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At least 19 recordsLinked to original sources

PubMed2002

Genetic mosaic analysis indicates that the bulb region of coat hair follicles contains a resident population of several active multipotent epithelial lineage progenitors.

The hair follicle represents an excellent model system for exploring the properties of lineage-forming units in a dynamic epithelium containing multiple cell types. During its growth (anagen) phase, the proximal-distal axis of the mouse coat hair (pelage) follicle provides a historical record of all epithelial lineages generated from its resident stem cell population. An unresolved question in the field is whether the bulb region of anagen pelage follicles contains multipotential progenitors and whether their individual contribution to cellular census fluctuates over time. To address this issue, chimeric follicles were harvested in midanagen from three types of genetic mosaic mouse models. Analysis of the distribution of genotypic markers, including digital three-dimensional reconstruction of serially sectioned chimeric follicles, revealed that on average the bulb contains four or fewer active progenitors, each capable of giving rise to all six follicular epithelial fates. Moreover, analysis of mosaic pelage, as well as cultured whisker follicles provided evidence that bulb-associated progenitors can give rise to expanding descendant clones during midanagen, leading to the conclusion that the bulb contains dormant or symmetrically dividing stem cells. This latter feature resembles the behavior of hematopoietic stem cells after bone marrow transplantation, and raises the question of whether this property may be shared by stem cells in other self-renewing epithelia.

Animals↗

PubMed2026

Multicellular ecosystems: Linking cellular diversity to tissue function and disease.

Tissue function emerges from coordinated interactions among diverse cell populations, whereas disruption of these interactions can lead to dysfunction. Recent advances in single-cell and spatial genomics have not only cataloged cellular diversity but also revealed how tissues are organized as dynamic multicellular ecosystems. Moving beyond descriptive cell atlases toward functional, system-level representations represents a major frontier in tissue biology. In this review, we outline conceptual and methodological frameworks for dissecting multicellular coordination, highlight recurrent multicellular ecosystems across physiological and pathological contexts, and explore translational opportunities such as patient stratification, therapeutic reprogramming, and regenerative strategies. Viewing tissues through an ecosystem lens provides a unifying framework that links cellular diversity to emergent tissue function and informs strategies for disease intervention.

Humans↗

PubMed2005

Domain architectural census of eukaryotic gene products containing O-protein phosphatases.

Intricate molecular signalling within cellular environment is manifested through phosphorylation of proteins. Regulation of the phosphorylation state is executed through complex networking among kinases and their biochemical antagonists, the protein phosphatases. Protein dephosphorylation in eukaryotic systems is largely performed through four structurally distinct Ser/Thr and Tyr O-protein phosphatase superfamilies. 555 O-protein phosphatases, belonging to the four distinct families, could be identified using sensitive sequence search techniques across five eukaryotic model organisms (yeast, fly, worm, mouse and humans). These phosphatases could be grouped into 49 subfamilies associated with distinct domain architecture and discrete biochemical function. Only five of the architectures are shared across the five eukaryotic genomes. Interestingly, the number of occurrence of tyrosine phosphatases is correlated to the complexity of the genome. Analysis of domain architectures suggests amenability of the tyrosine phosphatases to occur in complex architectures unlike Ser/Thr phosphatases. Domain duplication and shuffling is shown as the customary mechanism for the evolution of the phosphatases. Several architectures are common between humans and other genomes, which are probably non-linearly inherited in humans or specifically lost in several others.

Animals↗

PubMed1998

Cell lineage relationship in the stomach of normal and genetically manipulated mice.

The oxyntic mucosa of the mouse stomach is lined with a heterogeneous population of cells that form numerous short pits continuous with long tubular glands. Tritiated thymidine radioautography has made it possible to pinpoint the origin of all cell types and to follow the differentiation/migration of different cell lineages along the pit-gland unit. The proliferating multipotent stem cells functionally anchored in the upper glandular region, the isthmus, give rise to three main lineage precursors: 1) pre-pit cells, which migrate upward to the pit while differentiating into mucus-producing pit cells; 2) pre-neck cells, which migrate downward to the glandular neck while differentiating into mucus-producing neck cells that, by approaching the glandular base, gradually change their phenotype into pepsinogen- and intrinsic factor-producing zymogenic cells; 3) pre-parietal cells, which differentiate into acid-producing parietal cells in the isthmus and then undergo bipolar migration towards the pit and the glandular base. Thus, parietal cells are the only cells that complete their differentiation in the isthmus and then migrate to be scattered throughout the pit-gland unit. To determine whether parietal cells play a role in controlling decisions about cell fate within the pit-gland unit, the gastric epithelium has been examined in transgenic mice expressing the H,K-ATPase beta-subunit-1035 to +24/simian virus 40 large T antigen fusion gene. The blockade in parietal cell differentiation in these mice produces an amplification of lineage precursors, a marked depletion of zymogenic cells and an increase in pit cell census. Ablation of parietal cells in another transgenic mouse model expressing the H,K-ATPase beta-subunit-1035 to +24/diphtheria toxin fragment A fusion gene also produces amplification of lineage precursors, and similar effects on zymogenic and pit cell census. These findings strongly suggest that parietal cells produce regulatory signals that control the cellular differentiation program of both pit and zymogenic cell lineages, and would hopefully improve our ability to identify the cellular pathways leading to malignant transformation.

Animals↗

PubMed2025

A single-cell spatial transcriptomic census of human skin anatomy.

The skin is the largest human organ and a site of significant disease burden, yet its cellular and molecular organization across the body are largely undefined. Here, we construct a spatially-resolved single-cell atlas of 1.2 million cells from normal adult human skin to localize 45 cell types across 15 anatomic sites. We define principles of organ-wide cell composition, including axes of cell diversity and specialization, and distinguish site-enriched cell types. Each body site is comprised of 10 multicellular neighborhoods that define cell-cell communication. Notably, we identify a perivascular neighborhood enriched for immune-stromal crosstalk with features resembling a homeostatic immune niche similar to skin-associated lymphoid tissue. Finally, mapping these neighborhoods onto skin disease reveals pathogenic neighborhood disruptions, including pan-disease immune alterations in the perivascular neighborhood. We present a framework charting the skin's multiscale spatial organization across a molecular to macroanatomic scale. This work advances our understanding of organ-wide skin cellular organization and communication, and its architectural disruption in disease.

Journal Article↗

PubMed2002

Toxic inhalation fatalities of US construction workers, 1990 to 1999.

Construction workers account for a disproportionately large number of occupational fatalities. A small percentage of these deaths is attributable to poisoning. Risk factors for such deaths using national data have not been reported previously. Construction poisoning fatalities from 1990 to 1999 in the Occupational Safety and Health Administration Integrated Management and Information System data set were analyzed. Risk and risk factors were determined using Bureau of Labor Statistics and census data. Eighty-seven poisoning deaths of construction workers are characterized, all attributable to toxic inhalation. Cellular and simple asphyxiants accounted for the largest numbers of fatalities. The majority of these deaths occurred in confined spaces. Water, sewer, and utility line workers are at increased risk for poisoning fatality. Toxic inhalation fatalities in the construction industry are preventable. Extending the Occupational Safety and Health Administration's confined space standard could save lives, particularly among water, sewer, and utility line industry workers.

Administration, Inhalation↗

PubMed1995

Gastric cancer: prognosis and lymph node reactivity.

OBJECTIVE: To assess the prognostic value of various immunomorphological variables in the prognosis of gastric cancer after curative resection. DESIGN: Retrospective study. SETTING: University hospital, Italy. SUBJECTS: 180 Patients who underwent curative resection for carcinoma of the distal two thirds of stomach between January 1960 and December 1978. Curative was defined as no residual cancer at the resection margins and no distant metastases. INTERVENTIONS: All living patients were followed-up, and missing survival data were obtained from the Official Census Registry. MAIN OUTCOME MEASURES: Correlation between survival and nuclear grade, lymphocytic infiltration, and types of lymph node reaction such as sinus histiocytosis, paracortical lymphoid cellular hyperplasia, and follicular hyperplasia in the cortical area. RESULTS: Crude 5 year and 10 year survival rates were 46% and 36%, respectively. Sex, site, and histological type of the tumour did not correlate with survival. Multivariate analysis showed that only pTNM stage of disease and degree of sinus histiocytosis were significantly related to survival. CONCLUSION: There may be an argument for using the presence or absence of sinus histiocytosis to stratify patients in prospective studies of adjuvant treatment.

Female↗

PubMed2001

A millennial myosin census.

The past decade has seen a remarkable explosion in our knowledge of the size and diversity of the myosin superfamily. Since these actin-based motors are candidates to provide the molecular basis for many cellular movements, it is essential that motility researchers be aware of the complete set of myosins in a given organism. The availability of cDNA and/or draft genomic sequences from humans, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Dictyostelium discoideum has allowed us to tentatively define and compare the sets of myosin genes in these organisms. This analysis has also led to the identification of several putative myosin genes that may be of general interest. In humans, for example, we find a total of 40 known or predicted myosin genes including two new myosins-I, three new class II (conventional) myosins, a second member of the class III/ninaC myosins, a gene similar to the class XV deafness myosin, and a novel myosin sharing at most 33% identity with other members of the superfamily. These myosins are in addition to the recently discovered class XVI myosin with N-terminal ankyrin repeats and two human genes with similarity to the class XVIII PDZ-myosin from mouse. We briefly describe these newly recognized myosins and extend our previous phylogenetic analysis of the myosin superfamily to include a comparison of the complete or nearly complete inventories of myosin genes from several experimentally important organisms.

Animals↗

PubMed1976

Lung weight parallels disease severity in experimental coccidioidomycosis.

Evidence provided by histopathological study of lesions is a valuable adjunct for evaluating chemotherapeutic efficacy in experimental animal models, In addition, this should be correlated with a measure of disease severity in the same animal. The latter could be obtained by homogenization of infected organs and quantitative enumeration of viable cells of the etiological agent, but this would preclude histopathological studies in the same animal. Progression of disease in pulmonary infection is associated with replacement of air space by fluid, cells, and cellular debris. Therefore, an increase in lung weight should reflect severity of disease. Results with the murine model of coccidioidomycosis demonstrate that increasing lung weight parallels the increasing census of fungus cells in the lungs of both treated and nontreated infected mice. This was supported with evidence obtained from microscopic studies of lesions indicating that specific chemotherapy limited spread of the infection and inhibited multiplication of the fungus in the lung. Therefore, lung weight can be used as a measure of disease severity in the murine model of coccidioidomycosis.

Amphotericin B↗

PubMed2003

Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England.

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.

Acute Disease↗

PubMed2005

Neighborhood socioeconomic status and Hodgkin's lymphoma incidence in California.

Hodgkin's lymphoma occurrence has long been noted to associate with higher socioeconomic status (SES). However, the Hodgkin's lymphoma-SES association has not been examined recently or across important, possibly etiologically distinct, patient subgroups. In approximately 150 million person-years of observation in the multiethnic population of California, we examined the association of Hodgkin's lymphoma incidence with a composite measure of neighborhood-level SES in patient subgroups defined by age, sex, race/ethnicity, and Hodgkin's lymphoma histologic subtype. Using population-based cancer registry data on 3,794 Hodgkin's lymphoma patients diagnosed 1988 to 1992 and 1990 census data, we assigned a previously validated, multidimensional SES index to census block groups of patient residence. We then calculated neighborhood SES-specific incidence rates and estimated rate ratios using Poisson regression. Positive neighborhood SES gradients in Hodgkin's lymphoma incidence were observed only in young adults (ages 15-44 years at diagnosis) with nodular sclerosis Hodgkin's lymphoma and older adult (ages > or =45 years) White and Hispanic males with mixed cellularity Hodgkin's lymphoma. For young adults, associations were marked in Hispanic and Asian women, weaker in Hispanic and White men and White women, and subtle to nonexistent in Blacks and Asian men. Neighborhood SES gradients in Hodgkin's lymphoma incidence varied by age, sex, race/ethnicity, and histologic subtype, underscoring etiologic complexity in Hodgkin's lymphoma. Racial/ethnic gradients were not entirely explained by neighborhood SES. In California, etiologically relevant exposures for young adult Hodgkin's lymphoma, the most common form, could associate more with race/ethnicity or foreign birthplace than neighborhood SES and may be modified by reproductive or other sex-specific factors.

Adolescent↗

PubMed2006

Autophagy and related processes in trypanosomatids: insights from genomic and bioinformatic analyses.

The targeting in eukaryotic cells of cellular components to the lysosome or vacuole for degradation is called autophagy. Not only cytoplasmic macromolecules and bulk cytoplasm are subject to this process; entire organelles such as peroxisomes can be degraded. Autophagy of peroxisomes is called pexophagy. Unpublished evidence suggests that the analogous processing of glycosomes in the protozoan kinetoplastids occurs. Taking advantage of the (near-) complete status of three trypanosomatid genomes, a census of components of autophagy and related processes has been undertaken in these organisms. Simple database searches were supplemented by more advanced analyses where necessary. At most, only half of the components characterized in yeasts are present in trypanosomatids suggesting an unexpectedly streamlined version of autophagy occurs in these organisms. The cytoplasm-to-vacuole targeting (Cvt) system for delivery of proteins to the vacuole seems entirely absent in trypanosomatids. The accuracy of the census is supported by the coordinated absence of functionally linked components such as the conjugation system involving ATG12, ATG5, ATG10 and ATG16 that acts at the step of vesicle expansion and completion. Overall, the results are consistent with a scenario of taxon-specific addition of components to a minimal core, a hypothesis that should be readily testable by further genomic surveys allied to laboratory experiments. A bioinformatics analysis of the trypanosomatidal proteins was carried out, highlighting the paucity of information available regarding their structures and enabling prioritization of targets for future structural biology work.

Animals↗

PubMed2004

Assessing development pressure in the Chesapeake Bay watershed: an evaluation of two land-use change models.

Natural resource lands in the Chesapeake Bay watershed are increasingly susceptible to conversion into developed land uses, particularly as the demand for residential development grows. We assessed development pressure in the Baltimore-Washington, DC region, one of the major urban and suburban centers in the watershed. We explored the utility of two modeling approaches for forecasting future development trends and patterns by comparing results from a cellular automata model, SLEUTH (slope, land use, excluded land, urban extent, transportation), and a supply/demand/allocation model, the Western Futures Model. SLEUTH can be classified as a land-cover change model and produces projections on the basis of historic trends of changes in the extent and patterns of developed land and future land protection scenarios. The Western Futures Model derives forecasts from historic trends in housing units, a U.S. Census variable, and exogenously supplied future population projections. Each approach has strengths and weaknesses, and combining the two has advantages and limitations.

Baltimore↗

PubMed1997

Membrane polarity in epithelial cells: protein sorting and establishment of polarized domains.

Epithelial cells go to great trouble to organize the subdomains of their plasma membranes. The apical and basolateral surfaces of polarized epithelia are equipped with markedly distinct populations of channels, carriers, and pumps. This anisotropy is an absolute prerequisite for vectorial solute and fluid transport. The physiological properties of an individual epithelial cell type are determined not only by its census of transport proteins but also by the manner in which these proteins are segregated between the apical and basolateral portions of the plasmalemma (Curr. Top. Membr. 39: 37-86, 1991). To achieve this asymmetry, an epithelial cell must be able to establish distinct surface domains, to target newly synthesized transport proteins to their appropriate sites of functional residence, and to retain them there following their delivery. Studies of the cellular pathways involved in generating and maintaining the polarized state have begun to illuminate an elegant network of cell biological specializations that may be involved not only in establishing the distributions of transport proteins but in dynamically regulating their function as well.

Animals↗

PubMed1999

How many is enough? Exploring the myosin repertoire in the model eukaryote Dictyostelium discoideum.

The cytoplasm of eukaryotic cells is a very complex milieu and unraveling how its unique cytoarchitecture is achieved and maintained is a central theme in modern cell biology. It is crucial to understand how organelles and macro-complexes of RNA and/or proteins are transported to and/or maintained at their specific cellular locations. The importance of filamentous-actin-directed myosin-powered cargo transport was only recently realized, and after an initial explosion in the identification of new molecules, the field is now concentrating on their functional dissection. Direct connections of myosins to a variety of cellular tasks are now slowly emerging, such as in cytokinesis, phagocytosis, endocytosis, polarized secretion and exocytosis, axonal transport, etc. Unconventional myosins have been identified in a wide variety of organisms, making the presence of actin and myosins a hallmark of eukaryotism. The genome of S. cerevisiae encodes only five myosins, whereas a mammalian cell has the capacity to express between two and three dozen myosins. Why is it so crucial to arrive at this final census? The main questions that we would like to discuss are the following. How many distinct myosin-powered functions are carried out in a typical higher eukaryote? Or, in other words, what is the minimal set of myosins essential to accomplish the multitude of tasks related to motility and intracellular dynamics in a multicellular organism? And also, as a corollary, what is the degree of functional redundancy inside a given myosin class? In that respect, the choice of a model organism suitable for such an investigation is more crucial than ever. Here we argue that Dictyostelium discoideum is affirming its position as an ideal system of intermediate complexity to study myosin-powered trafficking and is or will soon become the second eukaryote for which complete knowledge of the whole repertoire of myosins is available.

Actins↗

PubMed1996

Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.

In this study of cancer in offspring we demonstrate that factors linked to horticulture and use of pesticides are associated with cancer at an early age, whereas factors in animal husbandry, in particular poultry farming, are associated with cancers in later childhood and young adulthood. Incident cancer was investigated in offspring born in 1952-1991 to parents identified as farm holders in agricultural censuses in Norway in 1969-1989. In the follow-up of 323,292 offspring for 5.7 million person-years, 1,275 incident cancers were identified in the Cancer Registry for 1965-1991. The standardized incidence for all cancers was equal to the total rural population of Norway, but cohort subjects had an excess incidence of nervous-system tumours and testicular cancers in certain regions and strata of time that could imply that specific risk factors were of importance. Classification of exposure indicators was based on information given at the agricultural censuses. Risk factors were found for brain tumours, in particular non-astrocytic neuroepithelial tumours: for all ages, pig farming tripled the risk [rate ratio (RR), 3.11; 95% confidence interval (CI), 1.89-5.13]; indicators of pesticide use had an independent effect of the same magnitude in a dose-response fashion, strongest in children aged 0 to 14 years (RR, 3.37; 95% CI, 1.63-6.94). Horticulture and pesticide indicators were associated with all cancers at ages 0 to 4 years, Wilms' tumour, non-Hodgkin's lymphoma, eye cancer and neuroblastoma. Chicken farming was associated with some common cancers of adolescence, and was strongest for osteosarcoma and mixed cellular type of Hodgkin's disease. The main problem in this large cohort study is the crude exposure indicators available; the resulting misclassification is likely to bias any true association towards unity.

Acute Disease↗

PubMed2006

Dual alterations in casein kinase I-epsilon and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia.

Casein kinase I (CKI)-epsilon and GSK-3beta phosphorylate beta-catenin at Ser(45) (beta-cat(45)) and Thr(41)/Ser(37,33) (beta-cat(33,37,41)) residues, thereby facilitating its ubiquitination and proteasomal degradation. We used a Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of beta-catenin during crypt hyperproliferation. TMCH was associated with 3-fold and 3.3-fold increases in CKI-epsilon cellular abundance and 2-fold and 1.8-fold increase in its activity at 6 and 12 days after infection, respectively. beta-Catenin coimmunoprecipitated with both cellular and nuclear CKI-epsilon and cellular axin at these time points. Cellular beta-catenin was constitutively phosphorylated at Ser(45) and underwent subcellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 of TMCH, respectively. beta-cat(33,37,41), however, exhibited only subtle changes in either phosphorylation status or subcellular distribution even after blocking proteasomal degradation in vivo. Interestingly, GSK-3beta underwent increased phosphorylation at Ser(9), leading to 40% and 70% decreases in its activity at these time points, respectively. Coimmunoprecipitation studies exhibited strong association of GSK-3beta with PKC-zeta at either time point. Cellular beta-cat(45) stabilized and, along with unphosphorylated beta-catenin, underwent nuclear translocation, associated with nuclear accumulated Tcf-4 and cAMP response element binding protein binding protein, and was significantly acetylated, leading to increases in DNA binding. Priming of beta-catenin at Ser(45) exists in vivo. However, beta-cat(45) does not necessarily enter the degradation pathway. Impairment in linking beta-cat(45) to subsequent GSK-3beta-mediated phosphorylation and degradation may account for increased steady-state levels of both unphosphorylated as well as Ser(45)-phosphorylated beta-catenin, which may be causally linked to increases in cell census during TMCH.

Animals↗

PubMed1985

Immunologic findings in healthy Haitians in Montreal.

To investigate the occurrence of acquired immune deficiency syndrome in Haitians, a health status questionnaire was administered and selected studies of immune status done in a randomly chosen sample of 189 healthy adult Haitians living in Montreal. The study group was comparable to a large sample of Haitians in Montreal interviewed in the 1981 census with respect to age, sex, number of persons per household and year of immigration, but the proportion of currently married people in the study was larger (60.8% v. 42.6%). The results in the study group were compared with those in a sample of 189 non-Haitians matched for age, sex and neighbourhood of residence. Persons with known causes of impaired immune function were excluded. The participation rate was 87.5%. The study and control groups both reported few symptoms and chronic health problems and had comparable demographic data, including rate of employment and income. The mean total numbers of lymphocytes, OKT3 and OKT4 (helper) and OKT8 (suppressor) cells were significantly higher in the Haitians than in the controls, though still within normal limits. There was a borderline elevation of the lymphocyte response to phytohemagglutinin in the Haitians. The ratios of helper to suppressor T cells in the two groups were, however, not significantly different. The Haitians, in comparison with non-Haitians living in the same community, had no demonstrable abnormalities of cellular immune function.

Acquired Immunodeficiency Syndrome↗