Higher Rank Levels Research Articles

Are Viruses Taxonomic Units? A Protein Domain and Loop-Centric Phylogenomic Assessment.

Virus taxonomy uses a Linnaean-like subsumption hierarchy to classify viruses into taxonomic units at species and higher rank levels. Virus species are considered monophyletic groups of mobile genetic elements (MGEs) often delimited by the phylogenetic analysis of aligned genomic or metagenomic sequences. Taxonomic units are assumed to be independent organizational, functional and evolutionary units that follow a 'natural history' rationale. Here, I use phylogenomic and other arguments to show that viruses are not self-standing genetically-driven systems acting as evolutionary units. Instead, they are crucial components of holobionts, which are units of biological organization that dynamically integrate the genetics, epigenetic, physiological and functional properties of their co-evolving members. Remarkably, phylogenomic analyses show that viruses share protein domains and loops with cells throughout history via massive processes of reticulate evolution, helping spread evolutionary innovations across a wider taxonomic spectrum. Thus, viruses are not merely MGEs or microbes. Instead, their genomes and proteomes conduct cellularly integrated processes akin to those cataloged by the GO Consortium. This prompts the generation of compositional hierarchies that replace the 'is-a-kind-of' by a 'is-a-part-of' logic to better describe the mereology of integrated cellular and viral makeup. My analysis demands a new paradigm that integrates virus taxonomy into a modern evolutionarily centered taxonomy of organisms.

Characterization of the Tumor Microenvironment in Jaw Osteosarcomas, towards Prognostic Markers and New Therapeutic Targets

Background-The purpose of this study was to investigate the bone resorption, as well as the vascular and immune microenvironment, of jaw osteosarcomas (JO) and to correlate these features with patient clinical outcomes. Methods-We studied 50 JO biopsy samples by immunohistochemical analysis of tissue microarrays (TMAs). We investigated the bone remodeling markers RANK/RANKL/OPG, the endothelial glycoprotein CD146, and biomarkers of the immune environment (CD163 and CD68 of macrophages, CD4+ and CD8+ of tumor-infiltrating lymphocytes (TILs), and an immune checkpoint PD-1/PD-L1). The biomarkers were analyzed for their influence on progression (recurrence and metastasis), overall survival (OS), and disease-free survival (DFS). Results-A strong and significant correlation has been found between CD163 staining and lower OS and DFS. The level of CD4+ and CD8+ staining was low and non-significantly associated with survival outcomes. High levels of RANK and RANKL were found in the tumor samples and correlated with lower DFS. Conclusion-Our findings suggest that CD163+ TAMs represent markers of poor prognosis in JO. Targeting TAMs could represent a valuable therapeutic strategy in JO.

3D Culture Modeling of Metastatic Breast Cancer Cells in Additive Manufactured Scaffolds.

Cancer biology research is increasingly moving toward innovative in vitro 3D culture models, as conventional and current 2D cell cultures fail to resemble in vivo cancer biology. In the current study, porous 3D scaffolds, designed with two different porosities along with 2D tissue culture polystyrene (TCP) plates were used with a model breast cancer human cell line. The 3D engineered system was evaluated for the optimal seeding method (dynamic versus static), adhesion, and proliferation rate of MDA-MB-231 breast cancer cells. The expression profiles of proliferation-, stemness-, and dormancy-associated cancer markers, namely, ki67, lamin A/C, SOX2, Oct3/4, stanniocalcin 1 (STC1), and stanniocalcin 2 (STC2), were evaluated in the 3D cultured cells and compared to the respective profiles of the cells cultured in the conventional 2D TCP. Our data suggested that static seeding was the optimal seeding method with porosity-dependent efficiency. Moreover, cells cultured in 3D scaffolds displayed a more dormant phenotype in comparison to 2D, which was manifested by the lower proliferation rate, reduced ki67 expression, increased lamin A/C expression, and overexpression of STCs. The possible relationship between the cell affinity to different extracellular matrix (ECM) proteins and the RANK expression levels was also addressed after deriving collagen type I (COL-I) and fibronectin (FN) MDA-MB-231 filial cell lines with enhanced capacity to attach to the respective ECM proteins. The new derivatives exhibited a more mesenchymal like phenotype and higher RANK levels in relation to the parental cells, suggesting a relationship between ECM cell affinity and RANK expression. Therefore, the present 3D cell culture model shows that cancer cells on printed scaffolds can work as better representatives in cancer biology and drug screening related studies.

RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

SummaryRank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.

Receptor Activator of NF Kappa B (RANK) Expression Indicates Favorable Prognosis in Patients with Muscle-invasive Bladder Cancer

BackgroundReceptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown. ObjectiveTo assess the relevance of RANK expression in patients with MIBC. Design, setting, and participantsExpression of RANK was assessed via immunohistochemistry of benign urothelium, MIBC tissue, and lymph node metastases from 153 patients undergoing radical cystectomy. Expression data from The Cancer Genome Atlas (TCGA) cohort were analyzed for potential associations with molecular subtypes and outcome. Outcome measurements and statistical analysisRANK expression was correlated with clinical and pathological parameters and to individual data for the clinical course of MIBC. Results and limitationsExpression of RANK was significantly higher in both primary tumors (p = 0.02) and lymph node metastases (p = 0.01) compared to normal urothelium. In tumor tissue, RANK expression was significantly lower in patients with locally advanced disease and lymph node involvement compared to those with organ-confined disease (p = 0.0009) and node-negative MIBC (p = 0.0002). In univariable and multivariable analyses, high expression of RANK was associated with a longer time to recurrence (p = 0.0005 and 0.01) and better cancer-specific (p = 0.0004 and 0.007) and overall survival (p = 0.002 and 0.04). High expression of RANK was associated with better outcome for patients with luminal infiltrated tumors in the TCGA cohort. ConclusionsRANK expression is increased in bladder cancer tissue compared to benign urothelium, with higher expression in organ-defined compared to locally advanced disease. High RANK expression indicates a favorable prognosis in MIBC. The prognostic role differs in tumors of different molecular subtypes. Patient summaryExpression of a protein involved in bone turnover regulation (RANK) is higher in bladder cancer tissue than in benign bladder tissue. However, high levels of RANK on tumor cells indicate favorable prognosis for patients with bladder cancer that invades the muscle layer of the bladder.

A note on the charring of spores and implications for coal petrographic analysis and maceral nomenclature

Spore walls have inherently low reflectance (although this will rise with increasing rank) and are assigned to the liptinite maceral sporinite using a combination of their reflectance properties and their morphology that reflects their botanical origin. However, when fern and lycopod spores are charred their reflectance increases. Charred spores, therefore, should be assigned to the inertinite maceral group based upon reflectance properties. At higher rank levels such as anthracites the distinction of macerals using reflectance would become more problematic. Based on morphology some charred spores could appear to be assignable to the fusinite, semifusinite or funginite macerals, none of which would be correct because they are neither a single plant cell nor fungal in origin. At 500 °C and above Lycopodium spores coalesced resulting in material that would be classified as macrinite, one of the inertinite group macerals, adding yet another possible origin to those already known for that maceral. Experiments on pollen have yet to be undertaken, however spores are a more suitable experimental material being present from Paleozoic to Recent. This research further underlines the complexities of maceral formation and the difficulties of identification linked to the combination of physical and biological properties used in the definitions. It is concluded that maceral analysis may not always be an appropriate or reliable method for interpretation of peat/coal formation and composition.

Quantitation of the Rank-Rankl Axis in Primary Biliary Cholangitis.

There is substantial data that suggests an abnormality of innate immunity in patients with primary biliary cholangitis (PBC) which includes the transcription factor nuclear factor-kB (NF-kB) and well as downstream inflammatory signaling pathways. In addition, ImmunoChip analysis has identified a novel PBC-associated locus near the receptor activator of NF-kB ligand (RANKL) gene. Based on these observations, we investigated the role of the RANKL axis in the liver of patients with PBC compared to controls. We used immunohistochemistry to quantitate liver expression of RANKL, its receptor (RANK), and importantly the decoy receptor osteoprotegerin (OPG), including a total of 122 liver samples (PBC = 37, primary sclerosing cholangitis = 20, autoimmune hepatitis = 26, chronic hepatitis B = 32 and unaffected controls = 7). In addition, we studied RANKL-RANK-OPG co-localization in CD4 and CD8 T cells, B cells, dendritic cells, macrophages, NK, NKT cells, hepatocytes, and cholangiocytes. We report herein that RANK is constitutively expressed by cholangiocytes in both unaffected and diseased liver. However, cholangiocytes from PBC express significantly higher levers of RANK than either the unaffected controls or liver diseased controls. CD4, CD8 and CD19 cells with in the portal areas around bile ducts in PBC express significantly higher levels of RANKL compared to controls. Importantly, the overall hepatic RANKL level and the ratio of hepatic RANKL/OPG correlated with disease severity in PBC. In conclusion, our data indicate a role of RANK-RANKL axis in the innate immune activation in PBC and we hypothesize that the damaged cholangiocytes, which express high levels of RANK, lead to the recruitment of RANKL positive cells and ultimately the classic portal tract infiltrates.

RANK expression on breast cancer cells promotes skeletal metastasis

RANK ligand (RANKL), acting through its cognate receptor RANK, is a key factor for bone remodeling and metastasis by regulating the differentiation, survival and activation of osteoclasts. RANKL is also crucial for the development of mouse mammary glands during pregnancy and has been recently linked to the etiology of breast cancer via its direct activity on RANK-expressing normal or transformed breast epithelial cells, leading to increased mitogenesis, enhanced regenerative potential of mammary stem cells, and increased invasion and migration. We demonstrate that higher RANK expression in MDA-MB-231 breast cancer cells (MDA-231-RANK cells) is sufficient to confer a significantly greater metastatic growth rate in the bone compared with MDA-MB-231 cells which do not express high levels of RANK. Blockade of osteoclastic bone resorption, achieved with treatment by either RANKL inhibition or zoledronic acid, did reduce skeletal tumor progression of MDA-231-RANK cells suggesting that the vicious cycle contributes to metastatic growth. However, RANKL inhibition reduced skeletal growth of MDA-231-RANK tumors to a significantly greater extent than zoledronic acid, indicating that skeletal growth of RANK-positive tumors is also driven by direct RANKL effects. RANKL stimulated the expression of multiple genes associated with cell invasive behavior, including several matrix metalloproteinases and other genes previously defined as part of a bone metastasis gene signature. These data indicate that RANKL provokes breast cancer bone metastases via two distinct, but potentially overlapping mechanisms: stimulation of tumor-associated osteoclastogenesis and stimulation of RANK-expressing tumor cells.

RANK Induces Epithelial–Mesenchymal Transition and Stemness in Human Mammary Epithelial Cells and Promotes Tumorigenesis and Metastasis

Paracrine signaling through receptor activator of NF-κB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial-mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44(+)CD24(-) cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis.

New immune therapy targets tumor-associated environment: from bone marrow to tumor site

New immune therapy targets tumor-associated environment: from bone marrow to tumor site

Ethical Attitudes of Accounting Practitioners: Are Rank and Ethical Attitudes Related?

We address a previous finding in the business ethics literature in which accounting professionals in higher rank levels, i.e., “manager” or “partner” of auditing firms, appear to have lower moral reasoning ability than their junior counterparts. Prior investigations have relied upon a similar methodology for estimating ethical beliefs, namely testing “moral reasoning ability” using either the Moral Judgment Interview or Defining Issues Test. In the present study, we use a multiple vignettes approach to test for the existence of the inverse rank-ethical beliefs effect. With only 2 of the 30 vignettes resulting in both managers and partners being more accepting of the ethically charged behaviors, the results presented here using this alternative methodology are generally not supportive of the inverse rank-ethical beliefs phenomenon. We also use a multivariate analysis in order to control for demographic characteristics. Our results suggest that the most robust predictor of ethical attitudes among accounting practitioners is age, not rank within a firm.

Goal and Personality Trait Development in a Transitional Period: Assessing Change and Stability in Personality Development

This longitudinal study examined continuity and change in the Big Five personality traits and in the importance of life goals from eight domains (Personal Growth, Relationships, Community, Health, Wealth, Fame, Image, and Hedonism) in 2,141 students in a 2-year period at the transition from school to college or employment. Both personality traits and life goals demonstrated high levels of rank-order and structural stability and showed significant individual differences in individual change. Moreover, mean-level changes were in line with the maturity principle: Scores on Agreeableness, Conscientiousness, and Openness increased over time, whereas Neuroticism decreased. However, the importance of life goals decreased in all domains except health. Reciprocal effects models revealed that there were effects of prior personality traits on subsequent life goal importance but almost no effects of prior life goal importance on subsequent personality traits. Separate analyses by gender showed that the findings were almost invariant across gender.

Metamorphism of mineral matter in coal from the Bukit Asam deposit, south Sumatra, Indonesia

Abstract The coal of the Miocene Bukit Asam deposit in south Sumatra is mostly sub-bituminous in rank, consistent with regional trends due to burial processes. However, effects associated with Plio–Pleistocene igneous intrusions have produced coal with vitrinite reflectance up to at least 4.17% (anthracite) in different parts of the deposit. The un-metamorphosed to slightly metamorphosed coals, with Rvmax values of 0.45–0.65%, contain a mineral assemblage made up almost entirely of well-ordered kaolinite and quartz. The more strongly heat-affected coals, with Rvmax values of more than 1.0%, are dominated by irregularly and regularly interstratified illite/smectite, poorly crystallized kaolinite and paragonite (Na mica), with chlorite in some of the anthracite materials. Kaolinite is abundant in the partings of the lower-rank coals, but is absent from the partings in the higher-rank areas, even at similar horizons in the same coal seam. Regularly interstratified illite/smectite, which is totally absent from the partings in the lower-rank coals, dominates the mineralogy in the partings associated with the higher-rank coal beds. A number of reactions involving the alteration of silicate minerals appear to have occurred in both the coal and the associated non-coal lithologies during the thermal metamorphism generated by the intrusions. The most prominent involve the disappearance of kaolinite, the appearance of irregularly interstratified illite/smectite, and the formation of regular I/S, paragonite and chlorite. Although regular I/S is identified in all of the non-coal partings associated with the higher-rank coals, illite/smectite with an ordered structure is only recognised in the coal samples collected from near the bases of the seams. The I/S in the coal samples adjacent to the floor of the highest rank seam also appears to have a greater proportion of illitic components. The availability of sodium and other non-mineral inorganic elements in the original coal to interact with the kaolinite, under different thermal and geochemical conditions, appears to be the significant factor in the formation of these new minerals, and distinguishes the mineralogical changes at Bukit Asam from those developed more generally with rank increases due to burial, and from the effects of intrusions into coals that were already at higher rank levels.

99/00101 A novel process for preparation of active carbon from sapropelitic coals

The coal of the Miocene Bukit Asam deposit in south Sumatra is mostly sub-bituminous in rank, consistent with regional trends due to burial processes. However, effects associated with Plio–Pleistocene igneous intrusions have produced coal with vitrinite reflectance up to at least 4.17% (anthracite) in different parts of the deposit. The un-metamorphosed to slightly metamorphosed coals, with Rvmax values of 0.45–0.65%, contain a mineral assemblage made up almost entirely of well-ordered kaolinite and quartz. The more strongly heat-affected coals, with Rvmax values of more than 1.0%, are dominated by irregularly and regularly interstratified illite/smectite, poorly crystallized kaolinite and paragonite (Na mica), with chlorite in some of the anthracite materials. Kaolinite is abundant in the partings of the lower-rank coals, but is absent from the partings in the higher-rank areas, even at similar horizons in the same coal seam. Regularly interstratified illite/smectite, which is totally absent from the partings in the lower-rank coals, dominates the mineralogy in the partings associated with the higher-rank coal beds. A number of reactions involving the alteration of silicate minerals appear to have occurred in both the coal and the associated non-coal lithologies during the thermal metamorphism generated by the intrusions. The most prominent involve the disappearance of kaolinite, the appearance of irregularly interstratified illite/smectite, and the formation of regular I/S, paragonite and chlorite. Although regular I/S is identified in all of the non-coal partings associated with the higher-rank coals, illite/smectite with an ordered structure is only recognised in the coal samples collected from near the bases of the seams. The I/S in the coal samples adjacent to the floor of the highest rank seam also appears to have a greater proportion of illitic components. The availability of sodium and other non-mineral inorganic elements in the original coal to interact with the kaolinite, under different thermal and geochemical conditions, appears to be the significant factor in the formation of these new minerals, and distinguishes the mineralogical changes at Bukit Asam from those developed more generally with rank increases due to burial, and from the effects of intrusions into coals that were already at higher rank levels.

Molecular phylogeny of the grass genusBrachypodiumP. Beauv. based on RFLP and RAPD analysis

Nuclear genome analysis using RFLPs and RAPDs has been assessed within different species of the genusBrachypodiumP. Beauv. and representatives of other grasses in order to determine the characteristics of theBrachypodiumgenome and to establish its evolutionary position in relation to other Pooideae. Distinctive features of theBrachypodiumgenome are its small size, the low amount of repetitive DNA, the lack of restriction fragment length polymorphisms within the genus for the assayed probe/enzyme combinations, and the genomic variability demonstrated at species level by random DNA amplification. These molecular studies confirmBrachypodiumas an isolated ancient genus best placed in its own tribe (Brachypodieae). Its relationships to other tribes—Bromeae, Triticeae, Poeae—are resolved, Brachypodieae being the earliest tribe to diverge from this core of pooids. Within the genus two major Old World clades are distinguishable: an annual clade, represented only byB. distachyon;and a perennial clade, represented by all the other species studied (exceptB. mexicanum). The perennial American speciesB. mexicanumappears equally attached to these two clades. RFLP data were found to be useful in obtaining phylogenies at generic and higher rank levels, whereas the highly variable RAPD data were more suitable for resolving interspecific and intraspecific evolutionary pathways.

Molecular phylogeny of the grass genus Brachypodium P. Beauv. based on RFLP and RAPD analysis

Abstract Nuclear genome analysis using RFLPs and RAPDs has been assessed within different species of the genus Brachypodium P. Beauv. and representatives of other grasses in order to determine the characteristics of the Brachypodium genome and to establish its evolutionary position in relation to other Pooideae. Distinctive features of the Brachypodium genome are its small size, the low amount of repetitive DNA, the lack of restriction fragment length polymorphisms within the genus for the assayed probe/enzyme combinations, and the genomic variability demonstrated at species level by random DNA amplification. These molecular studies confirm Brachypodium as an isolated ancient genus best placed in its own tribe (Brachypodieae). Its relationships to other tribes—Bromeae, Triticeae, Poeae—are resolved, Brachypodieae being the earliest tribe to diverge from this core of pooids. Within the genus two major Old World clades are distinguishable: an annual clade, represented only by B. distachyon; and a perennial clade, represented by all the other species studied (except B. mexicanum ). The perennial American species B. mexicanum appears equally attached to these two clades. RFLP data were found to be useful in obtaining phylogenies at generic and higher rank levels, whereas the highly variable RAPD data were more suitable for resolving interspecific and intraspecific evolutionary pathways.