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PubMed2026

Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.

We previously identified diverse genetic evolutionary patterns in whole-genome sequencing of paired normal tissue adjacent to tumor (NAT) and tumor tissues from Hong Kong breast cancer (HKBC) patients. Here, we investigated whether DNA methylation (DNAm) contributes to NAT heterogeneity and shapes the tumor microenvironment (TME). Genome-wide DNAm profiling was performed on paired NAT and tumor tissues from 188 HKBC patients using the Infinium 850 K array. RNA-seq data were available for 76 NATs and 177 tumors. Cellular composition was inferred using MethylCIBERSORT, CIBERSORTx, and EpiDISH, and histopathologic features were assessed on 115 H&E-stained sections. Unsupervised clustering identified two distinct NAT subtypes with divergent TME characteristics. Cluster 1 (N = 139) showed higher epithelial and fibroblast content and enrichment of estrogen response pathways. Cluster 2 (N = 49) exhibited an immune-metabolic phenotype characterized by increased fat and immune cells, stromal disruption, inflammatory pathway activation, and greater macrophage infiltration. Cluster 2 patients also demonstrated significantly younger epigenetic age estimated using multiple epigenetic clocks. These DNAm-defined NAT subtypes and associated TME features were validated in 97 NAT samples from TCGA breast cancer patients. Overall, our findings identify DNAm-driven NAT heterogeneity with distinct TME landscapes, providing new insights into field cancerization and tumor evolution in breast cancer.

Journal Article↗
PubMed1996

Spinally projecting neurons of the dorsal column nucleus in a reptile: locus of origin and trajectory of termination.

Interconnections between the dorsal column nucleus and the spinal cord were investigated in a reptile, Caiman crocodilus. After placement of an anterograde tracer into the dorsal column nucleus, descending fibers are seen to leave this nucleus to enter the dorsal funiculus where they course ventrally to terminate in lamina V of the spinal cord as far caudally as C2. Placement of a retrograde tracer into cut fibers of the cervical spinal cord identified the relay cells of the dorsal column nucleus that project to the spinal cord. These neurons were mainly clustered in a caudal and ventral part of this nucleus. The soma of these spinally projecting cells were small and were generally round or oval in shape. A number of these neurons had the long axis of their soma oriented dorsoventrally, with a primary dendrite extending dorsally. Fibers in the dorsal funiculus that originated from the spinal cord enter the caudal part of the dorsal column nucleus and turn ventral. In the dorsal column nucleus, these axons run parallel to the vertically oriented dendrites of these spinally projecting cells before termination in close relation to the cell bodies of these neurons. Quantitative observations (mean +/- standard error) were made on well labeled neurons and included several measurements: area, perimeter, and degree of eccentricity (greatest width/greatest length) in both the transverse as well as the sagittal plane. These spinally projecting neurons in Caiman are located in the dorsal column nucleus in a position similar to that of spinally projecting cells in cats.

Afferent Pathways↗
PubMed2005

Sequential generation of two structurally distinct ovine prion protein soluble oligomers displaying different biochemical reactivities.

In pathologies due to protein misassembly, low oligomeric states of the misfolded proteins rather than large aggregates play an important biological role. In prion diseases the lethal evolution is associated with formation of PrP(Sc), a misfolded and amyloid form of the normal cellular prion protein PrP. Although several molecular mechanisms were proposed to account for the propagation of the infectious agent, the events responsible for cell death are still unclear. The correlation between PrP(C) expression level and the rate of disease evolution on one side, and the fact that PrP(Sc) deposition in brain did not strictly correlate with the apparition of clinical symptoms on the other side, suggested a potential role for diffusible oligomers in neuronal death. To get better insight into the molecular mechanisms of PrP(C) oligomerization, we studied the heat-induced oligomerization pathway of the full-length recombinant ovine PrP at acidic pH. This led to the irreversible formation of two well-identified soluble oligomers that could be recovered by size-exclusion chromatography. Both oligomers displayed higher beta-sheet content when compared to the monomer. A sequential two-step multimolecular process accounted for the rate of their formation and their ratio partition, both depending on the initial protein concentration. Small-angle X-ray scattering allowed the determination of the molecular masses for each oligomer, 12mer and 36mer, as well as their distinct oblate shapes. The two species differed in accessibility of polypeptide chain epitopes and of pepsin-sensitive bonds, in a way suggesting distinct conformations for their monomeric unit. The conversion pathway leading to these novel oligomers, displaying contrasted biochemical reactivities, might be a clue to unravel their biological roles.

Animals↗
PubMed2001

Cellular models for river networks.

A cellular model introduced for the evolution of the fluvial landscape is revisited using extensive numerical and scaling analyses. The basic network shapes and their recurrence especially in the aggregation structure are then addressed. The roles of boundary and initial conditions are carefully analyzed as well as the key effect of quenched disorder embedded in random pinning of the landscape surface. It is found that the above features strongly affect the scaling behavior of key morphological quantities. In particular, we conclude that randomly pinned regions (whose structural disorder bears much physical meaning mimicking uneven landscape-forming rainfall events, geological diversity or heterogeneity in surficial properties like vegetation, soil cover or type) play a key role for the robust emergence of aggregation patterns bearing much resemblance to real river networks.

Biophysical Phenomena↗
PubMed2005

Isolation and characterization of a new type of chlorovirus that infects an endosymbiotic Chlorella strain of the heliozoon Acanthocystis turfacea.

A novel virus, named Acanthocystis turfacea Chlorella virus (ATCV), that infects endosymbiotic Chlorella algae of the heliozoon Acanthocystis turfacea was isolated from freshwater samples. Electron microscopic analysis of ATCV revealed that the viral capsid has a distinct icosahedral shape with a diameter of 140-190 nm. Filamentous structures extending from some of the virus vertices, which may aid attachment of the virus to host cells, were also observed. The capsid is made up of one major coat protein of about 50 kDa and contains a large dsDNA genome. ATCV is a member of the genus Chlorovirus, which belongs to the family Phycodnaviridae, a group of large, icosahedral, dsDNA-containing viruses that infect algae and are ubiquitous in natural environments. However, ATCV is clearly distinct from the prototype Chlorovirus, Paramecium bursaria Chlorella virus (PBCV-1), in some aspects of its genome structure and gene content and therefore must be regarded as a member of a new group of Chlorella viruses.

Biological Evolution↗
PubMed2003

Glycoprotein hormone receptors: determinants in leucine-rich repeats responsible for ligand specificity.

Glycoprotein hormone receptors [thyrotropin (TSHr), luteinizing hormone/chorionic gonadotropin (LH/CGr), follicle stimulating hormone (FSHr)] are rhodopsin-like G protein-coupled receptors with a large extracellular N-terminal portion responsible for hormone recognition and binding. In structural models, this ectodomain is composed of two cysteine clusters flanking nine leucine-rich repeats (LRRs). The LRRs form a succession of beta-strands and alpha-helices organized into a horseshoe-shaped structure. It has been proposed that glycoprotein hormones interact with residues of the beta-strands making the concave surface of the horseshoe. Gain-of-function homology scanning of the beta-strands of glycoprotein hormone receptors allowed identification of the critical residues responsible for the specificity towards human chorionic gonadotropin (hCG). Substitution of eight or two residues of the LH/CGr into the TSHr or FSHr, respectively, resulted in constructs displaying almost the same affinity and sensitivity for hCG as wild-type LH/CGr. Molecular dynamics simulations and additional site-directed mutagenesis provided a structural rationale for the evolution of binding specificity in this duplicated gene family.

Amino Acid Substitution↗
PubMed2001

Conservation of Hox/ParaHox-related genes in the early development of a cnidarian.

To clarify the relationship between axial patterning in cnidarians and bilaterians, we have investigated the embryonic development of the hydrozoan Podocoryne carnea. The expression of Hox-like homeobox genes was analyzed by RT-PCR and in situ hybridization. Cnox1-Pc, an anterior Hox gene, is a maternal message. It is present throughout larval development, first weakly in all blastomeres and later restricted mostly to the anterior pole of the planula. Gsx, an anterior ParaHox gene, is first seen in the anterior endoderm but also extends into posterior regions. Cnox4-Pc, an orphan Hox-like gene, is expressed in the egg as a ring-shaped cloud around the germinal vesicle. After fertilization, the message remains in most animal blastomeres. When the embryo elongates in late blastula, staining is restricted to a few cells at the posterior pole where gastrulation will start. However, once gastrulation starts, the Cnox4-Pc signal disappears and is absent in later stages of larval development. Phylogenetic analysis shows that not all cnidarian Hox-like genes have recognizable orthologues in bilaterian groups. However, the expression analysis of Cnox1-Pc and Gsx correlates to some extent with the expression pattern of cognate genes of bilaterians, confirming the conservation of genes involved in organizing animal body plans and their putative common ancestral origin.

Amino Acid Sequence↗
PubMed2000

Ancestral exonic organization of FUT8, the gene encoding the alpha6-fucosyltransferase, reveals successive peptide domains which suggest a particular three-dimensional core structure for the alpha6-fucosyltransferase family.

Based on PCR strategies and expression studies, we define the genomic organization of the FUT8b gene. This gene encodes the only known mammalian enzyme transferring fucose in an alpha1-->6 linkage on the asparagine-branched GlcNAc residue of the chitobiose unit of complex N:-glycans. The intron/exon organization of the bovine coding sequence determines five successive functional domains. The first exon encodes a domain homologous to cytoskeleton proteins, the second presents a proline-rich region including a motif XPXPPYXP similar to the peptide ligand of the SH3-domain proteins, the third encodes a gyrase-like domain (an enzyme which can bind nucleotides), and the fourth encodes a peptide sequence homologous to the catalytic domain of proteins transferring sugars. Finally, the last exon encodes a domain homologous to the SH3 conserved motif of the SH2-SH3 protein family. This organization suggests that intramolecular interactions might give a tulip-shaped scaffolding, including the catalytic pocket of the enzyme in the Golgi lumen. Deduced from the published sequence of chromosome 14 (AL109847), the human gene organization of FUT8 seems to be similar to that of bovine FUT8b, although the exon partition is more pronounced (bovine exons 1 and 2 correspond to human exons 1-6). The mosaicism and phylogenetic positions of the alpha6-fucosyltransferase genes are compared with those of other fucosyltransferase genes.

Amino Acid Sequence↗
PubMed2003

Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children.

OBJECTIVES: Evaluation of sequence evolution as well as structural defects and mutations of the human immunodeficiency virus-type 1 (HIV-1) nef gene in relation to disease progression in infected children. DESIGN: We examined a large number of nef alleles sequentially derived from perinatally HIV-1-infected children with different rates of disease progression: six non-progressors (NPs), four rapid progressors (RPs), and three slow progressors (SPs). METHODS: Nef alleles (182 total) were isolated from patients' peripheral blood mononuclear cells (PBMCs), sequenced and analysed for their evolutionary pattern, frequency of mutations and occurrence of amino acid variations associated with different stages of disease. RESULTS: The evolution rate of the nef gene apparently correlated with CD4+ decline in all progression groups. Evidence for rapid viral turnover and positive selection for changes were found only in two SPs and two RPs respectively. In NPs, a higher proportion of disrupted sequences and mutations at various functional motifs were observed. Furthermore, NP-derived Nef proteins were often changed at residues localized in the folded core domain at cytotoxic T lymphocytes (CTL) epitopes (E(105), K(106), E(110), Y(132), K(164), and R(200)), while other residues outside the core domain are more often changed in RPs (A(43)) and SPs (N(173) and Y(214)). CONCLUSIONS: Our results suggest a link between nef gene functions and the progression rate in HIV-1-infected children. Moreover, non-progressor-associated variations in the core domain of Nef, together with the genetic analysis, suggest that nef gene evolution is shaped by an effective immune system in these patients.

Adolescent↗
PubMedDate not supplied

Mutants highlight the modular control of butterfly eyespot patterns.

The eyespots on butterfly wings are thought to be serially homologous pattern elements. Yet eyespots differ greatly in number, shape, color, and size, within and among species. To what extent do these serially homologues have separate developmental identities, upon which selection acts to create diversity? We examined x-ray-induced mutations for the eyespots of the nymphalid butterfly Bicyclus anynana that highlight the modular control of these serially homologous wing pattern elements. These mutations reduce or eliminate individual eyespots, or groups of eyespots, with no further effect on the wing color pattern. The collection of mutants highlights a greater potential developmental repertoire than that observed across the genus Bicyclus. We studied in detail one such mutation, of codominant effect, that causes the elimination of two adjacent eyespots on the ventral hindwing. By analyzing the expression of genes known to be involved in eyespot formation, we found an alteration in the differentiation of the "organizing" cells at the eyespot's center. No such cells differentiate in the wing subdivisions lacking the two eyespots in the mutants. We propose several developmental models, based on wing compartmentalization in Drosophila, that provide the first framework for thinking about the molecular evolution of butterfly wing pattern modularity.

Animals↗
PubMed2005

Symmetry breaking and convergent extension in early chordate development.

The initiation of axis, polarity, cell differentiation, and gastrulation in the very early chordate development is due to the breaking of radial symmetry. It is believed that this occurs by an external signal. We suggest instead spontaneous symmetry breaking through the agency of the Turing-Child field. Increased size or decreased diffusivity, both brought about by mitotic activity, cause the spontaneous loss of stability of the homogeneous state and the evolution of the metabolic pattern during development. The polar metabolic pattern is the cause of polar gene expression, polar morphogenesis (gastrulation), and polar mitotic activity. The Turing-Child theory explains not only the spontaneous formation of the invagination in gastrulation but also the coherent cell movement observed in convergence and extension during gastrulation and neurulation. The theory is demonstrated with respect to experimental observations on the early development of fish, amphibian, and the chick. The theory can explain a multitude of experimental details. For example, it explains the splayed polar progression of reduction in the fish blastoderm. Reduction starts on that side of the blastoderm margin, which will initiate invagination several hours later. It progresses toward the blastoderm center and somewhat laterally from this future "dorsal lip". This is precisely as predicted by a Turing-Child system in a circle. And for a fish like zebrafish with a blastoderm that is slightly oval, reduction is observed to progress along the long axis of the ellipse, which is what Turing-Child theory predicts. In general the shape and the chemical nature of the experimental patterns are the same as predicted by the Turing couple (cAMP, ATP). Embryological polarity and convergent extension are based on polar eigenfunction and saddle-shaped eigenfunction, respectively.

Animals↗
PubMedDate not supplied

Rapid full-length genomic sequencing of two cytopathically heterogeneous Australian primary HIV-1 isolates.

Two Australian HIV-1 isolates, derived from patient blood (HIV(MBC200)) and cerebrospinal fluid (HIV(MBC925)), were characterized after in vitro culture in peripheral blood mononuclear cells (PBMC). Although virus replication was similar, as measured by cell-free reverse transcriptase activity, only one of the two isolates (HIV-1(MCB200)) consistently induced cell syncytia and depleted the PBMC population of CD4+ cells by cell killing. A novel technique, devised for rapidly obtaining high-quality viral sequence data and the full-length genomic sequence of these two isolates, is presented. Analysis of the predicted sequence of the viral Env proteins provides correlates of the observed phenotypes. Phylogenetic analysis derived using near full-length sequence of these and other HIV-1 subtype B genomic sequences (including two other Australian isolates) shows a star-shaped phylogeny with each member having a similar genetic diversity. These data expand the database of genomic sequence available from well-characterized primary clinical isolates of HIV-1 using a novel rapid technique.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Genome comparisons highlight similarity and diversity within the eukaryotic kingdoms.

In 2000, the number of completely sequenced eukaryotic genomes increased to four. The addition of Drosophila and Arabidopsis into this cohort permits additional insights into the processes that have shaped evolution. Analysis and comparisons of both completed genomes and partially sequenced genomes have already shed light on mechanisms such as gene duplication and gene loss that have long been hypothesized to be major forces in speciation. Indeed, duplicate gene pairs in Saccharomyces, Arabidopsis, Caenorhabditis and Drosophila are high: 30%, 60%, 48% and 40%, respectively. Evidence of horizontal gene-transfer, thought to be a major evolutionary force in bacteria, has been found in Arabidopsis. The release of the 'first draft' of the human genome sequence in 2000 heralds a new stage of biological study. Understanding the as-yet-unannotated human genome will be largely based on conclusions, techniques and tools developed during the analysis and comparison of the genome of these four model organisms.

Animals↗
PubMed2004

The radiographic evolution of radio frequency ablated renal tumors.

PURPOSE: Radio frequency ablation (RFA) of renal tumors is a relatively new technology. Few groups are familiar with the posttreatment appearance of these lesions and how they differ from cryoablated renal masses. We describe the evolution of the appearance of these lesions on followup contrast enhanced (CE) computerized tomography (CT). METHODS AND MATERIALS: A total of 64 consecutive renal tumors treated with RFA from April 2000 to September 2003 for which posttreatment CE-CT was done were included in this study. CE-CT was reviewed at 6 weeks, 3 months, 6 months and every 6 months thereafter to determine the characteristic features and evolution of these lesions. RESULTS: Renal tumors were treated with CT guided percutaneous (34), laparoscopic (28) or open (2) RFA. At a median followup of 13.7 months (range 6 weeks to 29 months) 62 RFA lesions demonstrated an absence of contrast enhancement on CE-CT. Treated endophytic tumors developed a low density, nonenhancing, wedge-shaped defect with fat infiltration seen between the ablated tissue and normal parenchyma. Treated exophytic tumors retained a configuration similar to that of the original with a lack of contrast enhancement and minimal shrinkage. Percutaneous treated lesions developed a peritumor scar or halo that demarcated ablated and nonablated tissue (perirenal fat). Persistent tumor was marked by contrast enhancement within the ablation borders of the original mass in 1 case, whereas tumor recurred after initial successful ablation with an enhancing nodule in 1. CONCLUSIONS: The radiographic features and evolution of radio frequency ablated renal tumors are unique. Successfully treated tumors demonstrated no contrast enhancement, minimal shrinkage and occasional retraction from normal parenchyma by fat infiltration.

Adenocarcinoma, Clear Cell↗
PubMed2002

Evolution of larger sperm in response to experimentally increased sperm competition in Caenorhabditis elegans.

Sperm morphology evolves rapidly, resulting in an exceptional diversity of sperm size and shape across animal phyla. This swift evolution has been thought to prevent fertilizations between closely related species. Alternatively, recent correlative analyses suggest that competition among sperm from more than one male may cause sperm diversity, but these hypotheses have not been tested. Here, we test experimentally the effect of sperm competition on sperm-size evolution using the nematode Caenorhabditis elegans. This worm has a three day generation time, which allowed the study to cover many generations. Sperm volume increased nearly 20% over 60 generations in lines genetically induced to have high levels of sperm competition compared with those of control lines. These results show that sperm competition can and does cause morphological evolution of sperm and, therefore, can explain much of the diversity in sperm morphology.

Animals↗
PubMed2005

[Centromere elasticity].

In addition to the role in the spindle apparatus and associated motors, the chromosome themselves play an important role in facilitating chromosome segregation. Sister chromatids are joined at the centromere through a protein complex called cohesin. Chromatids separation requires the degradation by separase of specific proteins acting as a glue to form the cohesin complex. This evolutionally complex is required for the establishment and maintenance of sister chromatids in a ring like structure. It is therefore a key question whether cohesin is indeed a main component of active centromere. Cohesin is insufficient to resist the splitting force exerted by microtubules until anaphase and must be renforced by cohesion provided by flanking DNA. The ring model suggests that cohesine might possess a considerable mobility when associated with chromatin. Observations demonstrate that the interior region of the centromere behaves as an elastic element. Chromosomes display remarkable elasticity, returning to their initial shape after being extended by up to 10 times. For larger deformations the thick filament is converted in thin filament which can be stretched six times before breaking. This article suggests an additional and novel role for the protein titin on chromosome structure and dynamic. Titine was identified as a chromosomal component and it was hypothesised that titin may provide elasticity to chromosome and resistance to chromosome breakages during mitosis. The elastic properties of purified titin correspond well to the elastic properties of chromosome in living cells. The deformability and bending rigidity are consistent with a model developed for titin elasticity. The association of the presence of cohesine ring and the activity of titin could be necessary for segregation.

Cell Cycle Proteins↗
PubMed2004

Does the shape of Plasmodium falciparum gametocytes have a function?

The gametocytes of Plasmodium falciparum have a characteristic banana-shape. One could wonder if this shape has been retained by selection forces because it favored transmission. By increasing the surface to volume ratio, the elongation that takes place during the maturation of P. falciparum gametocytes increases the susceptibility of gametocytes to rheological forces. This may facilitate their exit from the bone marrow and their subsequent impaction in the cutaneous capillaries that are lined with sequestered asexual parasites. The asymmetric curvature of gametocytes may tend to present gametocytes perpendicularly to the axis of the blood flow, thus increasing their chance to be retained and accumulate where they can be absorbed by the vector.

Animals↗
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗