day 14 and completed by postnatal day 28 in prepubertal animals of the ICR albino mouse strain. The formed entities that can be recognized within the oocyte nucleus during that period are the condensing bivalents, the heterochromatic knobs, the nucleolus and the extranucleolar bodies. At the onset of antral follicle development, the highly unravelled dictyate bivalents are seen to take on a lampbrush-type configuration. Subsequent condensation of these lampbursh bivalents appears to be a very gradual and lengthy process that extends over almost the entire period of antral follicle development. The shortening and thickening of the lampbrush bivalents are best interpreted as resulting from the withdrawal of their lateral loop-like projections into the chromosome axes and from the focal aggregation of these axes into compact chromatin masses. Electron-opaque granules, which appear within the oocyte nucleus during the preparatory and maturative follicle stages, are seen to be intimately associated with these condensing bivalents. A number of Feulgen-positive heterochromatic knobs make their appearance in contact with certain bivalents during the preparatory follicle stage. These knobs are not reincorporated as such into the condensing chromatin masses and undergo disintegration and dissolution during the preovulatory follicle stage. The size, shape and ultrastructural features of the nucleolus remain unchanged thoughout the period of antral follicle development. Breakdown and dissolution of the nucleolar mass is a swift process that takes place only in the fully mature preovulatory follicle and more or less concomitantly with the dismantling of the nuclear envelope. The extranucleolar bodies increase noticeably in size during the preparatory and the maturative follicle stages; they shrink in size and undergo dissolution during the preovulatory stage of antral follicle development. An attempt is made to interpret these morphological changes in the light of current knowledge concerning the architectural and functional organization of the oocyte nucleus in general during meiotic prophase. The relevant observational evidence would be consistent with the view that, during antral follicle deveopment, the mouse oocyte nucleus is not, as too often assumed, in a period of arrested evolution; its formed components undergo structural, maturational and functional changes which are of significance not only for the resumption of the first meiotic prophase but also for the early development of the embryo.

Age Factors↗
PubMed1988

The current state of intraoperative interstitial brachytherapy in lung cancer.

Low dose-rate intraoperative brachytherapy allows for a more precise tumor localization of the delivered radiation and its easier adaptation to the tumor shape than it is possible with external radiation. As a result a higher dose is usually delivered to the tumor volume and the damage to the normal lung is less. In an attempt to determine the value of lung brachytherapy we provide in this article a complete review of the evolution of brachytherapy in lung cancer at Memorial Sloan-Kettering Cancer Center, an experience which exceeds 1,000 patients. The use of encapsulated sources of I-125, greatly reduced radiation outside the treatment volume and simplified medical and nursing staff radiation protection. Lung brachytherapy in combination with surgery and postoperative external radiation, improved local tumor control in advanced tumors (from 63% to 76%) with no increase in late pulmonary morbidity, but only a modest survival advantage. The results of brachytherapy in patients with early lung cancer who had limited pulmonary reserve, suggest that intraoperative brachytherapy is an effective alternative treatment option. The limited experience with interstitial brachytherapy under fluoroscopic and CT guidance is encouraging, but needs more investigation.

Brachytherapy↗
PubMed1997

Structure of the RNA-dependent RNA polymerase of poliovirus.

BACKGROUND: The central player in the replication of RNA viruses is the viral RNA-dependent RNA polymerase. The 53 kDa poliovirus polymerase, together with other viral and possibly host proteins, carries out viral RNA replication in the host cell cytoplasm. RNA-dependent RNA polymerases comprise a distinct category of polymerases that have limited sequence similarity to reverse transcriptases (RNA-dependent DNA polymerases) and perhaps also to DNA-dependent polymerases. Previously reported structures of RNA-dependent DNA polymerases, DNA-dependent DNA polymerases and a DNA-dependent RNA polymerase show that structural and evolutionary relationships exist between the different polymerase categories. RESULTS: We have determined the structure of the RNA-dependent RNA polymerase of poliovirus at 2.6 A resolution by X-ray crystallography. It has the same overall shape as other polymerases, commonly described by analogy to a right hand. The structures of the 'fingers' and 'thumb' subdomains of poliovirus polymerase differ from those of other polymerases, but the palm subdomain contains a core structure very similar to that of other polymerases. This conserved core structure is composed of four of the amino acid sequence motifs described for RNA-dependent polymerases. Structure-based alignments of these motifs has enabled us to modify and extend previous sequence and structural alignments so as to relate sequence conservation to function. Extensive regions of polymerase-polymerase interactions observed in the crystals suggest an unusual higher order structure that we believe is important for polymerase function. CONCLUSIONS: As a first example of a structure of an RNA-dependent RNA polymerase, the poliovirus polymerase structure provides for a better understanding of polymerase structure, function and evolution. In addition, it has yielded insights into an unusual higher order structure that may be critical for poliovirus polymerase function.

Amino Acid Sequence↗
PubMed1992

Expression and biological significance of human endogenous retroviral sequences.

The human genome contains a variety of elements resembling mammalian retroviruses. Most of these sequences have been found to be related to primate and murine C-type viruses (BaEV, SSAV/GaLV, MuLV), murine B-type viruses and A-type particles (MMTV, IAP), or human T-cell lymphotropic viruses (HTLV). Altogether, human endogenous retroviruses and retroviral elements are estimated to comprise at least 0.1 to 0.6% of the human genome. Like other transposable elements they may contribute in shaping the eukaryotic genome by intracellular transposition events or by generating hot spots of recombination. Human retroviral sequences have been shown to be transcriptionally active, especially in human placenta and embryonic tissue and in human tumor cell lines. Some elements that are coexpressed with cellular sequences are supposed to play a role in regulation of gene expression. Furthermore, expression of human endogenous retroviral sequences may have a protective function against superinfection by related exogenous retroviruses. On the other hand, endogenous retroviruses and retroviral elements represent a cellular reservoir of possibly pathogenic retroviral genes. They may be involved in chromosomal aberrations by acting as sites for recombination events between different chromosomes. Furthermore, they can act as insertion mutagens and activate or inactivate cellular genes. Retroviral gene products themselves may also be pathogenic as has been shown for the immunosuppressive effects of p15E envelope proteins. Therefore, the role of human endogenous retroviruses and retroviral sequences in biological processes is currently a subject of great interest.

Animals↗
PubMed2006

Hatena arenicola gen. et sp. nov., a katablepharid undergoing probable plastid acquisition.

Hatena arenicola gen. et sp. nov., an enigmatic flagellate of the katablepharids, is described. It shows ultrastructural affinities to the katablepharids, including large and small ejectisomes, cell covering, and a feeding apparatus. Although molecular phylogenies of the 18S ribosomal DNA support its classification into the katablepharids, the cell is characterized by a dorsiventrally compressed cell shape and a crawling motion, both of which are unusual within this group. The most distinctive feature of Hatena arenicola is that it harbors a Nephroselmis symbiont. This symbiosis is distinct from previously reported cases of ongoing symbiosis in that the symbiont plastid is selectively enlarged, while other structures such as the mitochondria, Golgi body, cytoskeleton, and endomembrane system are degraded; the host and symbiont have developed a morphological association, i.e., the eyespot of the symbiont is always at the cell apex of Hatena arenicola; and only one daughter cell inherits the symbiont during cell division, resulting in a symbiont-bearing green cell and a symbiont-lacking colorless cell. Interestingly, the colorless cells have a feeding apparatus that corresponds to the location of the eyespot in symbiont-bearing cells, and they are able to feed on prey cells. This indicates that the morphology of the host depends on the presence or absence of the symbiont. These observations suggest that Hatena arenicola has a unique "half-plant, half-predator" life cycle; one cell divides into an autotrophic cell possessing a symbiotic Nephroselmis species, and a symbiont-lacking colorless cell, which later develops a feeding apparatus de novo. The evolutionary implications of Hatena arenicola as an intermediate step in plastid acquisition are discussed in the context of other examples of ongoing endosymbioses in dinoflagellates.

Animals↗
PubMed1998

The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway.

Dorsal closure in the Drosophila embryo occurs during the later stages of embryogenesis and involves changes in cell shape leading to the juxtaposition and subsequent adherence of the lateral epidermal primordia over the amnioserosa. Dorsal closure requires the activation of a conserved c-jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) module, as it is blocked by null mutations in JNK kinase [hemipterous (hep)] and JNK [basket (bsk)]. Drosophila JNK (DJNK) functions by phosphorylating and activating DJun, which in turn induces the transcription of decapentaplegic (dpp). We provide biochemical and genetic evidence that a Ste20-related kinase, misshapen (msn), functions upstream of hep and bsk to stimulate dorsal closure in the Drosophila embryo. Mammalian (NCK-interacting kinase [NIK]) and Caenorhabditis elegans (mig-15) homologs of msn have been identified; mig-15 is necessary for several developmental processes in C. elegans. These data suggest that msn, mig-15, and NIK are components of a signaling pathway that is conserved among flies, worms, and mammals to control developmentally regulated pathways.

Amino Acid Sequence↗
PubMed2002

History and function of scale microornamentation in lacertid lizards.

Differences in surface structure (ober-hautchen) of body scales of lacertid lizards involve cell size, shape and surface profile, presence or absence of fine pitting, form of cell margins, and the occurrence of longitudinal ridges and pustular projections. Phylogenetic information indicates that the primitive pattern involved narrow strap-shaped cells, with low posteriorly overlapping edges and relatively smooth surfaces. Deviations from this condition produce a more sculptured surface and have developed many times, although subsequent overt reversals are uncommon. Like variations in scale shape, different patterns of dorsal body microornamentation appear to confer different and conflicting performance advantages. The primitive pattern may reduce friction during locomotion and also enhances dirt shedding, especially in ground-dwelling forms from moist habitats. However, this smooth microornamentation generates shine that may compromise cryptic coloration, especially when scales are large. Many derived features show correlation with such large scales and appear to suppress shine. They occur most frequently in forms from dry habitats or forms that climb in vegetation away from the ground, situations where dirt adhesion is less of a problem. Microornamentation differences involving other parts of the body and other squamate groups tend to corroborate this functional interpretation. Microornamentation features can develop on lineages in different orders and appear to act additively in reducing shine. In some cases different combinations may be optimal solutions in particular environments, but lineage effects, such as limited reversibility and different developmental proclivities, may also be important in their genesis. The fine pits often found on cell surfaces are unconnected with shine reduction, as they are smaller than the wavelengths of most visible light.

Animals↗
PubMed1995

Isolation and characterization of a novel alkalitolerant thermophile, Anaerobranca horikoshii gen. nov., sp. nov.

Nine moderately alkalitolerant thermophilic bacteria with similar properties were isolated from water and soil samples obtained from Yellowstone National Park. These Gram-type-positive, rod-shaped bacteria produce cells with primary branches. The cells are peritrichous and exhibit only slight tumbling motility. At 60 degrees C the pH range for growth is 6.9 to 10.3, and the optimum pH is 8.5. At pH 8.5 the temperature range for growth is 34 to 66 degrees C, with an optimum temperature of 57 degrees C. The strains are mainly proteolytic. The fermentation products from yeast extract are acetate, CO2, and H2. Fumarate added to minimal medium containing yeast extract is stoichiometrically converted to succinate, indicating that it is used as an alternative electron acceptor. The DNA G + C content is 33 to 34 mol%. On the basis of its unique properties, such as branch formation, growth at alkaline pH values at elevated temperatures, and the relative distance of its 16S rRNA sequence from those of other known bacteria, we propose that strain JW/YL-138T (T = type strain) and eight similar strains represent a new genus and species, Anaerobranca horikoshii. Strain JW/YL-138 is designated the type strain of the type species, A. horikoshii, which was named in honor of Koki Horikoshi, a pioneer in the field of alkaliphilic bacteria.

Aminopeptidases↗
PubMed2004

Modifications of the falciform process in the eye of beloniformes (Teleostei: Atherinomorpha): evolution of a curtain-like septum in the eye.

In order to comparatively analyze curtain-like septa in the eyes of visually orientated "close-to-surface-predators" among atherinomorph teleosts, we examined the eyes of 24 atherinomorph species under a binocular microscope with regard to the falciform process and related structures in the vitreous cavity. Additionally, falciform process samples were analyzed by transmission electron microscopy. All the studied representatives of the Cyprinodontiformes and Atheriniformes, and of one of the beloniform suborder, Adrianichthyioidei, possess a "typical" processus falciformis. In the eyes of the representatives of the other beloniform suborder, Belonoidei, however, pigmented structures that originate in the region of the optic disc and protrude into the vitreous cavity were noted. In the Hemiramphidae (halfbeaks) and Exocoetidae (flying fishes) these pigmented structures have a more cone-like shape, whereas in the Belonidae (needlefishes) and Scomberesocidae (sauries) horizontally oriented heavily pigmented curtain-like septa occur that divide the vitreous cavity dorsoventrally. It is suggested that the "typical" processus falciformis represents a plesiomorphic feature within the Atherinomorpha, whereas the pigmented modifications of the falciform process must be seen as a synapomorphic character state of the Belonoidei. The curtain-like septum of the Belonidae and Scomberesocidae might have evolved from the cone-like structures that are found in the Exocoetoidea. The functional significance of the pigmented structures in the eye is as yet not clear, except for the curtain-like septum found in Belonidae. It might play a role in visual orientation near the water surface at Snell's window.

Animals↗
PubMed2005

External scaffold of spherical immature poxvirus particles is made of protein trimers, forming a honeycomb lattice.

During morphogenesis, poxviruses undergo a remarkable transition from spherical immature forms to brick-shaped infectious particles lacking helical or icosahedral symmetry. In this study, we show that the transitory honeycomb lattice coating the lipoprotein membrane of immature vaccinia virus particles is formed from trimers of a 62-kD protein encoded by the viral D13L gene. Deep-etch electron microscopy demonstrated that anti-D13 antibodies bound to the external protein coat and that lattice fragments were in affinity-purified D13 preparations. Soluble D13 appeared mostly trimeric by gel electrophoresis and ultracentrifugation, which is consistent with structural requirements for a honeycomb. In the presence or absence of other virion proteins, a mutated D13 with one amino acid substitution formed stacks of membrane-unassociated flat sheets that closely resembled the curved honeycombs of immature virions except for the absence of pentagonal facets. A homologous domain that is present in D13 and capsid proteins of certain other lipid-containing viruses support the idea that the developmental stages of poxviruses reflect their evolution from an icosahedral ancestor.

Capsid Proteins↗
PubMed2006

Virtual cooperativity in myoglobin oxygen saturation curve in skeletal muscle in vivo.

BACKGROUND: Myoglobin (Mb) is the simplest monomeric hemoprotein and its physicochemical properties including reversible oxygen (O2)binding in aqueous solution are well known. Unexpectedly, however, its physiological role in intact muscle has not yet been established in spite of the fact that the role of the more complex tetrameric hemoprotein, hemoglobin (Hb), in red cells is well established. Here, I report my new findings on an overlooked property of skeletal Mb. METHODS: I directly observed the oxygenation of Mb in perfused rat skeletal muscle under various states of tissue respiration. A computer-controlled rapid scanning spectrophotometer was used to measure the oxygenation of Mb in the transmission mode. The light beam was focused on the thigh (quadriceps) through a 5-mm-diameter light guide. The transmitted light was conducted to the spectrophotometer through another 5-mm-diameter light guide. Visible difference spectra in the range of 500-650 nm were recorded when O2 uptake in the hindlimb muscle reached a constant value after every stepwise change in the O2 concentration of the buffer. RESULTS: The O2 dissociation curve (ODC) of Mb, when the effluent buffer O2 pressure was used as the abscissa, was of a sigmoid shape under normal and increased respiratory conditions whereas it was of rectangular hyperbolic shape under a suppressed respiratory condition. The dissociation curve was shifted toward the right and became more sigmoid with an increase in tissue respiration activity. These observations indicate that an increase in O2 demand in tissues makes the O2 saturation of Mb more sensitive to O2 pressure change in the capillaries and enhances the Mb-mediated O2 transfer from Hb to cytochrome oxidase (Cyt. aa3), especially under heavy O2 demands. CONCLUSION: The virtual cooperativity and O2 demand-dependent shifts of the ODC may provide a basis for explaining why Mb has been preserved as monomer during molecular evolution.

Journal Article↗
PubMed1986

Nuclear division in the marine dinoflagellate Oxyrrhis marina.

The nuclear division of Oxyrrhis marina is a very distinct one among the mitoses of dinoflagellates that have been studies. Using synchronized populations, we have investigated the ultrastructural changes in this nuclear division. In interphase, nuclei can be classified into two groups on the basis of the shapes of the chromosomes. Y- and U-shaped chromosomes have been observed in both types of interphase nuclei. By prophase the nucleus becomes oval, many nuclear plaques appear on the nuclear envelope, and many microtubules radiate from these nuclear plaques within the nucleus. Metaphase can be identified by the characteristic arrangement of the chromosomes; an equatorial metaphase plate is absent. As in many higher organisms, anaphase includes two stages: anaphase A and anaphase B. During anaphase A the nucleus does not apparently elongate and the chromosomes migrate towards the poles by a combination of the shortening of the chromosome-associated microtubules and the elongation of those located between daughter chromosomes. During anaphase B the nucleus elongates to about twice its former length. This elongation may result from growth of the interzonal nuclear envelope. Dividing nucleoli are associated with microtubules, which suggests that microtubules may play an active role in the division of the nucleolus. The evolution of mitosis and the phylogenetic relationships between Oxyrrhis, typical dinoflagellates and Syndinium are discussed.

Animals↗
PubMed1989

New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies.

Ubiquitin has previously been identified as a component of neuronal inclusions in neurodegenerative disorders. In this investigation, we examined tissue from cases of Alzheimer's disease (AD), Pick's disease, Parkinson's disease (PD), and progressive supranuclear palsy (PSP) to identify previously unrecognized ubiquitinated structures and to assess the evolution of neuronal inclusions. In AD, approximately 60% of neurofibrillary tangles (NFTs) that were stained with an anti-paired helical filaments (PHF) serum were identified by the ubiquitin antibodies. Extracellular NFTs were not labelled with anti-PHF but were unlabelled or weakly labelled with anti-ubiquitin antibodies. In Pick's disease, most Pick bodies were strongly labelled by the ubiquitin antibodies, and in addition some hippocampal CA1 neurones contained granular or strand-like ubiquitin-immunoreactive (IR) inclusions associated with more typical Pick bodies. Typical Lewy bodies in PD cases showed an unlabelled central core with an outer ring intensely labelled by ubiquitin antibodies. Pale bodies in pigmented substantia nigra neurones appeared as large well-defined, rounded structures without an identifiable core or peripheral zone. Some pale bodies were unlabelled by ubiquitin antibodies, but others showed labelling of variable intensity. Pale bodies which were labelled by ubiquitin antibodies tended also to be labelled by BF10, a monoclonal antibody against phosphorylated neurofilaments. We suggest that pale bodies in PD may represent stages in the formation of Lewy bodies. In addition, we observed numerous spindle-shaped ubiquitin-IR swellings of dendrites of pigmented substantia nigra neurones. In contrast to inclusions of AD and Pick's disease, the PHF-positive fibrillary neuronal inclusions of PSP were either unlabelled or only weakly labelled by ubiquitin antibodies. No ubiquitinated structures were seen in neurones from corresponding areas in aged controls. Identification of ubiquitinated proteins in neurodegenerative disorders may provide insights into molecular events associated with cell death.

Aged↗
PubMed2025

CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Chromosomal Instability↗