Proliferative Units Research Articles

Deposition of cenomanian – Turonian organic-rich units on the mid-Norwegian margin: Controlling factors and regional implications

On the mid-Norwegian margin, extensive rifting and subsequent deposition of thick Cretaceous and Cenozoic sediments have buried the traditional Upper Jurassic organic-rich shales too deep. Consequently, these organic-rich shales are overmature and spent in the deep basins on the mid-Norwegian margin. The absence of well-control, variable seismic quality and in particularly, the great burial depth, makes it difficult to identify alternative Upper Jurassic and Lower Cretaceous organic-rich units. By combining high-resolution 2D seismic data, well logs, and Rock-Eval data, this study documents the presence of alternative organic-rich units in the Cretaceous succession on the Halten Terrace and the Vøring Basin. Multiple seismic horizons which correspond to regional flooding surfaces and define a series of seismic sequences have been mapped across the study area. The regionally extensive upper Cenomanian horizon is associated with wireline log signals and Rock-Eval parameters which imply the presence of a potential source rock unit. Source rock evaluation indicate that this unit contains mainly kerogen Type III on the Halten Terrace, suggesting an organofacies with significant contribution from terrestrial sources. In the Vøring Basin, the unit is sparsely drilled but appears to be mature, thus displaying a relatively limited potential. One well from the Vigrid Syncline demonstrate somewhat higher potential, with Rock-Eval data indicating a kerogen Type II composition. As such, more prolific units seems to exist in the Vøring Basin, albeit exhibiting a patchy distribution. We speculate that the deposition and preservation of this upper Cenomanian organic-rich unit record the development of an extended oxygen minimum zone attributable to increased primary production and sluggish water circulation, linked to the global Oceanic Anoxic Event 2 (OAE 2). However, local physiographic conditions, such as high sedimentation rates, erosion by gravity flows and periodically oxygenated conditions hindered preservation of a significant quantities of organic matter, thus limiting the thickness and quality of the upper Cenomanian organic-rich unit on the mid-Norwegian margin.

Mapping Global Research in Emergency Medicine; a Bibliometric Analysis of Documents Indexed in the Web of Science Database.

Emergency medicine is a relatively new and rapidly growing specialty, and its research monitoring is important for future policies. This study aimed to analyze the published literature related to emergency medicine, to create a documented research perspective for this field. This research is a bibliometric study that analyzes the research outputs of the subject area of emergency medicine indexed in the Web of Science database from the beginning to 2023. VOSviewer software was used to visualize and predict the trends in research on the topic. The findings showed that the University of California, The Journal of Neurotrauma and Brain Injury, Elsevier, and the USA were the most prolific units in the cycle of scientific productions in the field of emergency medicine. Results showed that most scientific productions in this field fall into 6 clusters: psychological impressions, injuries caused by traumatic events and the effects of traumas on children, pathophysiology and nervous system issues and related diseases, complications of traumatic events and injuries, biomechanics and complications caused by sports injuries, and consciousness. In addition to interventions and clinical complications, research in the field of emergency medicine has also focused on psychological structures. So, based on various measurement indicators, the subjects of this field have been the focus of researchers' attention.

Global trends of research on tuberculous pleurisy over the past 15 years: A bibliometric analysis.

Tuberculous pleurisy (TP) is a common type of extrapulmonary tuberculosis (EPTB). With the development of research and changes in TP patient characteristics, an increasing number of studies have revealed the prevalence, risk factors, and novel diagnosis techniques. Thus, this bibliometric analysis was performed to identify global scientific output characteristics and research hotspots and frontiers for TP over the past 15 years. We searched the Web of Science Core Collection (WoSCC) Science Citation Index Expanded (SCI-expanded) for literature published between 2007 and 2021 and recorded their information. The Bibliometrix software package was used for bibliometric indicator analysis, and VOSviewer was used to visualize the trends of and hotspots in TP research. A total of 1,464 original articles were reviewed, and the results indicated that the annual number of publications (Np) focusing on TP has increased over the past 15 years. China had the largest number of papers and the highest H-index, and the United States ranked first for number of citations (Nc). EGYPTIAN KNOWLEDGE BANK and PLOS ONE were the most prolific unit and journal, respectively. The use of the Xpert assay and immune-related biomarker detection to diagnose TP appears to be a recent research hotspot. This bibliometric study demonstrated that the number of publications related to TP have tended to increase. China is a major producer, and the United States is an influential country in this field. Research in the past 15 years has been predominantly clinical research. The diagnosis of TP was the focus of research, and the exploration of novel diagnostic techniques, verification of diagnostic markers, and combination of diagnostic methods have been recent research hotspots. Immune-related biomarkers should be given more attention in the field of TP diagnosis.

The Evolution of Research in Journalism and Communication: An Analysis of Scholarly CIOS-Indexed Journals From 1915 to Present

Assessments of programmatic research remain important in the current higher education landscape, as the field of Journalism & Mass Communication (JMC) enters its second century. This study profiles scholarly productivity across the larger discipline’s first century, focusing on scholarly output for institutions in referred journals indexed by the Communication Institute for Online Scholarship (CIOS) database since 1915. The 30 most prolific scholars all have at least a decade of experience and typically publish with a coauthor. All but four of the 30 most prolific units grant doctoral degrees. Implications of converging research areas wrought by emerging digital media—and their erasure of the field’s sub-domains—are discussed.

The evolution of metapopulation dynamics and the number of stem cells in intestinal crypts and other tissue structures in multicellular bodies.

Carcinogenesis is a process of somatic evolution. Previous models of stem and transient amplifying cells in epithelial proliferating units like colonic crypts showed that intermediate numbers of stem cells in a crypt should optimally prevent progression to cancer. If a stem cell population is too small, it is easy for a mutator mutation to drift to fixation. If it is too large, it is easy for selection to drive cell fitness enhancing carcinogenic mutations to fixation. Here, we show that a multiscale microsimulation, that captures both within‐crypt and between‐crypt evolutionary dynamics, leads to a different conclusion. Epithelial tissues are metapopulations of crypts. We measured time to initiation of a neoplasm, implemented as inactivation of both alleles of a tumor suppressor gene. In our model, time to initiation is dependent on the spread of mutator clones in the crypts. The proportion of selectively beneficial and deleterious mutations in somatic cells is unknown and so was explored with a parameter. When the majority of non‐neutral mutations are deleterious, the fitness of mutator clones tends to decline. When crypts are maintained by few stem cells, intercrypt competition tends to remove crypts with fixed mutators. When there are many stem cells within a crypt, there is virtually no crypt turnover, but mutator clones are suppressed by within‐crypt competition. If the majority of non‐neutral mutations are beneficial to the clone, then these results are reversed and intermediate‐sized crypts provide the most protection against initiation. These results highlight the need to understand the dynamics of turnover and the mechanisms that control homeostasis, both at the level of stem cells within proliferative units and at the tissue level of competing proliferative units. Determining the distribution of fitness effects of somatic mutations will also be crucial to understanding the dynamics of tumor initiation and progression.

The tetrapod fauna of the upper Permian Naobaogou Formation of China: 5. Caodeyao liuyufengi gen. et sp. nov., a new peculiar therocephalian.

The upper Permian Naobaogou Formation has been the goal of recent contributions that notably increased the knowledge of its terrestrial vertebrate fauna and unravelled a hidden late Permian therocephalian diversity in China. Two very different species of therocephalians have been documented in the Naobaogou Formation and they were recovered as basal akidnognathids in cladistic analyses. In this contribution we describe Caodeyao liuyufengi gen. et sp. nov., represented by a partial skull and mandible, and a humerus. The new taxon features a short, high snout and a wide temporal opening with the coronoid process of the mandible separated by a wide space medially to the zygomatic arch. The latter feature is only recognized in the Russian therocephalian Purlovia maxima and it is also characteristic of non-mammaliaform cynodonts. Phylogenetic analysis indicates a close relationship of the new Chinese taxon with Purlovia maxima, producing a monophyletic Laurasian group in therocephalian phylogeny. With the representation of three different species, the Naobaogou Formation is now the most prolific unit documenting therocephalian late Permian diversity in China.

Epidermal γδ T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult.

The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and γδ T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, albeit accelerated, facilitates DETC replenishment upon injury. Hematopoietic lineage tracing uncovered that DETCs are established independently of definitive hematopoietic stem cells and instead originate from YS hematopoiesis, again reminiscent of LCs. DETCs thus resemble LCs concerning their maintenance, replenishment mechanisms, and hematopoietic development, suggesting that the epidermal microenvironment exerts a lineage-independent influence on the initial seeding and homeostatic maintenance of its resident immune cells.

Clonal Proliferation and Stochastic Pruning Orchestrate Lymph Node Vasculature Remodeling

Lymph node (LN) expansion during an immune response relies on the transient remodeling of its vasculature. Although the mechanisms driving LN endothelial cell division are beginning to be understood, a comprehensive view of LN endothelial cell dynamics at the single-cell level is lacking. Here, we used multicolored fluorescent fate-mapping models to track the behavior of blood endothelial cells during LN expansion upon inflammation and subsequent return to homeostasis. We found that expansion of the LN vasculature relied on the sequential assembly of endothelial cell proliferative units. This segmented growth was sustained by the clonal proliferation of high endothelial venule (HEV) cells, which act as local progenitors to create capillaries and HEV neo-vessels at the periphery of the LN. Return to homeostasis was accompanied by the stochastic death of pre-existing and neo-synthesized LN endothelial cells. Thus, ourfate-mapping studies unravel-at a single-cell level-the complex dynamics of vascular-tree remodeling during LN expansion and contraction.

Multicolor fate mapping of Langerhans cell homeostasis

Langerhans cells (LCs) constitute a network of immune sentinels in the skin epidermis that is seeded during embryogenesis. Whereas the development of LCs has been extensively studied, much less is known about the homeostatic renewal of adult LCs in "nonmanipulated" animals. Here, we present a new multicolor fluorescent fate mapping system and quantification approach to investigate adult LC homeostasis. This novel approach enables us to propose and provide evidence for a model in which the adult epidermal LC network is not formed by mature coequal LCs endowed with proliferative capabilities, but rather constituted by adjacent proliferative units composed of "dividing" LCs and their terminally differentiated daughter cells. Altogether, our results demonstrate the general utility of our novel fate-mapping system to follow cell population dynamics in vivo and to establish an alternative model for LC homeostasis.

Epidermal Stem Cells in Homeostasis and Wound Repair of the Skin

The skin interfollicular epidermis (IFE) is an organism's first line of defense against a harmful environment and physical damage. During homeostasis and wound repair, the IFE is rejuvenated constantly by IFE stem cells (SCs) that are capable of both proliferation and differentiation. However, the identity and behavior of IFE SCs remain controversial. Two opposing theories exist regarding homeostasis of the IFE. On the basis of morphological and proliferative characteristics, one posits that the IFE is composed of a discrete epidermal proliferative unit comprised of ∼10 transit-amplifying (TA) cells and a centrally located SC in the basal layer. The other suggests that homeostasis of the IFE is maintained by a single progenitor population in the basal layer. A recent study has challenged these two apparently distinct models and demonstrated that the basal layer of the IFE contains both SCs and TA cells, which make distinct contributions to tissue homeostasis and repair. Moreover, phosphorylation levels of the transcription factor p63, the master regulator of the proliferative potential of epidermal SCs, can be used to distinguish self-renewing SCs from TA cells with more limited proliferative potential. As technologies advance, IFE SCs can be identified at a single-cell level. Refinements of their identification and characterization are critical, not only for SC biology but also for the development of novel clinical applications. Understanding the signaling pathways that control self-renewal and differentiation of IFE SCs will aid in developing novel cell-based therapeutics targeting degenerative epidermal diseases and wound repair.

An evolutionary explanation for the presence of cancer nonstem cells in neoplasms

Contrary to conventional views that assume all cells in a neoplasm can propagate the tumor, the cancer stem cell hypothesis posits that only a fraction of the cells (the cancer stem cells) can act as tumor-propagating cells, while most of the tumor is composed of cells with limited replication potential. Here, we offer an evolutionary approach to this controversy. We used several evolutionary, computational models to investigate cancer cell dynamics and conditions consistent with the stem cell hypothesis. Our models predict that if selection acts at the cell level, neoplasms should be primarily comprised of cancer stem cells, in contrast to experimental data indicating that neoplasms contain large fractions of cancer nonstem cells. We explore several solutions explaining the paradoxical existence of cancer nonstem cells in neoplasms, including the possibility that selection acts at the level of multicellular proliferative units.

Interfollicular epidermal homeostasis: dicing with differentiation

In the 1970s, studies of tissue architecture and cell proliferation were used to formulate a new model of epidermal homeostasis. This asserted that the tissue was maintained by long-lived, slow-cycling, self-renewing stem cells that generate a short-lived population of transit amplifying (TA) cells, which undergo terminal differentiation after a set number of cell divisions. It was further hypothesized that in the epidermis, the tissue was organized into clonal epidermal proliferative units (EPUs) comprising a central stem cell with surrounding TA cells, which maintain the overlying differentiated cell layers. The stem/TA and EPU hypotheses have been widely influential. Here, we first revaluate older literature, finding numerous studies that conflict with the EPU model. We then review recent large-scale lineage tracing studies in transgenic mice which exclude the stem/TA and EPU hypotheses, and reveal that the epidermis is maintained by a single population of functionally equivalent cycling progenitor cells. The outcome of individual progenitor cell divisions is random, but the probabilities of generating differentiated and progenitor cell daughters are equal, so that homeostasis is maintained across the progenitor population. We reconcile this model with the older literature and place the epidermis in the context of other tissues that are also maintained by continually cycling cells with stochastic fate.

The Ordered Architecture of Murine Ear Epidermis Is Maintained by Progenitor Cells with Random Fate

Typical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis.

Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling

The cerebral cortex is a laminated sheet of neurons composed of the arrays of intersecting radial columns. During development, excitatory projection neurons originating from the proliferative units at the ventricular surface of the embryonic cerebral vesicles migrate along elongated radial glial fibres to form a cellular infrastructure of radial (vertical) ontogenetic columns in the overlaying cortical plate. However, a subpopulation of these clonally related neurons also undergoes a short lateral shift and transfers from their parental to the neighbouring radial glial fibres, and intermixes with neurons originating from neighbouring proliferative units. This columnar organization acts as the primary information processing unit in the cortex. The molecular mechanisms, role and significance of this lateral dispersion for cortical development are not understood. Here we show that an Eph receptor A (EphA) and ephrin A (Efna) signalling-dependent shift in the allocation of clonally related neurons is essential for the proper assembly of cortical columns. In contrast to the relatively uniform labelling of the developing cortical plate by various molecular markers and retrograde tracers in wild-type mice, we found alternating labelling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and ephrin-As during neuronal migration. This so far unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization.

Locating the stem cell niche and tracing hepatocyte lineages in human liver #

We have used immunohistochemical and histochemical techniques to identify patches of hepatocytes deficient in the enzyme cytochrome c oxidase, a component of the electron transport chain and encoded by mitochondrial DNA (mtDNA). These patches invariably abutted the portal tracts and expanded laterally as they spread toward the hepatic veins. Here we investigate, using mtDNA mutations as a marker of clonal expansion, the clonality of these patches. Negative hepatocytes were laser-capture microdissected and mutations identified by polymerase chain reaction sequencing of the entire mtDNA genome. Patches of cytochrome c oxidase-deficient hepatocytes were clonal, suggesting an origin from a long-lived cell, presumably a stem cell. Immunohistochemical analysis of function and proliferation suggested that these mutations in cytochrome c oxidase-deficient hepatocytes were nonpathogenic. These data show, for the first time, that clonal proliferative units exist in the human liver, an origin from a periportal niche is most likely, and that the trajectory of the units is compatible with a migration of cells from the periportal regions to the hepatic veins.

Tiers of Clonal Organization in the Epidermis: The Epidermal Proliferation Unit Revisited

As one of the most proliferative tissues in adult mammals, the epidermis is a good example of the precise regulation necessary between stem cell self-renewal and differentiation. The epidermis is derived from ectodermal progenitor cells and contains three distinct classes of cells: epidermal stem cells which are capable of infinite rounds of cell division; their immediate descendants, transient amplifying cells, which are capable of numerous but finite rounds of cell division; and finally, non-dividing, differentiating cells (Aberdam in Cell and Tissue Research 331:103-107, 2008). This proliferative hierarchy must be tightly regulated both temporally and spatially during epidermal development and homeostasis in order to prevent uncontrolled growth leading to hyperproliferative states and/or tumorigenesis. Historically, the most basic unit of epidermal proliferation has been described as the epidermal proliferation unit (EPU). The EPU, as originally characterized by Christophers, Potten and Mackenzie, is a proliferation unit consisting of approximately 10 basal cells with a clonogenic cell in the center and overlaid by the suprabasal and corneocyte progeny (reviewed in Potten, C. S. (1974). The epidermal proliferative unit: the possible role of the central basal cell. Cell and Tissue Kinetics, 7(1), 77-88). Numerous researchers have identified this classical EPU structure, consisting of approximately 20 cells, in a variety of mammalian skin sources. Recently however, lineage analyses have provided evidence for much larger clonal epidermal units consisting of hundreds to thousands of cells. Furthermore, cutaneous mosaicism as well as a variety of cutaneous pathologies indicate that clonal areas extend to whole patches of mammalian skin many centimeters across. In this review we revisit four decades of experimental evidence and put forward a model of clonal units derived from multiple classes of epidermal progenitors ranging from the largest and most primitive units, clonal ectodermal units, to epidermal stem cell units, and finally, to the most basic structural unit, the EPU.

Review article: is there a common principle in the development of gastrointestinal cancers? Stem cells in the origin of cancer

SummaryBackgroundAccumulating evidence, outlined in this review, at last provides some elucidation of the orgin of gastrointestinal epithelial tumours.MethodsNew techniques, such as following the process of crypt or gastric gland purification following mutation in genes encoded by the mitochondrial genome, have shown that mutations spead within the proliferative unit, either gastric gland or intestinal crypt, by clonal purification or monoclonal conversion. Spreading otside the crypt or gland then takes place by fission.ResultsFuture research should focus on the mecanisim by which mutated stem cells colonize crypts, and on the mechanisms of crypt fission itself.

Review article: is there a common principle in the development of gastrointestinal cancers? Stem cells in the origin of cancer

SummaryBackgroundAccumulating evidence, outlined in this review, at last provides some elucidation of the orgin of gastrointestinal epithelial tumours.MethodsNew techniques, such as following the process of crypt or gastric gland purification following mutation in genes encoded by the mitochondrial genome, have shown that mutations spead within the proliferative unit, either gastric gland or intestinal crypt, by clonal purification or monoclonal conversion. Spreading otside the crypt or gland then takes place by fission.ResultsFuture research should focus on the mecanisim by which mutated stem cells colonize crypts, and on the mechanisms of crypt fission itself.

Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis

The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1-15 (Krt1-15) promoter. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.

Isolation and Characterization of a Putative Intestinal Stem Cell Fraction From Mouse Jejunum

Although there have been many recent advances regarding the biology of intestinal stem cells, the field has been hampered significantly by the lack of a method to isolate these cells. Therefore, the aim of this study was to explore the hypothesis that viable intestinal stem cells can be isolated as a side population (SP) by fluorescence-activated cell sorting after staining with the DNA-binding dye Hoechst 33342. Preparations of individual cells from either whole mucosa or epithelium of mouse jejunum were stained with Hoechst 33342 and propidium iodide and then sorted using fluorescence-activated cell sorting. Cells were characterized using fluorochrome-labeled antibodies to surface markers, intracellular markers, and annexin V to detect early apoptosis. Total RNA was isolated from sorted fractions and used for quantitative real-time reverse-transcription polymerase chain reaction to evaluate the expression of cell lineage markers and the intestinal stem-cell marker, Musashi-1. Adult and neonatal jejunum contain a viable population of cells that shows the SP phenotype and is sensitive to verapamil. This population of cells (from both mucosal and epithelial preparations) includes a CD45-negative fraction corresponding to nonhematopoietic cells, which shows minimal expression of surface markers typically found on stem cells from other tissues and of intracellular markers found in mesenchymal cells. Additionally, these cells were enriched for Musashi-1 and beta1-integrin, were cytokeratin positive, and survived in culture for up to 14 days. The CD45-negative SP fraction, although not pure, represents the successful isolation of a viable population significantly enriched in small intestinal epithelial stem cells.