Genetic and demographic recovery of an isolated population of brown bear Ursus arctos L., 1758

PubMed Central

Gonzalez, Elena G.; Ballesteros, Fernando; Alcaraz, Lourdes; Palomero, Guillermo; Doadrio, Ignacio

2016-01-01

The brown bear Ursus arctos L., 1758 population of the Cantabrian Mountains (northwestern Spain) became isolated from other bear populations in Europe about 500 years ago and has declined due to hunting and habitat degradation. At the beginning of the 20th century, the Cantabrian population split into eastern and western subpopulations, and genetic exchange between them ceased. In the early 1990s, total population size was estimated to be < 100 bears. Subsequently, reduction in human-caused mortality has brought about an increase in numbers, mainly in the western subpopulation, likely promoting male-mediated migration and gene flow from the western nucleus to the eastern. To evaluate the possible genetic recovery of the small and genetically depauperate eastern subpopulation, in 2013 and 2014 we genotyped hair and faeces samples (116 from the eastern subpopulation and 36 from the western) for 18 microsatellite markers. Data from the annual count of females with cubs of the year (COY) during the past twenty-six years was used to analyze demographic changes. The number of females with COY fell to a minimum of seven in the western and three in eastern subpopulations in the biennium 1993–1994 and reached a respective maximum of 54 and 10 individuals in 2013–2014. We also observed increased bear dispersal and gene flow, mainly from the western to the eastern subpopulation. Of the 26 unique genotypes detected in the eastern subpopulation, 14 (54%) presented an admixture composition, and seven (27%) were determined to be migrants from the western subpopulation. Hence, the two separated and clearly structured subpopulations identified in the past currently show some degree of genetic admixture. This research shows the partial demographic recovery and a change in genetic composition due to migration process in a population of bears that has been isolated for several centuries. PMID:27168963

Bone Marrow Regeneration Promoted by Biophysically Sorted Osteoprogenitors From Mesenchymal Stromal Cells

PubMed Central

Poon, Zhiyong; Lee, Wong Cheng; Guan, Guofeng; Nyan, Lin Myint; Lim, Chwee Teck; Han, Jongyoon

2015-01-01

Human tissue repair deficiencies can be supplemented through strategies to isolate, expand in vitro, and reimplant regenerative cells that supplant damaged cells or stimulate endogenous repair mechanisms. Bone marrow-derived mesenchymal stromal cells (MSCs), a subset of which is described as mesenchymal stem cells, are leading candidates for cell-mediated bone repair and wound healing, with hundreds of ongoing clinical trials worldwide. An outstanding key challenge for successful clinical translation of MSCs is the capacity to produce large quantities of cells in vitro with uniform and relevant therapeutic properties. By leveraging biophysical traits of MSC subpopulations and label-free microfluidic cell sorting, we hypothesized and experimentally verified that MSCs of large diameter within expanded MSC cultures were osteoprogenitors that exhibited significantly greater efficacy over other MSC subpopulations in bone marrow repair. Systemic administration of osteoprogenitor MSCs significantly improved survival rates (>80%) as compared with other MSC subpopulations (0%) for preclinical murine bone marrow injury models. Osteoprogenitor MSCs also exerted potent therapeutic effects as “cell factories” that secreted high levels of regenerative factors such as interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A, bone morphogenetic protein 2, epidermal growth factor, fibroblast growth factor 1, and angiopoietin-1; this resulted in increased cell proliferation, vessel formation, and reduced apoptosis in bone marrow. This MSC subpopulation mediated rescue of damaged marrow tissue via restoration of the hematopoiesis-supporting stroma, as well as subsequent hematopoiesis. Together, the capabilities described herein for label-freeisolation of regenerative osteoprogenitor MSCs can markedly improve the efficacy of MSC-based therapies. PMID:25411477

Bimolecular fluorescence complementation: visualization of molecular interactions in living cells.

PubMed

Kerppola, Tom K

2008-01-01

A variety of experimental methods have been developed for the analysis of protein interactions. The majority of these methods either require disruption of the cells to detect molecular interactions or rely on indirect detection of the protein interaction. The bimolecular fluorescence complementation (BiFC) assay provides a direct approach for the visualization of molecular interactions in living cells and organisms. The BiFC approach is based on the facilitated association between two fragments of a fluorescent protein when the fragments are brought together by an interaction between proteins fused to the fragments. The BiFC approach has been used for visualization of interactions among a variety of structurally diverse interaction partners in many different cell types. It enables detection of transient complexes as well as complexes formed by a subpopulation of the interaction partners. It is essential to include negative controls in each experiment in which the interface between the interaction partners has been mutated or deleted. The BiFC assay has been adapted for simultaneous visualization of multiple protein complexes in the same cell and the competition for shared interaction partners. A ubiquitin-mediated fluorescence complementation assay has also been developed for visualization of the covalent modification of proteins by ubiquitin family peptides. These fluorescence complementation assays have a great potential to illuminate a variety of biological interactions in the future.

Meta-STEPP: subpopulation treatment effect pattern plot for individual patient data meta-analysis.

PubMed

Wang, Xin Victoria; Cole, Bernard; Bonetti, Marco; Gelber, Richard D

2016-09-20

We have developed a method, called Meta-STEPP (subpopulation treatment effect pattern plot for meta-analysis), to explore treatment effect heterogeneity across covariate values in the meta-analysis setting for time-to-event data when the covariate of interest is continuous. Meta-STEPP forms overlapping subpopulations from individual patient data containing similar numbers of events with increasing covariate values, estimates subpopulation treatment effects using standard fixed-effects meta-analysis methodology, displays the estimated subpopulation treatment effect as a function of the covariate values, and provides a statistical test to detect possibly complex treatment-covariate interactions. Simulation studies show that this test has adequate type-I error rate recovery as well as power when reasonable window sizes are chosen. When applied to eight breast cancer trials, Meta-STEPP suggests that chemotherapy is less effective for tumors with high estrogen receptor expression compared with those with low expression. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Dendritic Cells Induce a Subpopulation of IL-12Rβ2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses

PubMed Central

Sela, Uri; Park, Chae Gyu; Park, Andrew; Olds, Peter; Wang, Shu; Fischetti, Vincent A.

2016-01-01

Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response. In the current study we used the mixed leukocyte reaction (MLR) to investigate the effect of allospecific Treg on IL-12, TNFα and IL-6 secretion by DCs. Treg cells were found to markedly down-regulate IL-12 secretion from DCs following stimulation with TLR7/8 agonist. This down-regulation of IL-12 was neither due to a direct suppression of its production by the DCs nor a result of marked DC death. We found that IL-12 was rather actively consumed by Treg cells. IL-12 consumption was mediated by a subpopulation of IL-12Rβ2-expressing Treg cells and was dependent on MHC class-II expressed on dendritic cells. Furthermore, IL-12 consumption by Tregs increased their suppressive effect on T cell proliferation and Th1 activation. These results provide a new pathway of Th1 response regulation where IL-12 secreted by DCs is consumed by a sub-population of IL-12Rβ2-expressing Treg cells. Consumption of IL-12 by Tregs not only reduces the availability of IL-12 to Th effector cells but also enhances the Treg immunosuppressive effect. This DC-induced IL-12Rβ2-expressing Treg subpopulation may have a therapeutic advantage in suppressing Th1 mediated autoimmunity. PMID:26745371

Coordination of the Arc Regulatory System and Pheromone-Mediated Positive Feedback in Controlling the Vibrio fischeri lux Operon

PubMed Central

Septer, Alecia N.; Stabb, Eric V.

2012-01-01

Bacterial pheromone signaling is often governed both by environmentally responsive regulators and by positive feedback. This regulatory combination has the potential to coordinate a group response among distinct subpopulations that perceive key environmental stimuli differently. We have explored the interplay between an environmentally responsive regulator and pheromone-mediated positive feedback in intercellular signaling by Vibrio fischeri ES114, a bioluminescent bacterium that colonizes the squid Euprymna scolopes. Bioluminescence in ES114 is controlled in part by N-(3-oxohexanoyl)-L-homoserine lactone (3OC6), a pheromone produced by LuxI that together with LuxR activates transcription of the luxICDABEG operon, initiating a positive feedback loop and inducing luminescence. The lux operon is also regulated by environmentally responsive regulators, including the redox-responsive ArcA/ArcB system, which directly represses lux in culture. Here we show that inactivating arcA leads to increased 3OC6 accumulation to initiate positive feedback. In the absence of positive feedback, arcA-mediated control of luminescence was only ∼2-fold, but luxI-dependent positive feedback contributed more than 100 fold to the net induction of luminescence in the arcA mutant. Consistent with this overriding importance of positive feedback, 3OC6 produced by the arcA mutant induced luminescence in nearby wild-type cells, overcoming their ArcA repression of lux. Similarly, we found that artificially inducing ArcA could effectively repress luminescence before, but not after, positive feedback was initiated. Finally, we show that 3OC6 produced by a subpopulation of symbiotic cells can induce luminescence in other cells co-colonizing the host. Our results suggest that even transient loss of ArcA-mediated regulation in a sub-population of cells can induce luminescence in a wider community. Moreover, they indicate that 3OC6 can communicate information about both cell density and the state of ArcA/ArcB. PMID:23152924

Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis

USDA-ARS?s Scientific Manuscript database

Autoimmune diseases are common, disabling immune disorders affecting millions of people. Recent studies indicate that dysregulated balance of different CD4+ T-cell subpopulations plays a key role in immune pathogenesis of several major autoimmune diseases. Green tea and its active ingredient, epigal...

The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

PubMed Central

2016-01-01

The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

PubMed Central

Garcia-Garcia, Alvaro; Tancredi, Adrian Newman-; Leonardo, E. David

2014-01-01

Rationale Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders. Objectives In this review, we examine the function of 5-HT1A receptor sub-populations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor vs heteroreceptor) and the temporal (developmental vs adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. Results It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for distinct roles of these populations in governing emotion related behavior are emerging. Conclusions There is strong and growing evidence for a functional dissociation between auto and heteroreceptor populations in mediating anxiety and depressive-like behaviors respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. PMID:24337875

Fluorescence Behavioral Imaging (FBI) Tracks Identity in Heterogeneous Groups of Drosophila

PubMed Central

Ramdya, Pavan; Schaffter, Thomas; Floreano, Dario; Benton, Richard

2012-01-01

Distinguishing subpopulations in group behavioral experiments can reveal the impact of differences in genetic, pharmacological and life-histories on social interactions and decision-making. Here we describe Fluorescence Behavioral Imaging (FBI), a toolkit that uses transgenic fluorescence to discriminate subpopulations, imaging hardware that simultaneously records behavior and fluorescence expression, and open-source software for automated, high-accuracy determination of genetic identity. Using FBI, we measure courtship partner choice in genetically mixed groups of Drosophila. PMID:23144871

Fluorescence behavioral imaging (FBI) tracks identity in heterogeneous groups of Drosophila.

PubMed

Ramdya, Pavan; Schaffter, Thomas; Floreano, Dario; Benton, Richard

2012-01-01

Distinguishing subpopulations in group behavioral experiments can reveal the impact of differences in genetic, pharmacological and life-histories on social interactions and decision-making. Here we describe Fluorescence Behavioral Imaging (FBI), a toolkit that uses transgenic fluorescence to discriminate subpopulations, imaging hardware that simultaneously records behavior and fluorescence expression, and open-source software for automated, high-accuracy determination of genetic identity. Using FBI, we measure courtship partner choice in genetically mixed groups of Drosophila.

Modeling Radicalization Phenomena in Heterogeneous Populations.

PubMed

Galam, Serge; Javarone, Marco Alberto

2016-01-01

The phenomenon of radicalization is investigated within a mixed population composed of core and sensitive subpopulations. The latest includes first to third generation immigrants. Respective ways of life may be partially incompatible. In case of a conflict core agents behave as inflexible about the issue. In contrast, sensitive agents can decide either to live peacefully adjusting their way of life to the core one, or to oppose it with eventually joining violent activities. The interplay dynamics between peaceful and opponent sensitive agents is driven by pairwise interactions. These interactions occur both within the sensitive population and by mixing with core agents. The update process is monitored using a Lotka-Volterra-like Ordinary Differential Equation. Given an initial tiny minority of opponents that coexist with both inflexible and peaceful agents, we investigate implications on the emergence of radicalization. Opponents try to turn peaceful agents to opponents driving radicalization. However, inflexible core agents may step in to bring back opponents to a peaceful choice thus weakening the phenomenon. The required minimum individual core involvement to actually curb radicalization is calculated. It is found to be a function of both the majority or minority status of the sensitive subpopulation with respect to the core subpopulation and the degree of activeness of opponents. The results highlight the instrumental role core agents can have to hinder radicalization within the sensitive subpopulation. Some hints are outlined to favor novel public policies towards social integration.

Modeling Radicalization Phenomena in Heterogeneous Populations

PubMed Central

2016-01-01

The phenomenon of radicalization is investigated within a mixed population composed of core and sensitive subpopulations. The latest includes first to third generation immigrants. Respective ways of life may be partially incompatible. In case of a conflict core agents behave as inflexible about the issue. In contrast, sensitive agents can decide either to live peacefully adjusting their way of life to the core one, or to oppose it with eventually joining violent activities. The interplay dynamics between peaceful and opponent sensitive agents is driven by pairwise interactions. These interactions occur both within the sensitive population and by mixing with core agents. The update process is monitored using a Lotka-Volterra-like Ordinary Differential Equation. Given an initial tiny minority of opponents that coexist with both inflexible and peaceful agents, we investigate implications on the emergence of radicalization. Opponents try to turn peaceful agents to opponents driving radicalization. However, inflexible core agents may step in to bring back opponents to a peaceful choice thus weakening the phenomenon. The required minimum individual core involvement to actually curb radicalization is calculated. It is found to be a function of both the majority or minority status of the sensitive subpopulation with respect to the core subpopulation and the degree of activeness of opponents. The results highlight the instrumental role core agents can have to hinder radicalization within the sensitive subpopulation. Some hints are outlined to favor novel public policies towards social integration. PMID:27166677

The Wnt/β-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells.

PubMed

Dong, Hye-Jin; Jang, Gyu-Beom; Lee, Hwa-Yong; Park, Se-Ra; Kim, Ji-Young; Nam, Jeong-Seok; Hong, In-Sun

2016-03-11

Hypoxia, a feature common to most solid tumors, is known to regulate many aspects of tumorigenesis. Recently, it was suggested that hypoxia increased the size of the cancer stem-cell (CSC) subpopulations and promoted the acquisition of a CSC-like phenotype. However, candidate hypoxia-regulated mediators specifically relevant to the stemness-related functions of colorectal CSCs have not been examined in detail. In the present study, we showed that hypoxia specifically promoted the self-renewal potential of CSCs. Through various in vitro studies, we found that hypoxia-induced Wnt/β-catenin signaling increased the occurrence of CSC-like phenotypes and the level of Id2 expression in colorectal-cancer cells. Importantly, the levels of hypoxia-induced CSC-sphere formation and Id2 expression were successfully attenuated by treatment with a Wnt/β-catenin-signaling inhibitor. We further demonstrated, for the first time, that the degree of hypoxia-induced CSC-sphere formation (CD44(+) subpopulation) in vitro and of tumor metastasis/dissemination in vivo were markedly suppressed by knocking down Id2 expression. Taken together, these data suggested that Wnt/β-catenin signaling mediated the hypoxia-induced self-renewal potential of colorectal-cancer CSCs through reactivating Id2 expression.

Effector CD4 cell tolerization is mediated through functional inactivation and involves preferential impairment of TNF-α and IFN-γ expression potentials

PubMed Central

Long, Meixiao; Higgins, Amy D.; Mihalyo, Marianne A.; Adler, Adam J.

2010-01-01

It has recently been shown that effector/memory T cells can undergo peripheral tolerization in response to self-antigen. In the present study, we found that within 24 h self-antigen profoundly impairs the ability of CD4 effectors to express TNF-α (and to a lesser extent IFN-γ); however, several days of self-antigen exposure is required to impair non-effector functions such as IL-2 expression and proliferation. Since only half of the initial effector CD4 cell population expresses effector cytokines following brief antigenic stimulation, tolerization might have been mediated either through functional inactivation of effector-competent cells, or alternatively by the selective deletion of competent and expansion of non-competent cells. When briefly stimulated effectors were fractionated based on their expression of IFN-γ, the IFN-γ− sub-population was able to express IFN-γ following secondary stimulation, indicating that all effector CD4 cells are functionally competent. Furthermore, both IFN-γ+ and IFN-γ− sub-populations underwent tolerization in response to self-HA (although the former was slightly more prone to deletion at later time points). Thus, effector CD4 cell tolerization is mediated primarily through the functional inactivation of effector-competent cells. PMID:14609577

Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

PubMed Central

Celià-Terrassa, Toni; Meca-Cortés, Óscar; Mateo, Francesca; Martínez de Paz, Alexia; Rubio, Nuria; Arnal-Estapé, Anna; Ell, Brian J.; Bermudo, Raquel; Díaz, Alba; Guerra-Rebollo, Marta; Lozano, Juan José; Estarás, Conchi; Ulloa, Catalina; ρlvarez-Simón, Daniel; Milà, Jordi; Vilella, Ramón; Paciucci, Rosanna; Martínez-Balbás, Marian; García de Herreros, Antonio; Gomis, Roger R.; Kang, Yibin; Blanco, Jerónimo; Fernández, Pedro L.; Thomson, Timothy M.

2012-01-01

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs. PMID:22505459

Emergent patterns in interacting neuronal sub-populations

NASA Astrophysics Data System (ADS)

Kamal, Neeraj Kumar; Sinha, Sudeshna

2015-05-01

We investigate an ensemble of coupled model neurons, consisting of groups of varying sizes and intrinsic dynamics, ranging from periodic to chaotic, where the inter-group coupling interaction is effectively like a dynamic signal from a different sub-population. We observe that the minority group can significantly influence the majority group. For instance, when a small chaotic group is coupled to a large periodic group, the chaotic group de-synchronizes. However, counter-intuitively, when a small periodic group couples strongly to a large chaotic group, it leads to complete synchronization in the majority chaotic population, which also spikes at the frequency of the small periodic group. It then appears that the small group of periodic neurons can act like a pacemaker for the whole network. Further, we report the existence of varied clustering patterns, ranging from sets of synchronized clusters to anti-phase clusters, governed by the interplay of the relative sizes and dynamics of the sub-populations. So these results have relevance in understanding how a group can influence the synchrony of another group of dynamically different elements, reminiscent of event-related synchronization/de-synchronization in complex networks.

Lung cancer risk associated with Thr495Pro polymorphism of GHR in Chinese population.

PubMed

Cao, Guochun; Lu, Hongna; Feng, Jifeng; Shu, Jian; Zheng, Datong; Hou, Yayi

2008-04-01

The incidence of lung cancer has been increasing over recent decades. Previous studies showed that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors for lung cancer. Recent observations revealed that the growth hormone receptor (GHR) might play important roles in carcinogenesis and Rudd et al. found that the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity). To test whether this variant of GHR would modify the risk of lung cancer in Chinese population, we compared the polymorphism between 778 lung cancer patients and 781 healthy control subjects. Our results indicate that the frequency of 495Thr (2.8%) allele in cases was significantly higher than in controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele might be a risk factor for lung cancer. Further analyses revealed Thr495Pro variant was associated with lung cancer in the subpopulation with higher risk for lung cancer: male subpopulation, still-smokers subpopulation and the subpopulation with familial history of cancer. In different histological types of lung cancer, Thr495Pro SNP was significantly associated with small cell and squamous cell lung cancer, but not with adenocarcinoma, which suggested a potential interaction between this polymorphism and metabolic pathways related to smoking. The potential gene-environment interaction on lung cancer risk was evaluated using MDR software. A significant redundant interaction between Thr495Pro polymorphism and smoking dose and familial history of cancer was identified and the combination of genetic factors and smoking status or familial history of cancer barely increased the cancer risk prediction accuracy. In conclusion, our results suggested that the Thr495Pro polymorphism of GHR was associated with the risk of lung cancer in a redundant interaction with smoking and familial history of cancer.

USE OF HIGH CONTENT IMAGE ANALYSES TO DETECT CHEMICAL-MEDIATED EFFECTS ON NEURITE SUB-POPULATIONS IN PRIMARY RAT CORTICAL NEURONS

EPA Science Inventory

Traditional developmental neurotoxicity tests performed in vivo are costly, time-consuming and utilize a large number of animals. In order to address these inefficiencies, in vitro models of neuronal development have been used in a first tier screening approach for developmenta...

Competition-colonization dynamics: An ecology approach to quasispecies dynamics and virulence evolution in RNA viruses.

PubMed

Ojosnegros, Samuel; Beerenwinkel, Niko; Domingo, Esteban

2010-07-01

A single and purified clone of foot-and-mouth disease virus diversified in cell culture into two subpopulations that were genetically distinct. The subpopulation with higher virulence was a minority and was suppressed by the dominant but less virulent one. These two populations follow the competitioncolonization dynamics described in ecology. Virulent viruses can be regarded as colonizers because they killed the cells faster and they spread faster. The attenuated subpopulation resembles competitors because of its higher replication efficiency in coinfected cells. Our results suggest a new model for the evolution of virulence which is based on interactions between components of the quasispecies. Competition between viral mutants takes place at two levels, intracellular competition and competition for new cells. The two strategies are subjected to densitydependent selection.

Ecogeographic Genetic Epidemiology

PubMed Central

Sloan, Chantel D.; Duell, Eric J.; Shi, Xun; Irwin, Rebecca; Andrew, Angeline S.; Williams, Scott M.; Moore, Jason H.

2009-01-01

Complex diseases such as cancer and heart disease result from interactions between an individual's genetics and environment, i.e. their human ecology. Rates of complex diseases have consistently demonstrated geographic patterns of incidence, or spatial “clusters” of increased incidence relative to the general population. Likewise, genetic subpopulations and environmental influences are not evenly distributed across space. Merging appropriate methods from genetic epidemiology, ecology and geography will provide a more complete understanding of the spatial interactions between genetics and environment that result in spatial patterning of disease rates. Geographic Information Systems (GIS), which are tools designed specifically for dealing with geographic data and performing spatial analyses to determine their relationship, are key to this kind of data integration. Here the authors introduce a new interdisciplinary paradigm, ecogeographic genetic epidemiology, which uses GIS and spatial statistical analyses to layer genetic subpopulation and environmental data with disease rates and thereby discern the complex gene-environment interactions which result in spatial patterns of incidence. PMID:19025788

External tufted cells in the main olfactory bulb form two distinct subpopulations.

PubMed

Antal, Miklós; Eyre, Mark; Finklea, Bryson; Nusser, Zoltan

2006-08-01

The glomeruli of the main olfactory bulb are the first processing station of the olfactory pathway, where complex interactions occur between sensory axons, mitral cells and a variety of juxtaglomerular neurons, including external tufted cells (ETCs). Despite a number of studies characterizing ETCs, little is known about how their morphological and functional properties correspond to each other. Here we determined the active and passive electrical properties of ETCs using in vitro whole-cell recordings, and correlated them with their dendritic arborization patterns. Principal component followed by cluster analysis revealed two distinct subpopulations of ETCs based on their electrophysiological properties. Eight out of 12 measured physiological parameters exhibited significant difference between the two subpopulations, including the membrane time constant, amplitude of spike afterhyperpolarization, variance in the interspike interval distribution and subthreshold resonance. Cluster analysis of the morphological properties of the cells also revealed two subpopulations, the most prominent dissimilarity between the groups being the presence or absence of secondary, basal dendrites. Finally, clustering the cells taking all measured properties into account also indicated the presence of two subpopulations that mapped in an almost perfect one-to-one fashion to both the physiologically and the morphologically derived groups. Our results demonstrate that a number of functional and structural properties of ETCs are highly predictive of one another. However, cells within each subpopulation exhibit pronounced variability, suggesting a large degree of specialization evolved to fulfil specific functional requirements in olfactory information processing.

External tufted cells in the main olfactory bulb form two distinct subpopulations

PubMed Central

Antal, Miklós; Eyre, Mark; Finklea, Bryson; Nusser, Zoltan

2006-01-01

The glomeruli of the main olfactory bulb are the first processing station of the olfactory pathway, where complex interactions occur between sensory axons, mitral cells and a variety of juxtaglomerular neurons, including external tufted cells (ETCs). Despite a number of studies characterizing ETCs, little is known about how their morphological and functional properties correspond to each other. Here we determined the active and passive electrical properties of ETCs using in vitro whole-cell recordings, and correlated them with their dendritic arborization patterns. Principal component followed by cluster analysis revealed two distinct subpopulations of ETCs based on their electrophysiological properties. Eight out of 12 measured physiological parameters exhibited significant difference between the two subpopulations, including the membrane time constant, amplitude of spike afterhyperpolarization, variance in the interspike interval distribution and subthreshold resonance. Cluster analysis of the morphological properties of the cells also revealed two subpopulations, the most prominent dissimilarity between the groups being the presence or absence of secondary, basal dendrites. Finally, clustering the cells taking all measured properties into account also indicated the presence of two subpopulations that mapped in an almost perfect one-to-one fashion to both the physiologically and the morphologically derived groups. Our results demonstrate that a number of functional and structural properties of ETCs are highly predictive of one another. However, cells within each subpopulation exhibit pronounced variability, suggesting a large degree of specialization evolved to fulfil specific functional requirements in olfactory information processing. PMID:16930438

Parasite-Antigen Driven Expansion of IL-5− and IL-5+ Th2 Human Subpopulations in Lymphatic Filariasis and Their Differential Dependence on IL-10 and TGFβ

PubMed Central

Anuradha, Rajamanickam; George, Parakkal Jovvian; Hanna, Luke E.; Chandrasekaran, Vedachalam; Kumaran, P. Paul; Nutman, Thomas B.; Babu, Subash

2014-01-01

Background Two different Th2 subsets have been defined recently on the basis of IL-5 expression – an IL-5+Th2 subset and an IL-5−Th2 subset in the setting of allergy. However, the role of these newly described CD4+ T cells subpopulations has not been explored in other contexts. Methods To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5+IL-4+IL-13+ CD4+ T cells and IL-5−IL-4 IL-13+ CD4+ T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). Results INF individuals exhibited a significant increase in the spontaneously expressed and antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5+Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4+IL-5−Th2 subpopulation and the levels of parasite antigen – specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. Conclusions Our findings suggest that both IL-5+ and IL-5−Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes. PMID:24498448

Academic Achievement of African American Boys: A City-Wide, Community-Based Investigation of Risk and Resilience

ERIC Educational Resources Information Center

Fantuzzo, John; LeBoeuf, Whitney; Rouse, Heather; Chen, Chin-Chih

2012-01-01

In light of persistent Black-White achievement gaps for boys, this study examined publicly monitored risks believed to be associated with being behind academically for an entire subpopulation of African American boys in a large urban public school district. Also examined were indicators of academic engagement hypothesized to mediate the relations…

Implications of recurrent disturbance for genetic diversity.

PubMed

Davies, Ian D; Cary, Geoffrey J; Landguth, Erin L; Lindenmayer, David B; Banks, Sam C

2016-02-01

Exploring interactions between ecological disturbance, species' abundances and community composition provides critical insights for ecological dynamics. While disturbance is also potentially an important driver of landscape genetic patterns, the mechanisms by which these patterns may arise by selective and neutral processes are not well-understood. We used simulation to evaluate the relative importance of disturbance regime components, and their interaction with demographic and dispersal processes, on the distribution of genetic diversity across landscapes. We investigated genetic impacts of variation in key components of disturbance regimes and spatial patterns that are likely to respond to climate change and land management, including disturbance size, frequency, and severity. The influence of disturbance was mediated by dispersal distance and, to a limited extent, by birth rate. Nevertheless, all three disturbance regime components strongly influenced spatial and temporal patterns of genetic diversity within subpopulations, and were associated with changes in genetic structure. Furthermore, disturbance-induced changes in temporal population dynamics and the spatial distribution of populations across the landscape resulted in disrupted isolation by distance patterns among populations. Our results show that forecast changes in disturbance regimes have the potential to cause major changes to the distribution of genetic diversity within and among populations. We highlight likely scenarios under which future changes to disturbance size, severity, or frequency will have the strongest impacts on population genetic patterns. In addition, our results have implications for the inference of biological processes from genetic data, because the effects of dispersal on genetic patterns were strongly mediated by disturbance regimes.

STRESS-INDUCED REDISTRIBUTION OF IMMUNE CELLS - FROM BARRACKS TO BOULEVARDS TO BATTLEFIELDS: A TALE OF THREE HORMONES - CURT RICHTER AWARD WINNER

PubMed Central

Dhabhar, Firdaus S.; Malarkey, William B.; Neri, Eric; McEwen, Bruce S.

2012-01-01

Background The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: 1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. 2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. 3) Effects of stress/stress hormones on adhesion molecule, L-selectin (CD62L), expression by each subpopulation to assess its adhesion / functional / maturation status. Methods Male Sprague Dawley rats were stressed (short-term restraint, 2–120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations. Results Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L−/+ neutrophils and CD62L− B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L−/+ neutrophils and CD62L− monocytes, but decreased lymphocyte numbers with CD62L−/+ CTL and CD62L+ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L− and CD62L+ cells being equally affected. Thus, naïve (CD62L+) vs. memory (CD62L−) T cells, classical (CD62L+) vs. non-classical (CD62L−) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones. Conclusion Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., resident or inflammatory monocyte, naïve or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: 1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. 2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. 3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. 4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function. PMID:22727761

Two-Stage, In Silico Deconvolution of the Lymphocyte Compartment of the Peripheral Whole Blood Transcriptome in the Context of Acute Kidney Allograft Rejection

PubMed Central

Shannon, Casey P.; Balshaw, Robert; Ng, Raymond T.; Wilson-McManus, Janet E.; Keown, Paul; McMaster, Robert; McManus, Bruce M.; Landsberg, David; Isbel, Nicole M.; Knoll, Greg; Tebbutt, Scott J.

2014-01-01

Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially expressed probe-set lists is consistent with the originating tissue and their functional enrichment consistent with allograft rejection. Finally, we demonstrate that the strategy described here can be used to derive useful hypotheses by validating a cell type-specific ratio in an independent cohort using the nanoString nCounter assay. PMID:24733377

Relationship of Sibling Structure and Interaction to Categorization Ability. Final Report.

ERIC Educational Resources Information Center

Cicirelli, Victor G.; And Others

This study identified behaviors of sibling pairs interacting on a cognitive task and related these behaviors to sibling structure variables (age and sex of each sibling and age spacing between them) and to measure of cognitive abilities of the younger sibling. Subjects were 160 sibling pairs randomly selected from appropriate subpopulations of…

Cardiac Subsarcolemmal and Interfibrillar Mitochondria Display Distinct Responsiveness to Protection by Diazoxide

PubMed Central

Holmuhamedov, Ekhson L.; Oberlin, Andrew; Short, Kevin; Terzic, Andre; Jahangir, Arshad

2012-01-01

Objective Cardiac subsarcolemmal (SSM) and interfibrillar (IFM) mitochondrial subpopulations possess distinct biochemical properties and differ with respect to their protein and lipid compositions, capacities for respiration and protein synthesis, and sensitivity to metabolic challenge, yet their responsiveness to mitochondrially active cardioprotective therapeutics has not been characterized. This study assessed the differential responsiveness of the two mitochondrial subpopulations to diazoxide, a cardioprotective agent targeting mitochondria. Methods Mitochondrial subpopulations were freshly isolated from rat ventricles and their morphologies assessed by electron microscopy and enzymatic activities determined using standard biochemical protocols with a plate reader. Oxidative phosphorylation was assessed from State 3 respiration using succinate as a substrate. Calcium dynamics and the status of Ca2+-dependent mitochondrial permeability transition (MPT) pore and mitochondrial membrane potential were assessed using standard Ca2+ and TPP+ ion-selective electrodes. Results Compared to IFM, isolated SSM exhibited a higher sensitivity to Ca2+ overload-mediated inhibition of adenosine triphosphate (ATP) synthesis with decreased ATP production (from 375±25 to 83±15 nmol ATP/min/mg protein in SSM, and from 875±39 to 583±45 nmol ATP/min/mg protein in IFM). In addition, SSM exhibited reduced Ca2+-accumulating capacity as compared to IFM (230±13 vs. 450±46 nmol Ca2+/mg protein in SSM and IFM, respectively), suggestive of increased Ca2+ sensitivity of MPT pore opening. Despite enhanced susceptibility to stress, SSM were more responsive to the protective effect of diazoxide (100 μM) against Ca2+ overload-mediated inhibition of ATP synthesis (67% vs. 2% in SSM and IFM, respectively). Conclusion These results provide evidence for the distinct sensitivity of cardiac SSM and IFM toward Ca2+-dependent metabolic stress and the protective effect of diazoxide on mitochondrial energetics. PMID:22973464

Microsatellite DNA and mitochondrial DNA variation in polar bears (Ursus maritimus) from the Beaufort and Chukchi seas, Alaska

USGS Publications Warehouse

Cronin, M.A.; Amstrup, Steven C.; Scribner, K.T.

2006-01-01

Radiotelemetry data have shown that polar bears (Ursus maritimus Phipps, 1774) occur in separate subpopulations in the Chukchi Sea and the southern Beaufort Sea. However, segregation is not absolute, and there is overlap of ranges of animals in each subpopulation. We used genetic variation at eight microsatellite DNA loci and mitochondrial DNA (mtDNA) to further assess the degree of spatial structure of polar bears from the Chukchi and southern Beaufort seas. Microsatellite allele frequencies and mtDNA haplotype frequencies of bears from the southern Beaufort and Chukchi seas did not differ significantly. Lack of differentiation at both maternally inherited mtDNA and bi-parentally inherited microsatellite loci suggests that gene flow between the two areas is mediated by both sexes. The genetic data indicate that polar bears in the southern Beaufort and Chukchi seas compose one interbreeding population. However, there is considerable fidelity to ranges in each area, particularly by adult females. The combined genetic and movement data suggest that polar bears could be managed as Beaufort Sea and Chukchi Sea subpopulations of a combined southern Beaufort Sea and Chukchi Sea population. ?? 2006 NRC.

Divergent branches of mitochondrial signaling regulate specific genes and the viability of specialized cell types of differentiated yeast colonies.

PubMed

Podholová, Kristýna; Plocek, Vítězslav; Rešetárová, Stanislava; Kučerová, Helena; Hlaváček, Otakar; Váchová, Libuše; Palková, Zdena

2016-03-29

Mitochondrial retrograde signaling mediates communication from altered mitochondria to the nucleus and is involved in many normal and pathophysiological changes, including cell metabolic reprogramming linked to cancer development and progression in mammals. The major mitochondrial retrograde pathway described in yeast includes three activators, Rtg1p, Rtg2p and Rtg3p, and repressors, Mks1p and Bmh1p/Bmh2p. Using differentiated yeast colonies, we show that Mks1p-Rtg pathway regulation is complex and includes three branches that divergently regulate the properties and fate of three specifically localized cell subpopulations via signals from differently altered mitochondria. The newly identified RTG pathway-regulated genes ATO1/ATO2 are expressed in colonial upper (U) cells, the cells with active TORC1 that metabolically resemble tumor cells, while CIT2 is a typical target induced in one subpopulation of starving lower (L) cells. The viability of the second L cell subpopulation is strictly dependent on RTG signaling. Additional co-activators of Rtg1p-Rtg3p specific to particular gene targets of each branch are required to regulate cell differentiation.

Hunger States Control the Directions of Synaptic Plasticity via Switching Cell Type-Specific Subunits of NMDA Receptors.

PubMed

Qi, Yong; Yang, Yunlei

2015-09-23

It remains largely unknown whether and how hunger states control activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). We here report that both LTP and LTD of excitatory synaptic strength within the appetite control circuits residing in hypothalamic arcuate nucleus (ARC) behave in a manner of hunger states dependence and cell type specificity. For instance, we find that tetanic stimulation induces LTP at orexigenic agouti-related protein (AgRP) neurons in ad libitum fed mice, whereas it induces LTD in food-deprived mice. In an opposite direction, the same induction protocol induces LTD at anorexigenic pro-opiomelanocortin (POMC) neurons in fed mice but weak LTP in deprived mice. Mechanistically, we also find that food deprivation increases the expressions of NR2C/NR2D/NR3-containing NMDA receptors (NMDARs) at AgRP neurons that contribute to the inductions of LTD, whereas it decreases their expressions at POMC neurons. Collectively, our data reveal that hunger states control the directions of activity-dependent synaptic plasticity by switching NMDA receptor subpopulations in a cell type-specific manner, providing insights into NMDAR-mediated interactions between energy states and associative memory. Significance statement: Based on the experiments performed in this study, we demonstrate that activity-dependent synaptic plasticity is also under the control of energy states by regulating NMDAR subpopulations in a cell type-specific manner. We thus propose a reversible memory configuration constructed from energy states-dependent cell type-specific bidirectional conversions of LTP and LTD. Together with the distinct functional roles played by NMDAR signaling in the control of food intake and energy states, these findings reveal a new reciprocal interaction between energy states and associative memory, one that might serve as a target for therapeutic treatments of the energy-related memory disorders or vice versa. Copyright © 2015 the authors 0270-6474/15/3513171-12$15.00/0.

Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins.

PubMed

Zhang, Mingce; Robinson, Tanya O; Duverger, Alexandra; Kutsch, Olaf; Heath, Sonya L; Cron, Randy Q

2018-03-01

During chronic HIV-1 infection, regulatory CD4 T cells (Tregs) frequently represent the largest subpopulation of CD4 T cell subsets, implying relative resistant to HIV-1. When HIV-1 infection of CD4 T cells was explored in vitro and ex vivo from patient samples, Tregs possessed lower levels of HIV-1 DNA and RNA in comparison with conventional effector and memory CD4 T cells. Moreover, Tregs suppressed HIV-1 expression in other CD4 T cells in an in vitro co-culture system. This suppression was mediated in part via multiple inhibitory surface proteins expressed on Tregs. Antibody blockade of CTLA-4, PD-1, and GARP on Tregs resulted in increased HIV-1 DNA integration and mRNA expression in neighboring CD4 T cells. Moreover, antibody blockade of Tregs inhibitory proteins resulted in increased HIV-1 LTR transcription in co-cultured CD4 T cells. Thus, Tregs inhibit HIV-1 infection of other CD4 T cell subsets via interactions with inhibitory cell surface proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of ACTH in the Interactive/Paracrine Regulation of Adrenal Steroid Secretion in Physiological and Pathophysiological Conditions

PubMed Central

Lefebvre, Hervé; Thomas, Michaël; Duparc, Céline; Bertherat, Jérôme; Louiset, Estelle

2016-01-01

In the normal human adrenal gland, steroid secretion is regulated by a complex network of autocrine/paracrine interactions involving bioactive signals released by endothelial cells, nerve terminals, chromaffin cells, immunocompetent cells, and adrenocortical cells themselves. ACTH can be locally produced by medullary chromaffin cells and is, therefore, a major mediator of the corticomedullary functional interplay. Plasma ACTH also triggers the release of angiogenic and vasoactive agents from adrenocortical cells and adrenal mast cells and, thus, indirectly regulates steroid production through modulation of the adrenal blood flow. Adrenocortical neoplasms associated with steroid hypersecretion exhibit molecular and cellular defects that tend to reinforce the influence of paracrine regulatory loops on corticosteroidogenesis. Especially, ACTH has been found to be abnormally synthesized in bilateral macronodular adrenal hyperplasia responsible for hypercortisolism. In these tissues, ACTH is detected in a subpopulation of adrenocortical cells that express gonadal markers. This observation suggests that ectopic production of ACTH may result from impaired embryogenesis leading to abnormal maturation of the adrenogonadal primordium. Globally, the current literature indicates that ACTH is a major player in the autocrine/paracrine processes occurring in the adrenal gland in both physiological and pathological conditions. PMID:27489549

Evidence for label-retaining tumour-initiating cells in human glioblastoma

PubMed Central

Deleyrolle, Loic P.; Harding, Angus; Cato, Kathleen; Siebzehnrubl, Florian A.; Rahman, Maryam; Azari, Hassan; Olson, Sarah; Gabrielli, Brian; Osborne, Geoffrey; Vescovi, Angelo

2011-01-01

Individual tumour cells display diverse functional behaviours in terms of proliferation rate, cell–cell interactions, metastatic potential and sensitivity to therapy. Moreover, sequencing studies have demonstrated surprising levels of genetic diversity between individual patient tumours of the same type. Tumour heterogeneity presents a significant therapeutic challenge as diverse cell types within a tumour can respond differently to therapies, and inter-patient heterogeneity may prevent the development of general treatments for cancer. One strategy that may help overcome tumour heterogeneity is the identification of tumour sub-populations that drive specific disease pathologies for the development of therapies targeting these clinically relevant sub-populations. Here, we have identified a dye-retaining brain tumour population that displays all the hallmarks of a tumour-initiating sub-population. Using a limiting dilution transplantation assay in immunocompromised mice, label-retaining brain tumour cells display elevated tumour-initiation properties relative to the bulk population. Importantly, tumours generated from these label-retaining cells exhibit all the pathological features of the primary disease. Together, these findings confirm dye-retaining brain tumour cells exhibit tumour-initiation ability and are therefore viable targets for the development of therapeutics targeting this sub-population. PMID:21515906

Use of stable isotopes to identify dietary differences across subpopulations and sex for a free-ranging generalist herbivore.

PubMed

Walter, W David

2014-01-01

Carbon and nitrogen isotopes in tissues can be used to understand plants consumed by various taxa, but can they provide additional information about consumers? Values of δ(13)C and δ(15)N were assessed from tissue of free-ranging elk (Cervus elaphus) occupying disparate habitats of mixed prairie-oak savannah that contained C3 agricultural crops in a C4-dominated landscape and in key plants consumed by elk. Muscle and hoof samples were collected from female and male elk in two subpopulations (forested land and grassland) from private land and one subpopulation from the Wichita Mountains Wildlife Refuge (refuge) in 2001-2006. Previous research identified differences between mean muscle δ(13)C and δ(15)N and mean hoof δ(13)C and δ(15)N indicating that isotopes differed between tissues of varying metabolic activity. Mean δ(13)C in hoof of elk on forested land and grassland were lower than hoof δ(13)C from elk in the refuge indicating greater long-term consumption of C3 plants by elk on forested land and grassland subpopulations. The δ(15)N in hoof was greater for elk outside the refuge than that for elk in the refuge. Interaction of sex and subpopulation only occurred for hoof δ(15)N suggesting that factors such as tissue type, sex, and habitat need to be considered to understand free-ranging ecology of generalist herbivores using stable isotopes. Availability of C3 agricultural crops high in percent nitrogen on a nearly annual basis in a C4-dominated landscape was likely driving differences in tissue δ(13)C and δ(15)N among subpopulations of free-ranging elk. An increase in tissue δ(15)N resulted from an increase in the consumption of higher δ(15)N in forage for sexes and subpopulations of a free-ranging ungulate in North America but δ(15)N should be further evaluated as an index of nutrition for subpopulations of generalist herbivores.

Morphological switch to a resistant subpopulation in response to viral infection in the bloom-forming coccolithophore Emiliania huxleyi.

PubMed

Frada, Miguel José; Rosenwasser, Shilo; Ben-Dor, Shifra; Shemi, Adva; Sabanay, Helena; Vardi, Assaf

2017-12-01

Recognizing the life cycle of an organism is key to understanding its biology and ecological impact. Emiliania huxleyi is a cosmopolitan marine microalga, which displays a poorly understood biphasic sexual life cycle comprised of a calcified diploid phase and a morphologically distinct biflagellate haploid phase. Diploid cells (2N) form large-scale blooms in the oceans, which are routinely terminated by specific lytic viruses (EhV). In contrast, haploid cells (1N) are resistant to EhV. Further evidence indicates that 1N cells may be produced during viral infection. A shift in morphology, driven by meiosis, could therefore constitute a mechanism for E. huxleyi cells to escape from EhV during blooms. This process has been metaphorically coined the 'Cheshire Cat' (CC) strategy. We tested this model in two E. huxleyi strains using a detailed assessment of morphological and ploidy-level variations as well as expression of gene markers for meiosis and the flagellate phenotype. We showed that following the CC model, production of resistant cells was triggered during infection. This led to the rise of a new subpopulation of cells in the two strains that morphologically resembled haploid cells and were resistant to EhV. However, ploidy-level analyses indicated that the new resistant cells were diploid or aneuploid. Thus, the CC strategy in E. huxleyi appears to be a life-phase switch mechanism involving morphological remodeling that is decoupled from meiosis. Our results highlight the adaptive significance of morphological plasticity mediating complex host-virus interactions in marine phytoplankton.

Morphological switch to a resistant subpopulation in response to viral infection in the bloom-forming coccolithophore Emiliania huxleyi

PubMed Central

Rosenwasser, Shilo; Shemi, Adva; Sabanay, Helena; Vardi, Assaf

2017-01-01

Recognizing the life cycle of an organism is key to understanding its biology and ecological impact. Emiliania huxleyi is a cosmopolitan marine microalga, which displays a poorly understood biphasic sexual life cycle comprised of a calcified diploid phase and a morphologically distinct biflagellate haploid phase. Diploid cells (2N) form large-scale blooms in the oceans, which are routinely terminated by specific lytic viruses (EhV). In contrast, haploid cells (1N) are resistant to EhV. Further evidence indicates that 1N cells may be produced during viral infection. A shift in morphology, driven by meiosis, could therefore constitute a mechanism for E. huxleyi cells to escape from EhV during blooms. This process has been metaphorically coined the ‘Cheshire Cat’ (CC) strategy. We tested this model in two E. huxleyi strains using a detailed assessment of morphological and ploidy-level variations as well as expression of gene markers for meiosis and the flagellate phenotype. We showed that following the CC model, production of resistant cells was triggered during infection. This led to the rise of a new subpopulation of cells in the two strains that morphologically resembled haploid cells and were resistant to EhV. However, ploidy-level analyses indicated that the new resistant cells were diploid or aneuploid. Thus, the CC strategy in E. huxleyi appears to be a life-phase switch mechanism involving morphological remodeling that is decoupled from meiosis. Our results highlight the adaptive significance of morphological plasticity mediating complex host–virus interactions in marine phytoplankton. PMID:29244854

Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines

PubMed Central

BAHARUDDIN, PUTERI; SATAR, NAZILAH; FAKIRUDDIN, KAMAL SHAIK; ZAKARIA, NORASHIKIN; LIM, MOON NIAN; YUSOFF, NARAZAH MOHD; ZAKARIA, ZUBAIDAH; YAHAYA, BADRUL HISHAM

2016-01-01

Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10–40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC. PMID:26531053

Strategies of Mesenchymal Invasion of Patient-derived Brain Tumors: Microenvironmental Adaptation.

PubMed

Cha, Junghwa; Kang, Seok-Gu; Kim, Pilnam

2016-04-25

The high mortality in glioblastoma multiforme (GBM) patients is primarily caused by extensive infiltration into adjacent tissue and subsequent rapid recurrence. There are no clear therapeutic strategies that target the infiltrative subpopulation of GBM mass. Using mesenchymal mode of invasion, the GBM is known to widely infiltrate by interacting with various unique components within brain microenvironment such as hyaluronic acid (HA)-rich matrix and white matter tracts. However, it is unclear how these GBM microenvironments influence the strategies of mesenchymal invasion. We hypothesize that GBM has different strategies to facilitate such invasion through adaptation to their local microenvironment. Using our in vitro biomimetic microenvironment platform for three-dimensional GBM tumorspheres (TSs), we found that the strategies of GBM invasion were predominantly regulated by the HA-rich ECM microenvironment, showing marked phenotypic changes in the presence of HA, which were mainly mediated by HA synthase (HAS). Interestingly, after inhibition of the HAS gene, GBM switched their invasion strategies to a focal adhesion (FA)-mediated invasion. These results demonstrate that the microenvironmental adaptation allowed a flexible invasion strategy for GBM. Using our model, we suggest a new inhibitory pathway for targeting infiltrative GBM and propose an importance of multi-target therapy for GBM, which underwent microenvironmental adaptation.

[Role of fatty acids in the nervous control of energy balance].

PubMed

Magnan, Christophe; Luquet, Serge

2015-01-01

Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy and glucose homeostasis including feeding behavior, insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects include ion channels such as chloride, potassium or calcium. In addition at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, a FA translocator/receptor that does not require intracellular metabolism to activate downstream signaling. Recently, an important role of lipoprotein lipase in FA sensing has also been demonstrated not only in hypothalamus, but also in the hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects. © Société de Biologie, 2016.

HIP1 exhibits an early recruitment and a late stage function in the maturation of coated pits.

PubMed

Gottfried, Irit; Ehrlich, Marcelo; Ashery, Uri

2009-09-01

Huntingtin interacting protein 1 (HIP1) is an accessory protein of the clathrin-mediated endocytosis (CME) pathway, yet its precise role and the step at which it becomes involved are unclear. We employed live-cell imaging techniques to focus on the early steps of CME and characterize HIP1 dynamics. We show that HIP1 is highly colocalized with clathrin at the plasma membrane and shares similar dynamics with a subpopulation of clathrin assemblies. Employing transferrin receptor fused to pHluorin, we distinguished between open pits to which HIP1 localizes and newly internalized vesicles that are devoid of HIP1. Moreover, shRNA knockdown of clathrin compromised HIP1 membranal localization, unlike the reported behavior of Sla2p. HIP1 fragment, lacking its ANTH and Talin-like domains, inhibits internalization of transferrin, but retains colocalization with membranal clathrin assemblies. These data demonstrate HIP1's role in pits maturation and formation of the coated vesicle, and its strong dependence on clathrin for membranal localization.

Dopaminergic stimulation increases selfish behavior in the absence of punishment threat.

PubMed

Pedroni, Andreas; Eisenegger, Christoph; Hartmann, Matthias N; Fischbacher, Urs; Knoch, Daria

2014-01-01

People often face decisions that pit self-interested behavior aimed at maximizing personal reward against normative behavior such as acting cooperatively, which benefits others. The threat of social sanctions for defying the fairness norm prevents people from behaving overly selfish. Thus, normative behavior is influenced by both seeking rewards and avoiding punishment. However, the neurochemical processes mediating the impact of these influences remain unknown. Several lines of evidence link the dopaminergic system to reward and punishment processing, respectively, but this evidence stems from studies in non-social contexts. The present study investigates dopaminergic drug effects on individuals' reward seeking and punishment avoidance in social interaction. Two-hundred one healthy male participants were randomly assigned to receive 300 mg of L-3,4-dihydroxyphenylalanine (L-DOPA) or a placebo before playing an economic bargaining game. This game involved two conditions, one in which unfair behavior could be punished and one in which unfair behavior could not be punished. In the absence of punishment threats, L-DOPA administration led to more selfish behavior, likely mediated through an increase in reward seeking. In contrast, L-DOPA administration had no significant effect on behavior when faced with punishment threats. The results of this study broaden the role of the dopaminergic system in reward seeking to human social interactions. We could show that even a single dose of a dopaminergic drug may bring selfish behavior to the fore, which in turn may shed new light on potential causal relationships between the dopaminergic system and norm abiding behaviors in certain clinical subpopulations.

Sex differences in the regulation of spatially distinct cardiac mitochondrial subpopulations.

PubMed

Ribeiro, Rogério Faustino; Ronconi, Karoline Sousa; Morra, Elis Aguiar; Do Val Lima, Patrícia Ribeiro; Porto, Marcella Leite; Vassallo, Dalton Valentim; Figueiredo, Suely Gomes; Stefanon, Ivanita

2016-08-01

Spatially distinct mitochondrial subpopulation may mediate myocardial pathology through permeability transition pore opening (MPTP). The goal of this study was to assess sex differences on the two spatially distinct mitochondrial subpopulations: subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria (IFM) based on morphology, membrane potential, mitochondrial function, oxidative phosphorylation, and MPTP. Aged matched Wistar rats were used to study SSM and IFM. Mitochondrial size was larger in SSM than in IFM in both genders. However, SSM internal complexity, yield, and membrane potential were higher in male than in female. The maximal rate of mitochondrial respiration, states 3 and 4, using glutamate + malate as substrate, were higher in IFM and SSM in the male group compared to female. The respiratory control ratio (RCR-state3/state 4), was not different in both SSM and IFM with glutamate + malate. The ADP:O ratio was found higher in IFM and SSM from female compared to males. When pyruvate was used, state 3 was found unchanged in both IFM and SSM, state 4 was also greater in male IFM compared to female. The RCR increased in the SSM while IFM remained the same. State 4 was higher in male SSM while in the IFM remained the same. The IFM presented a higher Ca(2+) retention capacity compared with SSM, however, there was a greater sensitivity to Ca(2+)-induced MPTP in SSM and IFM in the male group compared to female. In conclusion, our data show that spatially distinct mitochondrial subpopulations have sex-based differences in oxidative phosphorylation, morphology, and calcium retention capacity.

Relation of Gemfibrozil Treatment and High Density Lipoprotein (HDL) Subpopulation Profile with Cardiovascular Events in the Veterans Affairs HDL Intervention Trial (VA-HIT)

PubMed Central

Asztalos, Bela F.; Collins, Dorothea; Horvath, Katalin V.; Bloomfield, Hanna E.; Robins, Sander J.; Schaefer, Ernst J.

2007-01-01

Objective The significant cardiovascular disease (CVD) event reduction in VA-HIT could not be fully explained by the 6% increase in HDL-C with the fibrate, gemfibrozil. We examined whether measurement of HDL subpopulations provided additional information relative to CVD-risk reduction. Methods and Results HDL subpopulations were characterized by 2-dimensional gel-electrophoresis in subjects who were treated with gemfibrozil (n=754) or placebo (n=741). In this study, samples obtained at the 3-month visit were used and data were analyzed prospectively using CVD events (CHD death, MI, or stroke) during the 5.1 years follow up. Analyses in the gemfibrozil arm showed that subjects with recurrent CVD events had significantly higher preβ-1 and had significantly lower α-1 and α-2 HDL levels than those without such events. Preβ-1 level was a significant positive predictor; α-1 and α-2 levels were significant negative risk factors for future CVD events. α-2 level was superior to HDL-C level in CVD-risk assessment after adjustment for established risk factors. Gemfibrozil treatment was associated with 3%-6% decreases in the small, lipid-poor preβ-1 HDL and in the large, lipid-rich α-1 and α-2 HDL and with increases in the small α-3 (3%) and preα-3 (16%) HDLs. Conclusions While the use of gemfibrozil has been associated with reduction in CVD events in VA-HIT, HDL subpopulation analysis indicates that gemfibrozil-mediated improvement in CVD risk might not be the result of its effects on HDL. It is quite possible that much of the cardiovascular benefits of gemfibrozil are due to a much wider spectrum of effects on metabolic processes that is not reflected by changes in blood lipids and HDL subpopulations. PMID:18078862

Differential expression of muscarinic acetylcholine receptor subtypes in Jurkat cells and their signaling.

PubMed

Alea, Mileidys Perez; Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Fuxe, Kjell; Garriga, Pere

2011-08-15

Muscarinic acetylcholine receptors expression and signaling in the human Jurkat T cell line were investigated. Semiquantitative real-time PCR and radioligand binding studies, using a wide set of antagonist compounds, showed the co-existence of M(3), M(4), and M(5) subtypes. Stimulation of these subpopulations caused a concentration and time- dependent activation of second messengers and ERK signaling pathways, with a major contribution of the M(3) subtype in a G(q/11)-mediated response. In addition, we found that T-cell stimulation leads to increased expression of M(3) and M(5) both at transcriptional and protein levels in a PLC/PKCθ dependent manner. Our data clarifies the functional role of AChR subtypes in Jurkat cells and pave the way to future studies on the potential cross-talk among these subpopulations and their regulation of T lymphocytes immune function. Copyright © 2011 Elsevier B.V. All rights reserved.

Characterization and Targeting of the Aldehyde Dehydrogenase Subpopulation in Ovarian Cancer

DTIC Science & Technology

2012-07-01

Targeting the Hedgehog pathway reverses taxane resistance in ovarian cancer. Proceedings of the 42 nd Annual Society of Gynecologic Oncologists...Meeting, 2011. Steg AD, Ziebarth AA, Katre A, Landen CN Jr. Targeting hedgehog reverses taxane resistance by Gli-dependent and independent mechanisms in...pathways ( Hedgehog , Notch, TGF-b, and Wnt). Select genes of interest were validated as important targets using siRNA-mediated downregulation. Results

Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin alpha4beta1.

PubMed

Parmo-Cabañas, Marisa; García-Bernal, David; García-Verdugo, Rosa; Kremer, Leonor; Márquez, Gabriel; Teixidó, Joaquin

2007-08-01

The alpha4beta1 integrin is expressed on thymocytes and mediates cell attachment to its ligands CS-1/fibronectin (CS-1/FN) and VCAM-1 in the thymus. The chemokine CCL25 is highly expressed in the thymus, where it binds to its receptor CCR9 on thymocytes promoting migration and activation. We show here that alpha4beta1 and CCR9 are coexpressed mainly on double- and single-positive thymocytes and that CCL25 strongly stimulates CD4(+)CD8(+) and CD4(+)CD8(-) adhesion to CS-1/FN and VCAM-1. CCL25 rapidly activated the GTPases Rac and Rap1 on thymocytes, and this activation was required for stimulation of adhesion, as detected using the CCR9(+)/alpha4beta1(+) human T cell line Molt-4. To study the role on CCL25-stimulated adhesion of the Rac downstream effector Wiskott-Aldrich syndrome protein family verproline-homologous protein 2 (WAVE2) as well as of Rap1-GTP-interacting proteins, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP-interacting adapter molecule (RIAM), we knocked down their expression and tested transfectant attachment to alpha4beta1 ligands. We found that WAVE2 and RAPL but not RIAM were required for efficient triggering by CCL25 of T cell adhesion to CS-1/FN and VCAM-1. Although Rac and Rap1 activation was required during early steps of T cell adhesion stimulated by CCL25, WAVE2 was needed for the development of actin-dependent T cell spreading subsequent to adhesion strengthening but not during initial alpha4beta1-ligand interactions. These results suggest that regulation by CCL25 of adhesion of thymocyte subpopulations mediated by alpha4beta1 could contribute to control their trafficking in the thymus during maturation, and identify Rac-WAVE2 and Rap1-RAPL as pathways whose activation is required in inside-out signaling, leading to stimulated adhesion.

Diffusion of multiple species with excluded-volume effects.

PubMed

Bruna, Maria; Chapman, S Jonathan

2012-11-28

Stochastic models of diffusion with excluded-volume effects are used to model many biological and physical systems at a discrete level. The average properties of the population may be described by a continuum model based on partial differential equations. In this paper we consider multiple interacting subpopulations/species and study how the inter-species competition emerges at the population level. Each individual is described as a finite-size hard core interacting particle undergoing brownian motion. The link between the discrete stochastic equations of motion and the continuum model is considered systematically using the method of matched asymptotic expansions. The system for two species leads to a nonlinear cross-diffusion system for each subpopulation, which captures the enhancement of the effective diffusion rate due to excluded-volume interactions between particles of the same species, and the diminishment due to particles of the other species. This model can explain two alternative notions of the diffusion coefficient that are often confounded, namely collective diffusion and self-diffusion. Simulations of the discrete system show good agreement with the analytic results.

Odour dialects among wild mammals.

PubMed

Kean, Eleanor Freya; Bruford, Michael William; Russo, Isa-Rita M; Müller, Carsten Theodor; Chadwick, Elizabeth Anna

2017-10-19

Across multiple taxa, population structure and dynamics depend on effective signalling between individuals. Among mammals, chemical communication is arguably the most important sense, underpinning mate choice, parental care, territoriality and even disease transmission. There is a growing body of evidence that odours signal genetic information that may confer considerable benefits including inbreeding avoidance and nepotism. To date, however, there has been no clear evidence that odours encode population-level information in wild mammals. Here we demonstrate for the first time the existence of 'odour dialects' in genetically distinct mammalian subpopulations across a large geographical scale. We found that otters, Lutra lutra, from across the United Kingdom possess sex and biogeography-specific odours. Subpopulations with the most distinctive odour profiles are also the most genetically diverse but not the most genetically differentiated. Furthermore, geographic distance between individuals does not explain regional odour differences, refuting other potential explanations such as group odour sharing behaviour. Differences in the language of odours between subpopulations have the potential to affect individual interactions, which could impact reproduction and gene-flow.

Statistical analysis of suprathermal electron drivers at 67P/Churyumov-Gerasimenko

NASA Astrophysics Data System (ADS)

Broiles, Thomas W.; Burch, J. L.; Chae, K.; Clark, G.; Cravens, T. E.; Eriksson, A.; Fuselier, S. A.; Frahm, R. A.; Gasc, S.; Goldstein, R.; Henri, P.; Koenders, C.; Livadiotis, G.; Mandt, K. E.; Mokashi, P.; Nemeth, Z.; Odelstad, E.; Rubin, M.; Samara, M.

2016-11-01

We use observations from the Ion and Electron Sensor (IES) on board the Rosetta spacecraft to study the relationship between the cometary suprathermal electrons and the drivers that affect their density and temperature. We fit the IES electron observations with the summation of two kappa distributions, which we characterize as a dense and warm population (˜10 cm-3 and ˜16 eV) and a rarefied and hot population (˜0.01 cm-3 and ˜43 eV). The parameters of our fitting technique determine the populations' density, temperature, and invariant kappa index. We focus our analysis on the warm population to determine its origin by comparing the density and temperature with the neutral density and magnetic field strength. We find that the warm electron population is actually two separate sub-populations: electron distributions with temperatures above 8.6 eV and electron distributions with temperatures below 8.6 eV. The two sub-populations have different relationships between their density and temperature. Moreover, the two sub-populations are affected by different drivers. The hotter sub-population temperature is strongly correlated with neutral density, while the cooler sub-population is unaffected by neutral density and is only weakly correlated with magnetic field strength. We suggest that the population with temperatures above 8.6 eV is being heated by lower hybrid waves driven by counterstreaming solar wind protons and newly formed, cometary ions created in localized, dense neutral streams. To the best of our knowledge, this represents the first observations of cometary electrons heated through wave-particle interactions.

Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection.

PubMed

Kasahara, Y; Yachie, A; Takei, K; Kanegane, C; Okada, K; Ohta, K; Seki, H; Igarashi, N; Maruhashi, K; Katayama, K; Katoh, E; Terao, G; Sakiyama, Y; Koizumi, S

2001-09-15

Unusual Epstein-Barr virus (EBV) infection into T or natural killer cells plays a pivotal role in the pathogenesis of acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic active EBV infection (CAEBV). The precise frequency and localization of EBV genome in lymphocyte subpopulations especially within T-cell subpopulations are unclear in these EBV-related disorders. This study analyzed the frequency of EBV-infected cells in circulating lymphocyte subpopulations from 4 patients with acute EBV-HLH and 4 with CAEBV. EBV- encoded small RNA-1 in situ hybridization examination of peripheral blood lymphocytes showed a significantly higher frequency of EBV-infected cells of 1.0% to 13.4% in EBV-HLH and 1.6% to 25.6% in CAEBV, respectively. The patterns of EBV infection in lymphocyte subpopulations were quite different between acute EBV-HLH and CAEBV. EBV infection was predominant in CD8(+) T cells in all EBV-HLH patients, whereas the dominant EBV-infected cell populations were non-CD8(+) lymphocyte subpopulations in CAEBV patients. Phenotypical analysis revealed that EBV-infected cell populations from both EBV-HLH and CAEBV were activated. There was no predominance of any EBV substrain of latent membrane protein-1, EBV-associated nuclear antigen (EBNA)-1, and EBNA-2 genes between the 2 abnormal EBV-associated disorders, and self-limited acute infectious mononucleosis. These results showing differential virus-cell interactions between acute EBV-HLH and CAEBV indicated different pathogenic mechanisms against EBV infection between the 2 EBV-associated diseases, which accounts for the difference in clinical manifestations between the 2 diseases.

Fittin' in: Do Diverse Interactions with Peers Affect Sense of Belonging for Black Men at Predominantly White Institutions?

ERIC Educational Resources Information Center

Strayhorn, Terrell L.

2008-01-01

Prior research on interacting with diverse peers focuses on pooled samples including all racial/ethnic groups or specific subpopulations such as women and White men. Research on sense of belonging has tended to include part-time learners, Asians, and Latinos, but no studies were readily uncovered that focus on Black men. Addressing this gap in the…

Dietary habits of polar bears in Foxe Basin, Canada: possible evidence of a trophic regime shift mediated by a new top predator.

PubMed

Galicia, Melissa P; Thiemann, Gregory W; Dyck, Markus G; Ferguson, Steven H; Higdon, Jeff W

2016-08-01

Polar bear (Ursus maritimus) subpopulations in several areas with seasonal sea ice regimes have shown declines in body condition, reproductive rates, or abundance as a result of declining sea ice habitat. In the Foxe Basin region of Nunavut, Canada, the size of the polar bear subpopulation has remained largely stable over the past 20 years, despite concurrent declines in sea ice habitat. We used fatty acid analysis to examine polar bear feeding habits in Foxe Basin and thus potentially identify ecological factors contributing to population stability. Adipose tissue samples were collected from 103 polar bears harvested during 2010-2012. Polar bear diet composition varied spatially within the region with ringed seal (Pusa hispida) comprising the primary prey in northern and southern Foxe Basin, whereas polar bears in Hudson Strait consumed equal proportions of ringed seal and harp seal (Pagophilus groenlandicus). Walrus (Odobenus rosmarus) consumption was highest in northern Foxe Basin, a trend driven by the ability of adult male bears to capture large-bodied prey. Importantly, bowhead whale (Balaena mysticetus) contributed to polar bear diets in all areas and all age and sex classes. Bowhead carcasses resulting from killer whale (Orcinus orca) predation and subsistence harvest potentially provide an important supplementary food source for polar bears during the ice-free period. Our results suggest that the increasing abundance of killer whales and bowhead whales in the region could be indirectly contributing to improved polar bear foraging success despite declining sea ice habitat. However, this indirect interaction between top predators may be temporary if continued sea ice declines eventually severely limit on-ice feeding opportunities for polar bears.

CD24 Expression Identifies Teratogen-Sensitive Fetal Neural Stem Cell Subpopulations: Evidence from Developmental Ethanol Exposure and Orthotopic Cell Transfer Models

PubMed Central

Tingling, Joseph D.; Bake, Shameena; Holgate, Rhonda; Rawlings, Jeremy; Nagsuk, Phillips P.; Chandrasekharan, Jayashree; Schneider, Sarah L.; Miranda, Rajesh C.

2013-01-01

Background Ethanol is a potent teratogen. Its adverse neural effects are partly mediated by disrupting fetal neurogenesis. The teratogenic process is poorly understood, and vulnerable neurogenic stages have not been identified. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures. Methods We used flow cytometry and qRT-PCR to screen fetal mouse-derived neurosphere cultures for ethanol-sensitive neural stem cell (NSC) subpopulations, to study NSC renewal and differentiation. The identity of vulnerable NSC populations was validated in vivo, using a maternal ethanol exposure model. Finally, the effect of ethanol exposure on the ability of vulnerable NSC subpopulations to integrate into the fetal neurogenic environment was assessed following ultrasound guided, adoptive transfer. Results Ethanol decreased NSC mRNAs for c-kit, Musashi-1and GFAP. The CD24+ NSC population, specifically the CD24+CD15+ double-positive subpopulation, was selectively decreased by ethanol. Maternal ethanol exposure also resulted in decreased fetal forebrain CD24 expression. Ethanol pre-exposed CD24+ cells exhibited increased proliferation, and deficits in cell-autonomous and cue-directed neuronal differentiation, and following orthotopic transplantation into naïve fetuses, were unable to integrate into neurogenic niches. CD24depleted cells retained neurosphere regeneration capacity, but following ethanol exposure, generated increased numbers of CD24+ cells relative to controls. Conclusions Neuronal lineage committed CD24+ cells exhibit specific vulnerability, and ethanol exposure persistently impairs this population’s cell-autonomous differentiation capacity. CD24+ cells may additionally serve as quorum sensors within neurogenic niches; their loss, leading to compensatory NSC activation, perhaps depleting renewal capacity. These data collectively advance a mechanistic hypothesis for teratogenesis leading to microencephaly. PMID:23894503

Histone methylation mediates plasticity of human FOXP3(+) regulatory T cells by modulating signature gene expressions.

PubMed

He, Haiqi; Ni, Bing; Tian, Yi; Tian, Zhiqiang; Chen, Yanke; Liu, Zhengwen; Yang, Xiaomei; Lv, Yi; Zhang, Yong

2014-03-01

CD4(+) FOXP3(+) regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4(+) CD25(high) CD127(low/-) Treg cells convert to two subpopulations with distinctive FOXP3(+) and FOXP3(-) phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. © 2013 John Wiley & Sons Ltd.

SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice

PubMed Central

Percopo, Caroline M.; Brenner, Todd A.; Ma, Michelle; Kraemer, Laura S.; Hakeem, Reem M. A.; Lee, James J.; Rosenberg, Helene F.

2017-01-01

Although eosinophils as a group are readily identified by their unique morphology and staining properties, flow cytometry provides an important means for identification of subgroups based on differential expression of distinct surface Ags. Here, we characterize an eosinophil subpopulation defined by high levels of expression of the neutrophil Ag Gr1 (CD45+CD11c−SiglecF+Gr1hi). SiglecF+Gr1hi eosinophils, distinct from the canonical SiglecF+Gr1− eosinophil population, were detected in allergen-challenged wild-type and granule protein-deficient (EPX−/− and MBP-1−/−) mice, but not in the eosinophil-deficient ΔdblGATA strain. In contrast to Gr1+ neutrophils, which express both cross-reacting Ags Ly6C and Ly6G, SiglecF+Gr1hi eosinophils from allergen-challenged lung tissue are uniquely Ly6G+. Although indistinguishable from the more-numerous SiglecF+Gr1− eosinophils under light microscopy, FACS-isolated populations revealed prominent differences in cytokine contents. The lymphocyte-targeting cytokines CXCL13 and IL-27 were identified only in the SiglecF+Gr1hi eosinophil population (at 3.9 and 4.8 pg/106 cells, respectively), as was the prominent proinflammatory mediator IL-13 (72 pg/106 cells). Interestingly, bone marrow-derived (SiglecF+), cultured eosinophils include a more substantial Gr1+ subpopulation (∼50%); Gr1+ bmEos includes primarily a single Ly6C+ and a smaller, double-positive (Ly6C+Ly6G+) population. Taken together, our findings characterize a distinct SiglecF+Gr1hi eosinophil subset in lungs of allergen-challenged, wild-type and granule protein-deficient mice. SiglecF+Gr1hi eosinophils from wild-type mice maintain a distinct subset of cytokines, including those active on B and T lymphocytes. These cytokines may facilitate eosinophil-mediated immunomodulatory responses in the allergen-challenged lung as well as in other distinct microenvironments. PMID:27531929

SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice.

PubMed

Percopo, Caroline M; Brenner, Todd A; Ma, Michelle; Kraemer, Laura S; Hakeem, Reem M A; Lee, James J; Rosenberg, Helene F

2017-01-01

Although eosinophils as a group are readily identified by their unique morphology and staining properties, flow cytometry provides an important means for identification of subgroups based on differential expression of distinct surface Ags. Here, we characterize an eosinophil subpopulation defined by high levels of expression of the neutrophil Ag Gr1 (CD45 + CD11c - SiglecF + Gr1 hi ). SiglecF + Gr1 hi eosinophils, distinct from the canonical SiglecF + Gr1 - eosinophil population, were detected in allergen-challenged wild-type and granule protein-deficient (EPX -/- and MBP-1 -/- ) mice, but not in the eosinophil-deficient ΔdblGATA strain. In contrast to Gr1 + neutrophils, which express both cross-reacting Ags Ly6C and Ly6G, SiglecF + Gr1 hi eosinophils from allergen-challenged lung tissue are uniquely Ly6G + Although indistinguishable from the more-numerous SiglecF + Gr1 - eosinophils under light microscopy, FACS-isolated populations revealed prominent differences in cytokine contents. The lymphocyte-targeting cytokines CXCL13 and IL-27 were identified only in the SiglecF + Gr1 hi eosinophil population (at 3.9 and 4.8 pg/10 6 cells, respectively), as was the prominent proinflammatory mediator IL-13 (72 pg/10 6 cells). Interestingly, bone marrow-derived (SiglecF + ), cultured eosinophils include a more substantial Gr1 + subpopulation (∼50%); Gr1 + bmEos includes primarily a single Ly6C + and a smaller, double-positive (Ly6C + Ly6G + ) population. Taken together, our findings characterize a distinct SiglecF + Gr1 hi eosinophil subset in lungs of allergen-challenged, wild-type and granule protein-deficient mice. SiglecF + Gr1 hi eosinophils from wild-type mice maintain a distinct subset of cytokines, including those active on B and T lymphocytes. These cytokines may facilitate eosinophil-mediated immunomodulatory responses in the allergen-challenged lung as well as in other distinct microenvironments. © Society for Leukocyte Biology.

Adeno Associated Viral-mediated intraosseus labeling of bone marrow derived cells for CNS tracking

PubMed Central

Selenica, Maj-Linda B.; Reid, Patrick; Pena, Gabriela; Alvarez, Jennifer; Hunt, Jerry B.; Nash, Kevin R.; Morgan, Dave; Gordon, Marcia N.; Lee, Daniel C.

2016-01-01

Inflammation, including microglial activation in the CNS, is an important hallmark in many neurodegenerative diseases. Microglial stimuli not only impact the brain microenvironment by production and release of cytokines and chemokines, but also influence the activity of bone marrow derived cells and blood born macrophage populations. In many diseases including brain disorders and spinal cord injury, researchers have tried to harbor the neuroprotective and repair properties of these subpopulations. Hematopoietic bone marrow derived cells (BMDCs) are of great interest, especially during gene therapy because certain hematopoietic cell subpopulations traffic to the sites of injury and inflammation. The aim of this study was to develop a method of labeling endogenous bone marrow derived cells through intraosseus impregnation of recombinant adeno-associated virus (rAAV) or lentivirus. We utilized rAAV serotype 9 (rAAV-9) or lentivirus for gene delivery of green florescence protein (GFP) to the mouse bone marrow cells. Flow cytometry showed that both viruses were able to efficiently transduce mouse bone marrow cells in vivo. However, the rAAV9–GFP viral construct transduced BMDCs more efficiently than the lentivirus (11.2% vs. 6.8%), as indicated by cellular GFP expression. We also demonstrate that GFP labeled cells correspond to bone marrow cells of myeloid origin using CD11b as a marker. Additionally, we characterized the ability of bone marrow derived, GFP labeled cells to extravasate into the brain parenchyma upon acute and subchronic neuroinflammatory stimuli in the mouse CNS. Viral mediated over expression of chemokine (C-C motif) ligand 2 (CCL2) or intracranial injection of lipopolysaccharide (LPS) recruited GFP labeled BMDCs from the periphery into the brain parenchyma compared to vehicle treated mice. Altogether our findings demonstrate a useful method of labeling endogenous BMDCs via viral transduction and the ability to track subpopulations throughout the body following insult or injury. Alternatively, this method might find utility in delivering therapeutic genes for neuroinflammatory conditions. PMID:26784524

Quantifying rates of cell migration and cell proliferation in co-culture barrier assays reveals how skin and melanoma cells interact during melanoma spreading and invasion.

PubMed

Haridas, Parvathi; Penington, Catherine J; McGovern, Jacqui A; McElwain, D L Sean; Simpson, Matthew J

2017-06-21

Malignant spreading involves the migration of cancer cells amongst other native cell types. For example, in vivo melanoma invasion involves individual melanoma cells migrating through native skin, which is composed of several distinct subpopulations of cells. Here, we aim to quantify how interactions between melanoma and fibroblast cells affect the collective spreading of a heterogeneous population of these cells in vitro. We perform a suite of circular barrier assays that includes: (i) monoculture assays with fibroblast cells; (ii) monoculture assays with SK-MEL-28 melanoma cells; and (iii) a series of co-culture assays initiated with three different ratios of SK-MEL-28 melanoma cells and fibroblast cells. Using immunostaining, detailed cell density histograms are constructed to illustrate how the two subpopulations of cells are spatially arranged within the spreading heterogeneous population. Calibrating the solution of a continuum partial differential equation to the experimental results from the monoculture assays allows us to estimate the cell diffusivity and the cell proliferation rate for the melanoma and the fibroblast cells, separately. Using the parameter estimates from the monoculture assays, we then make a prediction of the spatial spreading in the co-culture assays. Results show that the parameter estimates obtained from the monoculture assays lead to a reasonably accurate prediction of the spatial arrangement of the two subpopulations in the co-culture assays. Overall, the spatial pattern of spreading of the melanoma cells and the fibroblast cells is very similar in monoculture and co-culture conditions. Therefore, we find no clear evidence of any interactions other than cell-to-cell contact and crowding effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.

PubMed

Pesce, Silvia; Greppi, Marco; Tabellini, Giovanna; Rampinelli, Fabio; Parolini, Silvia; Olive, Daniel; Moretta, Lorenzo; Moretta, Alessandro; Marcenaro, Emanuela

2017-01-01

Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. We performed multiparametric cytofluorimetric analysis of PD-1 + NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A - KIR + CD57 + phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets. We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Interaction between organophosphate compounds and cholinergic functions during development.

PubMed

Aluigi, M G; Angelini, C; Falugi, C; Fossa, R; Genever, P; Gallus, L; Layer, P G; Prestipino, G; Rakonczay, Z; Sgro, M; Thielecke, H; Trombino, S

2005-12-15

Organophosphate (OP) compounds exert inhibition on cholinesterase (ChE) activity by irreversibly binding to the catalytic site of the enzymes. For this reason, they are employed as insecticides for agricultural, gardening and indoor pest control. The biological function of the ChE enzymes is well known and has been studied since the beginning of the XXth century; in particular, acetylcholinesterase (AChE, E.C. 3.1.1.7) is an enzyme playing a key role in the modulation of neuromuscular impulse transmission. However, in the past decades, there has been increasing interest concerning its role in regulating non-neuromuscular cell-to-cell interactions mediated by electrical events, such as intracellular ion concentration changes, as the ones occurring during gamete interaction and embryonic development. An understanding of the mechanisms of the cholinergic regulation of these events can help us foresee the possible impact on environmental and human health, including gamete efficiency and possible teratogenic effects on different models, and help elucidate the extent to which OP exposure may affect human health. The chosen organophosphates were the ones mainly used in Europe: diazinon, chlorpyriphos, malathion, and phentoate, all of them belonging to the thionophosphate chemical class. This research has focused on the comparison between the effects of exposure on the developing embryos at different stages, identifying biomarkers and determining potential risk factors for sensitive subpopulations. The effects of OP oxonisation were not taken into account at this level, because embryonic responses were directly correlated to the changes of AChE activity, as determined by histochemical localisation and biochemical measurements. The identified biomarkers of effect for in vitro experiments were: cell proliferation/apoptosis as well as cell differentiation. For in vivo experiments, the endpoints were: developmental speed, size and shape of pre-gastrula embryos; developmental anomalies on neural tube, head, eye, heart. In all these events, we had evidence that the effects are mediated by ion channel activation, through the activation/inactivation of acetylcholine receptors (AChRs).

A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

PubMed Central

2012-01-01

5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA. In addition, we performed patch-clamp recordings followed by single-cell PCR in ePet1-eGFP mice. From 134 recorded 5-HT neurons located in the dorsal, lateral, and median raphe, we found lack of 5-HT1A mRNA expression in 22 cells, evenly distributed across raphe subfields. We compared the cellular characteristics of these neuronal types and found no difference in passive membrane properties and general excitability. However, when injected with large depolarizing current, 5-HT1A-negative neurons fired more action potentials, suggesting a lack of autoinhibitory action of local 5-HT release. Our results support the hypothesis that the 5-HT system is composed of subpopulations of serotonergic neurons with different capacity for adaptation. PMID:23336048

The Characterization of AT1 Expression in the Dorsal Root Ganglia After Chronic Constriction Injury.

PubMed

Oroszova, Zuzana; Hricova, Ludmila; Stropkovska, Andrea; Lukacova, Nadezda; Pavel, Jaroslav

2017-04-01

To clarify the role of Angiotensin II in the regulation of sensory signaling, we characterized the AT 1 expression in neuronal subpopulation of lower lumbar dorsal root ganglia under normal conditions and its alteration in neuropathic pain model. The characterization of AT 1 expression was done under control and after the chronic constriction injury induced by four loose ligatures of the sciatic nerve representing the model of posttraumatic painful peripheral neuropathy. Major Angiotensin II receptor type was expressed in approximately 43 % of small-sized and 62 % of large-sized neurons in control. The AT 1 overexpression after sciatic nerve ligation lasting 7 days was detected predominantly in small-sized AT 1 immunoreactive neurons (about 38 % increase). Chronic constriction injury caused a statistically marked increase in number of the small-sized peptidergic (CGRP immunoreactive) neuronal subpopulation expressing AT 1 (about 64 %). The subpopulations of AT 1 -immunoreactive and nonpeptide-containing primary sensory neurons revealed by IB4 binding, tyrosine hydroxylase- and parvalbumin-immunoreactive neurons were not markedly changed. Our results indicate that: (1) the AT 1 overexpression after the chronic constriction injury is an important factor in Angiotensin II-potentiated pain perception; (2) Angiotensin II is involved in pathological mechanisms of neuropathic pain and this effect can be mediated perhaps in combination with other neuropeptides synthesized in the primary sensory neurons.

Genome-Wide Association Analysis Reveals Different Genetic Control in Panicle Architecture Between and Rice.

PubMed

Bai, Xufeng; Zhao, Hu; Huang, Yong; Xie, Weibo; Han, Zhongmin; Zhang, Bo; Guo, Zilong; Yang, Lin; Dong, Haijiao; Xue, Weiya; Li, Guangwei; Hu, Gang; Hu, Yong; Xing, Yongzhong

2016-07-01

Panicle architecture determines the number of spikelets per panicle (SPP) and is highly associated with grain yield in rice ( L.). Understanding the genetic basis of panicle architecture is important for improving the yield of rice grain. In this study, we dissected panicle architecture traits into eight components, which were phenotyped from a germplasm collection of 529 cultivars. Multiple regression analysis revealed that the number of secondary branch (NSB) was the major factor that contributed to SPP. Genome-wide association analysis was performed independently for the eight particle architecture traits observed in the and rice subpopulations compared with the whole rice population. In total, 30 loci were associated with these traits. Of these, 13 loci were closely linked to known panicle architecture genes, and 17 novel loci were repeatedly identified in different environments. An association signal cluster was identified for NSB and number of spikelets per secondary branch (NSSB) in the region of 31.6 to 31.7 Mb on chromosome 4. In addition to the common associations detected in both and subpopulations, many associated loci were unique to one subpopulation. For example, and were specifically associated with panicle length (PL) in and rice, respectively. Moreover, the -mediated flowering genes and were associated with the formation of panicle architecture in rice. These results suggest that different gene networks regulate panicle architecture in and rice. Copyright © 2016 Crop Science Society of America.

Heterogeneous Structure of Stem Cells Dynamics: Statistical Models and Quantitative Predictions

PubMed Central

Bogdan, Paul; Deasy, Bridget M.; Gharaibeh, Burhan; Roehrs, Timo; Marculescu, Radu

2014-01-01

Understanding stem cell (SC) population dynamics is essential for developing models that can be used in basic science and medicine, to aid in predicting cells fate. These models can be used as tools e.g. in studying patho-physiological events at the cellular and tissue level, predicting (mal)functions along the developmental course, and personalized regenerative medicine. Using time-lapsed imaging and statistical tools, we show that the dynamics of SC populations involve a heterogeneous structure consisting of multiple sub-population behaviors. Using non-Gaussian statistical approaches, we identify the co-existence of fast and slow dividing subpopulations, and quiescent cells, in stem cells from three species. The mathematical analysis also shows that, instead of developing independently, SCs exhibit a time-dependent fractal behavior as they interact with each other through molecular and tactile signals. These findings suggest that more sophisticated models of SC dynamics should view SC populations as a collective and avoid the simplifying homogeneity assumption by accounting for the presence of more than one dividing sub-population, and their multi-fractal characteristics. PMID:24769917

Evaluation of blood T-lymphocyte subpopulations involved in host cellular immunity in dogs with mammary cancer.

PubMed

Karayannopoulou, Maria; Anagnostou, Tilemachos; Margariti, Apostolia; Kostakis, Charalampos; Kritsepi-Konstantinou, Maria; Psalla, Dimitra; Savvas, Ioannis

2017-04-01

Cancer-bearing patients are often immunosuppressed. In dogs with mammary or other cancers, various alterations in blood cell populations involved in host cellular immunity have been reported; among these cell populations some T-lymphocyte subsets play an important role against cancer. The purpose of the present study was to investigate any alterations in circulating T-lymphocyte subpopulations involved in cellular immunity in bitches with mammary cancer, in comparison to age-matched healthy intact bitches. Twenty eight dogs with mammary cancer and 14 control dogs were included in this study. Twelve out of the 28 bitches had mammary cancer of clinical stage II and 16/28 of stage III. Histological examination revealed that 23/28 animals had carcinomas, 3/28 sarcomas and 2/28 carcinosarcomas. White blood cell, neutrophil and lymphocyte absolute numbers were measured by complete blood count. Furthermore, blood T-lymphocyte population (CD3 + ) and the subpopulations CD4 + , CD8 + and CD5 low+ were assessed by flow cytometry. White blood cell and neutrophil but not lymphocyte absolute numbers were higher (P=0.003 and P=0.001, respectively) in cancer patients than controls. Flow cytometric analysis revealed that the relative percentage of T-lymphocytes (CD3 + ) and of CD4 + , CD8 + subpopulations was lower (the CD4 + /CD8 + ratio was higher), whereas the percentage of CD5 low+ T-cells was higher, in dogs with cancer compared to controls; however, a statistically significant difference was found only in the case of CD8 + T-cells (P=0.014), whereas in the case of the CD4 + /CD8 + ratio the difference almost reached statistical significance (P=0.059). Based on these findings, it can be suggested that, although the absolute number of blood lymphocytes is unchanged, the relative percentages of T-lymphocyte subpopulations involved in host cell-mediated immunity are altered, but only cytotoxic CD8 + T-cells are significantly suppressed, in dogs with mammary cancer of clinical stage II or III compared to age-matched healthy controls. Copyright © 2017 Elsevier B.V. All rights reserved.

Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress.

PubMed

Bangasser, Debra A; Lee, Catherine S; Cook, Philip A; Gee, James C; Bhatnagar, Seema; Valentino, Rita J

2013-10-02

Responses to acute stressors are determined in part by stress history. For example, a history of chronic stress results in facilitated responses to a novel stressor and this facilitation is considered to be adaptive. We previously demonstrated that repeated exposure of rats to the resident-intruder model of social stress results in the emergence of two subpopulations that are characterized by different coping responses to stress. The submissive subpopulation failed to show facilitation to a novel stressor and developed a passive strategy in the Porsolt forced swim test. Because a passive stress coping response has been implicated in the propensity to develop certain psychiatric disorders, understanding the unique circuitry engaged by exposure to a novel stressor in these subpopulations would advance our understanding of the etiology of stress-related pathology. An ex vivo functional imaging technique, manganese-enhanced magnetic resonance imaging (MEMRI), was used to identify and distinguish brain regions that are differentially activated by an acute swim stress (15 min) in rats with a history of social stress compared to controls. Specifically, Mn(2+) was administered intracerebroventricularly prior to swim stress and brains were later imaged ex vivo to reveal activated structures. When compared to controls, all rats with a history of social stress showed greater activation in specific striatal, hippocampal, hypothalamic, and midbrain regions. The submissive subpopulation of rats was further distinguished by significantly greater activation in amygdala, bed nucleus of the stria terminalis, and septum, suggesting that these regions may form a circuit mediating responses to novel stress in individuals that adopt passive coping strategies. The finding that different circuits are engaged by a novel stressor in the two subpopulations of rats exposed to social stress implicates a role for these circuits in determining individual strategies for responding to stressors. Finally, these data underscore the utility of ex vivo MEMRI to identify and distinguish circuits engaged in behavioral responses. Copyright © 2013 Elsevier Inc. All rights reserved.

Featural and temporal attention selectively enhance task-appropriate representations in human V1

PubMed Central

Warren, Scott; Yacoub, Essa; Ghose, Geoffrey

2015-01-01

Our perceptions are often shaped by focusing our attention toward specific features or periods of time irrespective of location. We explore the physiological bases of these non-spatial forms of attention by imaging brain activity while subjects perform a challenging change detection task. The task employs a continuously varying visual stimulus that, for any moment in time, selectively activates functionally distinct subpopulations of primary visual cortex (V1) neurons. When subjects are cued to the timing and nature of the change, the mapping of orientation preference across V1 was systematically shifts toward the cued stimulus just prior to its appearance. A simple linear model can explain this shift: attentional changes are selectively targeted toward neural subpopulations representing the attended feature at the times the feature was anticipated. Our results suggest that featural attention is mediated by a linear change in the responses of task-appropriate neurons across cortex during appropriate periods of time. PMID:25501983

Endocannabinoids and stress.

PubMed

Riebe, Caitlin J; Wotjak, Carsten T

2011-07-01

Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans.

Recruitment of Staufen2 Enhances Dendritic Localization of an Intron-Containing CaMKIIα mRNA.

PubMed

Ortiz, Raúl; Georgieva, Maya V; Gutiérrez, Sara; Pedraza, Neus; Fernández-Moya, Sandra M; Gallego, Carme

2017-07-05

Regulation of mRNA localization is a conserved cellular process observed in many types of cells and organisms. Asymmetrical mRNA distribution plays a particularly important role in the nervous system, where local translation of localized mRNA represents a key mechanism in synaptic plasticity. CaMKIIα is a very abundant mRNA detected in neurites, consistent with its crucial role at glutamatergic synapses. Here, we report the presence of CaMKIIα mRNA isoforms that contain intron i16 in dendrites, RNA granules, and synaptoneurosomes from primary neurons and brain. This subpopulation of unspliced mRNA preferentially localizes to distal dendrites in a synaptic-activity-dependent manner. Staufen2, a well-established marker of RNA transport in dendrites, interacts with intron i16 sequences and enhances its distal dendritic localization, pointing to the existence of intron-mediated mechanisms in the molecular pathways that modulate dendritic transport and localization of synaptic mRNAs. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Receptor-mediated Drp1 oligomerization on endoplasmic reticulum

PubMed Central

Ji, Wei-Ke; Fan, Xintao; Strack, Stefan

2017-01-01

Drp1 is a dynamin guanosine triphosphatase important for mitochondrial and peroxisomal division. Drp1 oligomerization and mitochondrial recruitment are regulated by multiple factors, including interaction with mitochondrial receptors such as Mff, MiD49, MiD51, and Fis. In addition, both endoplasmic reticulum (ER) and actin filaments play positive roles in mitochondrial division, but mechanisms for their roles are poorly defined. Here, we find that a population of Drp1 oligomers is associated with ER in mammalian cells and is distinct from mitochondrial or peroxisomal Drp1 populations. Subpopulations of Mff and Fis1, which are tail-anchored proteins, also localize to ER. Drp1 oligomers assemble on ER, from which they can transfer to mitochondria. Suppression of Mff or inhibition of actin polymerization through the formin INF2 significantly reduces all Drp1 oligomer populations (mitochondrial, peroxisomal, and ER bound) and mitochondrial division, whereas Mff targeting to ER has a stimulatory effect on division. Our results suggest that ER can function as a platform for Drp1 oligomerization, and that ER-associated Drp1 contributes to mitochondrial division. PMID:29158231

Select host cell proteins coelute with monoclonal antibodies in protein A chromatography.

PubMed

Nogal, Bartek; Chhiba, Krishan; Emery, Jefferson C

2012-01-01

The most significant factor contributing to the presence of host cell protein (HCP) impurities in Protein A chromatography eluates is their association with the product monoclonal antibodies (mAbs) has been reported previously, and it has been suggested that more efficacious column washes may be developed by targeting the disruption of the mAbs-HCP interaction. However, characterization of this interaction is not straight forward as it is likely to involve multiple proteins and/or types of interaction. This work is an attempt to begin to understand the contribution of HCP subpopulations and/or mAb interaction propensity to the variability in HCP levels in the Protein A eluate. We performed a flowthrough (FT) recycling study with product respiking using two antibody molecules of apparently different HCP interaction propensities. In each case, the ELISA assay showed depletion of select subpopulations of HCP in Protein A eluates in subsequent column runs, while the feedstock HCP in the FTs remained unchanged from its native harvested cell culture fluid (HCCF) levels. In a separate study, the final FT from each molecule's recycling study was cross-spiked with various mAbs. In this case, Protein A eluate levels remained low for all but two molecules which were known as having high apparent HCP interaction propensity. The results of these studies suggest that mAbs may preferentially bind to select subsets of HCPs, and the degree of interaction and/or identity of the associated HCPs may vary depending on the mAb. Copyright © 2012 American Institute of Chemical Engineers (AIChE).

Cellular and Molecular Level Responses After Radiofrequency Radiation Exposure, Alone or in Combination with X-rays or Chemicals

DTIC Science & Technology

1992-07-27

cell surface marker CD22 , which plays a role in early B-cell activation, is present within the cytoplasm of all B- cells, but expressed only on the...surface of a subpopulation of those cells. CD22 is an activation receptor associated with cell proliferation of small resting B-cells, and acts as an...adhesion molecule mediating the binding of B-cells to other hematopoietic cells (Stamenkovic & Seed, 1990). The CD22 surface glycoprotein is the putative

Can multi-subpopulation reference sets improve the genomic predictive ability for pigs?

PubMed

Fangmann, A; Bergfelder-Drüing, S; Tholen, E; Simianer, H; Erbe, M

2015-12-01

In most countries and for most livestock species, genomic evaluations are obtained from within-breed analyses. To achieve reliable breeding values, however, a sufficient reference sample size is essential. To increase this size, the use of multibreed reference populations for small populations is considered a suitable option in other species. Over decades, the separate breeding work of different pig breeding organizations in Germany has led to stratified subpopulations in the breed German Large White. Due to this fact and the limited number of Large White animals available in each organization, there was a pressing need for ascertaining if multi-subpopulation genomic prediction is superior compared with within-subpopulation prediction in pigs. Direct genomic breeding values were estimated with genomic BLUP for the trait "number of piglets born alive" using genotype data (Illumina Porcine 60K SNP BeadChip) from 2,053 German Large White animals from five different commercial pig breeding companies. To assess the prediction accuracy of within- and multi-subpopulation reference sets, a random 5-fold cross-validation with 20 replications was performed. The five subpopulations considered were only slightly differentiated from each other. However, the prediction accuracy of the multi-subpopulations approach was not better than that of the within-subpopulation evaluation, for which the predictive ability was already high. Reference sets composed of closely related multi-subpopulation sets performed better than sets of distantly related subpopulations but not better than the within-subpopulation approach. Despite the low differentiation of the five subpopulations, the genetic connectedness between these different subpopulations seems to be too small to improve the prediction accuracy by applying multi-subpopulation reference sets. Consequently, resources should be used for enlarging the reference population within subpopulation, for example, by adding genotyped females.

Finding vulnerable subpopulations in the Seychelles Child Development Study: effect modification with latent groups.

PubMed

Love, Tanzy Mt; Thurston, Sally W; Davidson, Philip W

2017-04-01

The Seychelles Child Development Study is a research project with the objective of examining associations between prenatal exposure to low doses of methylmercury from maternal fish consumption and children's developmental outcomes. Whether methylmercury has neurotoxic effects at low doses remains unclear and recommendations for pregnant women and children to reduce fish intake may prevent a substantial number of people from receiving sufficient nutrients that are abundant in fish. The primary findings of the Seychelles Child Development Study are inconsistent with adverse associations between methylmercury from fish consumption and neurodevelopmental outcomes. However, whether there are subpopulations of children who are particularly sensitive to this diet is an open question. Secondary analysis from this study found significant interactions between prenatal methylmercury levels and both caregiver IQ and income on 19-month IQ. These results are sensitive to the categories chosen for these covariates and are difficult to interpret collectively. In this paper, we estimate effect modification of the association between prenatal methylmercury exposure and 19-month IQ using a general formulation of mixture regression. Our mixture regression model creates a latent categorical group membership variable which interacts with methylmercury in predicting the outcome. We also fit the same outcome model when in addition the latent variable is assumed to be a parametric function of three distinct socioeconomic measures. Bayesian methods allow group membership and the regression coefficients to be estimated simultaneously and our approach yields a principled choice of the number of distinct subpopulations. The results show three groups with different response patterns between prenatal methylmercury exposure and 19-month IQ in this population.

Role of the Microenvironment in Liver Metastasis: From Pre- to Prometastatic Niches.

PubMed

Brodt, Pnina

2016-12-15

Liver metastases remain a major barrier to successful management of malignant disease, particularly for cancers of the gastrointestinal tract but also for other malignancies, such as breast carcinoma and melanoma. The ability of metastatic cells to survive and proliferate in the liver is determined by the outcome of complex, reciprocal interactions between tumor cells and different local resident subpopulations, including the sinusoidal endothelium, stellate, Kupffer, and inflammatory cells that are mediated through cell-cell and cell-extracellular matrix adhesion and the release of soluble factors. Cross-communication between different hepatic resident cells in response to local tissue damage and inflammation and the recruitment of bone marrow cells further enhance this intercellular communication network. Both resident and recruited cells can play opposing roles in the progression of metastasis, and the balance of these divergent effects determines whether the tumor cells will die, proliferate, and colonize the new site or enter a state of dormancy. Moreover, this delicate balance can be tilted in favor of metastasis, if factors produced by the primary tumor precondition the microenvironment to form niches of activated resident cells that promote tumor expansion. This review aims to summarize current knowledge on these diverse interactions and the impact they can have on the clinical management of hepatic metastases. Clin Cancer Res; 22(24); 5971-82. ©2016 AACR. ©2016 American Association for Cancer Research.

Types of Mathematics-Language Reading Interactions that Unnecessarily Hinder Algebra Learning and Assessment

ERIC Educational Resources Information Center

Lager, Carl A.

2006-01-01

English language learners (ELLs)--one of the lowest-achieving and fastest growing middle-school subpopulations--are challenged in the classroom by language components which could potentially jumpstart real mathematical growth for these and, eventually, all other students as well. Going beyond traditional word problems, this study documented and…

Isolating Fungal Pathogens from a Dynamic Disease Outbreak in a Native Plant Population to Establish Plant-Pathogen Bioassays for the Ecological Model Plant Nicotiana attenuata

PubMed Central

Schuck, Stefan; Baldwin, Ian T.

2014-01-01

The wild tobacco species Nicotiana attenuata has been intensively used as a model plant to study its interaction with insect herbivores and pollinators in nature, however very little is known about its native pathogen community. We describe a fungal disease outbreak in a native N. attenuata population comprising 873 plants growing in an area of about 1500 m2. The population was divided into 14 subpopulations and disease symptom development in the subpopulations was monitored for 16 days, revealing a waxing and waning of visible disease symptoms with some diseased plants recovering fully. Native fungal N. attenuata pathogens were isolated from diseased plants, characterized genetically, chemotaxonomically and morphologically, revealing several isolates of the ascomycete genera Fusarium and Alternaria, that differed in the type and strength of the disease symptoms they caused in bioassays on either detached leaves or intact soil-grown plants. These isolates and the bioassays will empower the study of N. attenuata-pathogen interactions in a realistic ecological context. PMID:25036191

Personality Profiles of Effective Leadership Performance in Assessment Centers.

PubMed

Parr, Alissa D; Lanza, Stephanie T; Bernthal, Paul

2016-01-01

Most research examining the relationship between effective leadership and personality has focused on individual personality traits. However, profiles of personality traits more fully describe individuals, and these profiles may be important as they relate to leadership. This study used latent class analysis to examine how personality traits combine and interact to form subpopulations of leaders, and how these subpopulations relate to performance criteria. Using a sample of 2,461 executive-level leaders, six personality profiles were identified: Unpredictable Leaders with Low Diligence (7.3%); Conscientious, Backend Leaders (3.6%); Unpredictable Leaders (8.6%); Creative Communicators (20.8%); Power Players (32.4%); and Protocol Followers (27.1%). One profile performed well on all criteria in an assessment center; remaining profiles exhibited strengths and weaknesses across criteria. Implications and future directions for research are highlighted.

In vivo T cell depletion regulates resistance and morbidity in murine schistosomiasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phillips, S.M.; Linette, G.P.; Doughty, B.L.

1987-08-01

These studies assessed the roles of subpopulations of T lymphocytes in inducing and modulating resistance to schistosomiasis and thereby influencing subsequent morbidity. C57BL/6 mice were depleted in vivo of Lyt-1+, Lyt-2+, and L3T4+ cells by the daily administration of monoclonal antibodies. The development of protective immunity, induced by exposure to irradiated Schistosoma mansoni cercariae as expressed in depleted animals, was compared to that demonstrated in undepleted, normal, and congenitally athymic C57BL/6 mice. The development of morbidity was determined by spleen weight, portal pressure and reticuloendothelial system activity. The results indicated that depletion of specific subpopulations of T lymphocytes minimally affectedmore » the primary development of parasites; however, depletion strongly influenced the development of resistance to the parasite and subsequent morbidity due to infection. Depletion of T lymphocytes by anti-Lyt-1+ or anti-L3T4+ antibody decreased the development of resistance, antibody and delayed-type hypersensitivity directed against schistosome antigens. Morbidity due to disease was increased. Depletion of Lyt-2+ cells produced opposite changes with augmented resistance and reduced morbidity. Congenitally athymic mice developed minimal resistance and morbidity. Moreover, resistance was inversely related to the morbidity shown by a given animal. These studies indicate that the development of protective immunity to S. mansoni cercariae is regulated by discrete subpopulations of T lymphocytes. The feasibility of decreasing morbidity by increasing specific immunologically mediated resistance is suggested.« less

Dynamics of heterogeneous oscillator ensembles in terms of collective variables

NASA Astrophysics Data System (ADS)

Pikovsky, Arkady; Rosenblum, Michael

2011-04-01

We consider general heterogeneous ensembles of phase oscillators, sine coupled to arbitrary external fields. Starting with the infinitely large ensembles, we extend the Watanabe-Strogatz theory, valid for identical oscillators, to cover the case of an arbitrary parameter distribution. The obtained equations yield the description of the ensemble dynamics in terms of collective variables and constants of motion. As a particular case of the general setup we consider hierarchically organized ensembles, consisting of a finite number of subpopulations, whereas the number of elements in a subpopulation can be both finite or infinite. Next, we link the Watanabe-Strogatz and Ott-Antonsen theories and demonstrate that the latter one corresponds to a particular choice of constants of motion. The approach is applied to the standard Kuramoto-Sakaguchi model, to its extension for the case of nonlinear coupling, and to the description of two interacting subpopulations, exhibiting a chimera state. With these examples we illustrate that, although the asymptotic dynamics can be found within the framework of the Ott-Antonsen theory, the transients depend on the constants of motion. The most dramatic effect is the dependence of the basins of attraction of different synchronous regimes on the initial configuration of phases.

Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

PubMed

Parrilla-Carrero, Jeffrey; Buchta, William C; Goswamee, Priyodarshan; Culver, Oliver; McKendrick, Greer; Harlan, Benjamin; Moutal, Aubin; Penrod, Rachel; Lauer, Abigail; Ramakrishnan, Viswanathan; Khanna, Rajesh; Kalivas, Peter; Riegel, Arthur C

2018-04-25

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues. SIGNIFICANCE STATEMENT Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability. Copyright © 2018 the authors 0270-6474/18/384212-18$15.00/0.

Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion

PubMed Central

Hoang, John; Bruce-Keller, Annadora; Berthoud, Hans-Rudolf; Morrison, Christopher D.

2017-01-01

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHAGABA), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHAGABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHAGABA neurons that coexpress the neuropeptide galanin (LHAGal). These LHAGal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHAGal neurons may represent a subpopulation of LHAGABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHAGal or LHAGABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHAGal or LHAGABA neuronal activation both increased operant food-seeking behavior, but only activation of LHAGABA neurons increased overall chow consumption. Additionally, LHAGal or LHAGABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHAGABA neurons induced compulsive-like locomotor behavior; while LHAGal neurons induced locomotor activity without compulsivity. Thus, LHAGal neurons define a subpopulation of LHAGABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified. SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHAGABA neurons is heterogeneous and largely undefined. Here we introduce LHAGal neurons as a subset of LHAGABA neurons that lack direct innervation of the ventral tegmental area (VTA). LHAGal neurons are sufficient to drive motivated feeding and locomotor activity similar to LHAGABA neurons, but without inducing compulsive-like behaviors, which we propose to require direct VTA innervation. Our study integrates galanin-expressing LHA neurons into our current understanding of the neuronal circuits and molecular mechanisms of the LHA that contribute to motivated feeding behaviors. PMID:28539422

Histone methylation mediates plasticity of human FOXP3+ regulatory T cells by modulating signature gene expressions

PubMed Central

He, Haiqi; Ni, Bing; Tian, Yi; Tian, Zhiqiang; Chen, Yanke; Liu, Zhengwen; Yang, Xiaomei; Lv, Yi; Zhang, Yong

2014-01-01

CD4+ FOXP3+ regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4+ CD25high CD127low/− Treg cells convert to two subpopulations with distinctive FOXP3+ and FOXP3− phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. PMID:24152290

B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events

PubMed Central

Hou, Ping; Araujo, Elizabeth; Zhao, Tong; Zhang, Miao; Massenburg, Don; Veselits, Margaret; Doyle, Colleen; Dinner, Aaron R; Clark, Marcus R

2006-01-01

Engagement of the B cell antigen receptor initiates two concurrent processes, signaling and receptor internalization. While both are required for normal humoral immune responses, the relationship between these two processes is unknown. Herein, we demonstrate that following receptor ligation, a small subpopulation of B cell antigen receptors are inductively phosphorylated and selectively retained at the cell surface where they can serve as scaffolds for the assembly of signaling molecules. In contrast, the larger population of non-phosphorylated receptors is rapidly endocytosed. Each receptor can undergo only one of two mutually exclusive fates because the tyrosine-based motifs that mediate signaling when phosphorylated mediate internalization when not phosphorylated. Mathematical modeling indicates that the observed competition between receptor phosphorylation and internalization enhances signaling responses to low avidity ligands. PMID:16719564

Slug promoted vasculogenic mimicry in hepatocellular carcinoma

PubMed Central

Sun, Dan; Sun, Baocun; Liu, Tieju; Zhao, Xiulan; Che, Na; Gu, Qiang; Dong, Xueyi; Yao, Zhi; Li, Rui; Li, Jing; Chi, Jiadong; Sun, Ran

2013-01-01

Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumour cells to mimic the pattern of embryonic vasculogenic networks. Epithelial–mesenchymal transition (EMT) regulator slug have been implicated in the tumour invasion and metastasis of human hepatocellular carcinoma (HCC). However, the relationship between slug and VM formation is not clear. In the study, we demonstrated that slug expression was associated with EMT and cancer stem cell (CSCs) phenotype in HCC patients. Importantly, slug showed statistically correlation with VM formation. We consistently demonstrated that an overexpression of slug in HCC cells significantly increased CSCs subpopulation that was obvious by the increased clone forming efficiency in soft agar and by flowcytometry analysis. Meantime, the VM formation and VM mediator overexpression were also induced by slug induction. Finally, slug overexpression lead to the maintenance of CSCs phenotype and VM formation was demonstrated in vivo. Therefore, the results of this study indicate that slug induced the increase and maintenance of CSCs subpopulation and contributed to VM formation eventually. The related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis. PMID:23815612

Changes in the structures of motile sperm subpopulations in dog spermatozoa after both cryopreservation and centrifugation on PureSperm(®) gradient.

PubMed

Dorado, J; Alcaráz, L; Duarte, N; Portero, J M; Acha, D; Hidalgo, M

2011-05-01

The aims of the present study were to: (1) determine if discrete motile sperm subpopulations exist and their incidence in fresh dog ejaculates, (2) evaluate the effects of cryopreservation on the distribution of spermatozoa within the different subpopulations, and (3) determine the effect of the discontinuous PureSperm(®) gradient on the sperm subpopulation structure of frozen-thawed dog spermatozoa. Semen from 5 dogs were collected and cryopreserved following a standard protocol. After thawing, semen samples were selected by centrifugation on PureSperm(®). Sperm motility (assessed by computerized-assisted semen analysis, CASA) was assessed before freezing, just after thawing and after preparation on the PureSperm(®) gradients. Cryopreservation had a significant (P<0.001) effect on CASA-derived parameters. PureSperm(®) centrifugation yielded sperm suspensions with improved motility (P<0.01). A multivariate clustering procedure separated 19414 motile spermatozoa into four subpopulations: Subpopulation 1 consisting of poorly active and non-progressive spermatozoa (20.97%), Subpopulation 2 consisting of slow and low-linear spermatozoa (18.24%), Subpopulation 3 consisting of highly active but non-progressive spermatozoa (20.75%), and Subpopulation 4 consisting of high speed and progressive spermatozoa (40.03%). Although, cryopreservation had a significant (P<0.001) effect on both the frequency distribution of spermatozoa within subpopulations and the motion characteristics of each subpopulation, the sperm subpopulation structure was perfectly maintained after freezing and thawing. The selected sperm samples was enrich in Subpopulation 4, reaching a proportion of 31.9% of the present spermatozoa, in contrast with the unselected sperm samples, where this sperm subpopulation accounted for 24.9% of the total. From these results, we concluded that four well-defined motile sperm subpopulations were present either in fresh semen, in unselected sperm samples or in selected preparations from dogs. The discontinuous PureSperm(®) gradient is a simple method to improve the quality of canine frozen-thawed semen samples, since Subpopulation 4 (high-speed and progressive spermatozoa) was more frequently observed after preparation on the gradient. Finally, this study also demonstrated that the general motile sperm structure present in dog remains constant despite the effect caused by either cryopreservation or separation on PureSperm(®) gradient. Copyright © 2011 Elsevier B.V. All rights reserved.

Observations Of General Learning Patterns In An Upper-Level Thermal Physics Course

NASA Astrophysics Data System (ADS)

Meltzer, David E.

2009-11-01

I discuss some observations from using interactive-engagement instructional methods in an upper-level thermal physics course over a two-year period. From the standpoint of the subject matter knowledge of the upper-level students, there was a striking persistence of common learning difficulties previously observed in students enrolled in the introductory course, accompanied, however, by some notable contrasts between the groups. More broadly, I comment on comparisons and contrasts regarding general pedagogical issues among different student sub-populations, for example: differences in the receptivity of lower- and upper-level students to diagrammatic representations; varying receptivity to tutorial-style instructional approach within the upper-level population; and contrasting approaches to learning among physics and engineering sub-populations in the upper-level course with regard to use of symbolic notation, mathematical equations, and readiness to employ verbal explanations.

Personality Profiles of Effective Leadership Performance in Assessment Centers

PubMed Central

Parr, Alissa D.; Lanza, Stephanie T.; Bernthal, Paul

2016-01-01

Most research examining the relationship between effective leadership and personality has focused on individual personality traits. However, profiles of personality traits more fully describe individuals, and these profiles may be important as they relate to leadership. This study used latent class analysis to examine how personality traits combine and interact to form subpopulations of leaders, and how these subpopulations relate to performance criteria. Using a sample of 2,461 executive-level leaders, six personality profiles were identified: Unpredictable Leaders with Low Diligence (7.3%); Conscientious, Backend Leaders (3.6%); Unpredictable Leaders (8.6%); Creative Communicators (20.8%); Power Players (32.4%); and Protocol Followers (27.1%). One profile performed well on all criteria in an assessment center; remaining profiles exhibited strengths and weaknesses across criteria. Implications and future directions for research are highlighted. PMID:27746587

Effect of Priming of Multipotent Mesenchymal Stromal Cells with Interferon γ on Their Immunomodulating Properties.

PubMed

Kapranov, N M; Davydova, Y O; Galtseva, I V; Petinati, N A; Drize, N I; Kuzmina, L A; Parovichnikova, E N; Savchenko, V G

2017-10-01

Multipotent mesenchymal stromal cells (MSCs) are widely used for cell therapy, in particular for prophylaxis and treatment of graft-versus-host disease. Due to their immunomodulatory properties, MSCs affect the composition of lymphocyte subpopulations, which depends on the immunological state of the organism and can change in different diseases and during treatment. Administration of MSCs is not always effective. Treatment of MSCs with different cytokines (in particular IFN-γ) leads to enhancement of their immunomodulatory properties. The aim of this study was to investigate subpopulational alterations and activation markers in lymphocytes (activated and non-activated) after interaction with MSCs and MSCs pretreated with IFN-γ (γMSCs) in vitro. Lymphocytes were co-cultured with MSCs or γMSCs for 4 days. The proportion of CD4+ and CD8 + expressing CD25, CD38, CD69, HLA-DR, and PD-1 and distribution of memory and effector subsets were measured by flow cytometry after co-cultivation of lymphocytes with MSCs or γMSCs. The distribution of lymphocyte subpopulations changes during culturing. In non-activated lymphocytes cultured without MSCs, decrease in the proportion of naïve cells and increase in the number of effector cells was observed. That could be explained as activation of lymphocytes in the presence of serum in culturing medium. Co-culturing of lymphocytes with MSCs and γMSCs leads to retention of their non-activated state. Activation of lymphocytes with phytohemagglutinin increases the number of central memory cells and activates marker expression. Interaction with MSCs and γMSCs prevents activation of lymphocytes and keeps their naïve state. Priming with IFN-γ did not induce MSCs inhibitory effect on activation of lymphocytes.

Trace element concentrations in two subpopulations of lesser snow geese from Wrangel Island, Russia

USGS Publications Warehouse

Hui, A.; Takekawa, John Y.; Baranyuk, Vasily V.; Litvin, K.V.

1998-01-01

Lesser snow geese (Anser c. caerulescens) from the Wrangel Island, Russia breeding colony spend the winter in two widely separated areas: the northern subpopulation in southern British Columbia and northern Washington and the southern subpopulation in the Central Valley of California. We examined 19 trace elements in the eggs and livers of geese from these two subpopulations to examine whether geese from the different wintering areas have similar trace element burdens. Eggs collected at the breeding colony from geese of the southern subpopulation had slightly higher levels of manganese, an element that can cause neurological damage and behavioral changes in chicks, than geese of the northern subpopulation. Livers from adult geese collected on the two wintering areas showed significant differences in trace elements including copper, iron, magnesium, molybdenum, and zinc. Copper concentrations in the livers of geese from the southern subpopulation were much higher than those from the northern subpopulation (x¯ = 116 vs. 46 ppm; dry weight). Elevated levels of copper may induce anemia in birds. The differences in trace element concentrations of these two subpopulations may be related to farming practices in their wintering areas. Geese from the northern subpopulation feed in pastures and coastal marshes and migrate along the coast, but geese from the southern subpopulation feed predominantly in rice fields and migrate over farm land. Copper and manganese are major components of fertilizers and fungicides commonly applied during rice cultivation.

BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors.

PubMed

Morikawa, Masato; Koinuma, Daizo; Mizutani, Anna; Kawasaki, Natsumi; Holmborn, Katarina; Sundqvist, Anders; Tsutsumi, Shuichi; Watabe, Tetsuro; Aburatani, Hiroyuki; Heldin, Carl-Henrik; Miyazono, Kohei

2016-01-12

Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Epidemiological and economic impact of pandemic influenza in Chicago: Priorities for vaccine interventions

PubMed Central

Dorratoltaj, Nargesalsadat; Marathe, Achla; Swarup, Samarth; Eubank, Stephen G.

2017-01-01

The study objective is to estimate the epidemiological and economic impact of vaccine interventions during influenza pandemics in Chicago, and assist in vaccine intervention priorities. Scenarios of delay in vaccine introduction with limited vaccine efficacy and limited supplies are not unlikely in future influenza pandemics, as in the 2009 H1N1 influenza pandemic. We simulated influenza pandemics in Chicago using agent-based transmission dynamic modeling. Population was distributed among high-risk and non-high risk among 0–19, 20–64 and 65+ years subpopulations. Different attack rate scenarios for catastrophic (30.15%), strong (21.96%), and moderate (11.73%) influenza pandemics were compared against vaccine intervention scenarios, at 40% coverage, 40% efficacy, and unit cost of $28.62. Sensitivity analysis for vaccine compliance, vaccine efficacy and vaccine start date was also conducted. Vaccine prioritization criteria include risk of death, total deaths, net benefits, and return on investment. The risk of death is the highest among the high-risk 65+ years subpopulation in the catastrophic influenza pandemic, and highest among the high-risk 0–19 years subpopulation in the strong and moderate influenza pandemics. The proportion of total deaths and net benefits are the highest among the high-risk 20–64 years subpopulation in the catastrophic, strong and moderate influenza pandemics. The return on investment is the highest in the high-risk 0–19 years subpopulation in the catastrophic, strong and moderate influenza pandemics. Based on risk of death and return on investment, high-risk groups of the three age group subpopulations can be prioritized for vaccination, and the vaccine interventions are cost saving for all age and risk groups. The attack rates among the children are higher than among the adults and seniors in the catastrophic, strong, and moderate influenza pandemic scenarios, due to their larger social contact network and homophilous interactions in school. Based on return on investment and higher attack rates among children, we recommend prioritizing children (0–19 years) and seniors (65+ years) after high-risk groups for influenza vaccination during times of limited vaccine supplies. Based on risk of death, we recommend prioritizing seniors (65+ years) after high-risk groups for influenza vaccination during times of limited vaccine supplies. PMID:28570660

A unification of mediation and interaction: a four-way decomposition

PubMed Central

VanderWeele, Tyler J.

2014-01-01

It is shown that the overall effect of an exposure on an outcome, in the presence of a mediator with which the exposure may interact, can be decomposed into four components: (i) the effect of the exposure in the absence of the mediator, (ii) the interactive effect when the mediator is left to what it would be in the absence of exposure, (iii) a mediated interaction, and (iv) a pure mediated effect. These four components, respectively, correspond to the portion of the effect that is due to neither mediation nor interaction, to just interaction (but not mediation), to both mediation and interaction, and to just mediation (but not interaction). This four-way decomposition unites methods that attribute effects to interactions and methods that assess mediation. Certain combinations of these four components correspond to measures for mediation, while other combinations correspond to measures of interaction previously proposed in the literature. Prior decompositions in the literature are in essence special cases of this four-way decomposition. The four-way decomposition can be carried out using standard statistical models, and software is provided to estimate each of the four components. The four-way decomposition provides maximum insight into how much of an effect is mediated, how much is due to interaction, how much is due to both mediation and interaction together, and how much is due to neither. PMID:25000145

Demographic and traditional knowledge perspectives on the current status of Canadian polar bear subpopulations.

PubMed

York, Jordan; Dowsley, Martha; Cornwell, Adam; Kuc, Miroslaw; Taylor, Mitchell

2016-05-01

Subpopulation growth rates and the probability of decline at current harvest levels were determined for 13 subpopulations of polar bears (Ursus maritimus) that are within or shared with Canada based on mark-recapture estimates of population numbers and vital rates, and harvest statistics using population viability analyses (PVA). Aboriginal traditional ecological knowledge (TEK) on subpopulation trend agreed with the seven stable/increasing results and one of the declining results, but disagreed with PVA status of five other declining subpopulations. The decline in the Baffin Bay subpopulation appeared to be due to over-reporting of harvested numbers from outside Canada. The remaining four disputed subpopulations (Southern Beaufort Sea, Northern Beaufort Sea, Southern Hudson Bay, and Western Hudson Bay) were all incompletely mark-recapture (M-R) sampled, which may have biased their survival and subpopulation estimates. Three of the four incompletely sampled subpopulations were PVA identified as nonviable (i.e., declining even with zero harvest mortality). TEK disagreement was nonrandom with respect to M-R sampling protocols. Cluster analysis also grouped subpopulations with ambiguous demographic and harvest rate estimates separately from those with apparently reliable demographic estimates based on PVA probability of decline and unharvested subpopulation growth rate criteria. We suggest that the correspondence between TEK and scientific results can be used to improve the reliability of information on natural systems and thus improve resource management. Considering both TEK and scientific information, we suggest that the current status of Canadian polar bear subpopulations in 2013 was 12 stable/increasing and one declining (Kane Basin). We do not find support for the perspective that polar bears within or shared with Canada are currently in any sort of climate crisis. We suggest that monitoring the impacts of climate change (including sea ice decline) on polar bear subpopulations should be continued and enhanced and that adaptive management practices are warranted.

Genetic differences among Anopheles vestitipennis subpopulations collected using different methods in Chiapas state, southern México.

PubMed

Arredondo-Jiménez, J I; Gimnig, J; Rodríguez, M H; Washino, R K

1996-09-01

Biting activity and population genetic studies of the malaria vector Anopheles vestitipennis were conducted in southern México. Three subpopulations were collected from 2 villages; 2 subpopulations were from the same village, one on human bait and one with an animal-baited trap; the third was collected from a cattle corral in the 2nd village (280 km away SSE). The anthropophilic subpopulation had steady activity with 61% of bites occurring before midnight, significantly different from those of the 2 zoophilic subpopulations, which had 78-82% of bites before midnight and 2 biting peaks, one at 1900-2100 h and the other at 0400-0500 h. Isozyme analysis (13 enzymes) of these subpopulations indicated that differences between the 2 sympatric subpopulations (D = 0.07), collected using 2 different methods, were greater than that between the 2 allopatric ones (D = 0.03). These studies suggest the existence of 2 genetically different subpopulations of An. vestitipennis with specific host preferences.

Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart

PubMed Central

Croston, Tara L.; Thapa, Dharendra; Holden, Anthony A.; Tveter, Kevin J.; Lewis, Sara E.; Shepherd, Danielle L.; Nichols, Cody E.; Long, Dustin M.; Olfert, I. Mark; Jagannathan, Rajaganapathi

2014-01-01

The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with a concomitant decline in their levels (P ≤ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels. PMID:24778174

Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.

PubMed

Haass, Nikolas K; Gabrielli, Brian

2017-07-01

The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep.

PubMed

Cheng, Guanliang; Coolen, Lique M; Padmanabhan, Vasantha; Goodman, Robert L; Lehman, Michael N

2010-01-01

Recent work in sheep has identified a neuronal subpopulation in the arcuate nucleus that coexpresses kisspeptin, neurokinin B, and dynorphin (referred to here as KNDy cells) and that mediate the negative feedback influence of progesterone on GnRH secretion. We hypothesized that sex differences in progesterone negative feedback are due to sexual dimorphism of KNDy cells and compared neuropeptide and progesterone receptor immunoreactivity in this subpopulation between male and female sheep. In addition, because sex differences in progesterone negative feedback and neurokinin B are due to the influence of testosterone (T) during fetal life, we determined whether prenatal T exposure would mimic sex differences in KNDy cells. Adult rams had nearly half the number of kisspeptin, neurokinin B, dynorphin, and progesterone receptor-positive cells in the arcuate nucleus as did females, but the percentage of KNDy cells colocalizing progesterone receptors remained high in both sexes. Prenatal T treatment also reduced the number of dynorphin, neurokinin B, and progesterone receptor-positive cells in the female arcuate nucleus; however, the number of kisspeptin cells remained high and at levels comparable to control females. Thus, sex differences in kisspeptin in the arcuate nucleus, unlike that of dynorphin and neurokinin B, are not due solely to exposure to prenatal T, suggesting the existence of different critical periods for multiple peptides coexpressed within the same neuron. In addition, the imbalance between inhibitory (dynorphin) and stimulatory (kisspeptin) neuropeptides in this subpopulation provides a potential explanation for the decreased ability of progesterone to inhibit GnRH neurons in prenatal T-treated ewes.

Midbrain dopamine neurons reflect affiliation phenotypes in finches and are tightly coupled to courtship.

PubMed

Goodson, James L; Kabelik, David; Kelly, Aubrey M; Rinaldi, Jacob; Klatt, James D

2009-05-26

Mesolimbic dopamine (DA) circuits mediate a wide range of goal-oriented behavioral processes, and DA strongly influences appetitive and consummatory aspects of male sexual behavior. In both birds and mammals, mesolimbic projections arise primarily from the ventral tegmental area (VTA), with a smaller contribution from the midbrain central gray (CG). Despite the well known importance of the VTA cell group for incentive motivation functions, relationships of VTA subpopulations to specific aspects of social phenotype remain wholly undescribed. We now show that in male zebra finches (Estrildidae: Taeniopygia guttata), Fos activity within a subpopulation of tyrosine hydroxylase-immunoreactive (TH-ir; presumably dopaminergic) neurons in the caudal VTA is significantly correlated with courtship singing and coupled to gonadal state. In addition, the number of TH-ir neurons in this caudal subpopulation dichotomously differentiates courting from non-courting male phenotypes, and evolves in relation to sociality (flocking vs. territorial) across several related finch species. Combined, these findings for the VTA suggest that divergent social phenotypes may arise due to the differential assignment of "incentive value" to conspecific stimuli. TH-ir neurons of the CG (a population of unknown function in mammals) exhibit properties that are even more selectively and tightly coupled to the expression of courtship phenotypes (and appetitive courtship singing), both in terms of TH-ir cell number, which correlates significantly with constitutive levels of courtship motivation, and with TH-Fos colocalization, which increases in direct proportion to the phasic expression of song. We propose that these neurons may be core components of social communication circuits across diverse vertebrate taxa.

Differences in Spontaneously Avoiding or Approaching Mice Reflect Differences in CB1-Mediated Signaling of Dorsal Striatal Transmission

PubMed Central

Laricchiuta, Daniela; Rossi, Silvia; Musella, Alessandra; De Chiara, Valentina; Cutuli, Debora; Centonze, Diego; Petrosini, Laura

2012-01-01

Approach or avoidance behaviors are accompanied by perceptual vigilance for, affective reactivity to and behavioral predisposition towards rewarding or punitive stimuli, respectively. We detected three subpopulations of C57BL/6J mice that responded with avoiding, balancing or approaching behaviors not induced by any experimental manipulation but spontaneously displayed in an approach/avoidance conflict task. Although the detailed neuronal mechanisms underlying the balancing between approach and avoidance are not fully clarified, there is growing evidence that endocannabinoid system (ECS) plays a critical role in the control of these balancing actions. The sensitivity of dorsal striatal synapses to the activation of cannabinoid CB1 receptors was investigated in the subpopulations of spontaneously avoiding, balancing or approaching mice. Avoiding animals displayed decreased control of CB1 receptors on GABAergic striatal transmission and in parallel increase of behavioral inhibition. Conversely, approaching animals exhibited increased control of CB1 receptors and in parallel increase of explorative behavior. Balancing animals reacted with balanced responses between approach and avoidance patterns. Treating avoiding animals with URB597 (fatty acid amide hydrolase inhibitor) or approaching animals with AM251 (CB1 receptor inverse agonist) reverted their respective behavioral and electrophysiological patterns. Therefore, enhanced or reduced CB1-mediated control on dorsal striatal transmission represents the synaptic hallmark of the approach or avoidance behavior, respectively. Thus, the opposite spontaneous responses to conflicting stimuli are modulated by a different involvement of endocannabinoid signaling of dorsal striatal neurons in the range of temperamental traits related to individual differences. PMID:22413007

Identification of cells initiating human melanomas.

PubMed

Schatton, Tobias; Murphy, George F; Frank, Natasha Y; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M; Weishaupt, Carsten; Fuhlbrigge, Robert C; Kupper, Thomas S; Sayegh, Mohamed H; Frank, Markus H

2008-01-17

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.

Interaction of microbial agents with the immune system during infectious disease.

PubMed

Frøland, S S

1984-01-01

Research during the last years has revealed a considerable complexity of the immune system. It is clear that immunological reactions depend on extensive and only partly clarified interactions between a number of different cell types (e.g. B lymphocytes, plasma cells, T cell subpopulations, cytotoxic K and NK cells, monocytic cells, neutrophilic and eosinophilic granulocytes) and their molecular products (e.g. immunoglobulins, lymphokines and interleukins). These components further interact with the complement system, as well as with immunologically nonspecific components like acute phase proteins (e.g. C-reactive protein) and with other pathophysiological phenomena occurring during infections, e.g. the fever response. The application of these observations from basic and experimental immunology to the investigation of antimicrobial immune reactions is still only in its beginning, but has already resulted in new concepts of clinical value for the understanding of infectious diseases. The present paper briefly describes certain aspects of the immune response to infections with various microbial agents, with particular emphasis on reactions of clinical importance. In addition to B and T cell reactions, possible antimicrobial functions of K cells and NK cells are discussed, and the possible importance in infectious disease of various T cell subpopulations, particularly T suppressor cells, is discussed. Lastly, various escape mechanisms are mentioned whereby certain microbial agents may evade elimination by the immune response of the host.

Macroenvironment effects on oocytes and embryos in swine.

PubMed

Foxcroft, G R; Vinsky, M D; Paradis, F; Tse, W-Y; Town, S C; Putman, C T; Dyck, M K; Dixon, W T

2007-09-01

As in other domestic mammals, the interaction between genotype and environment in swine has profound effects on the ultimate phenotype of the individual born. Interactions within the litter in utero add an additional level of complexity in a litter-bearing species like the pig. Nutritional manipulations during the preovulatory period affect the maturity of the follicle and enclosed oocyte, and the metabolic and endocrine mechanisms potentially mediating these effects have been described. Extensive research on lactational catabolism in the first parity sow has established an association between the development of immature follicles and oocytes, and the reduced fertility of these sows when bred at the first postweaning estrus. This negative impact of lactational catabolism appears to be exaggerated in contemporary dam-lines by a minimal delay between weaning and first estrus, further limiting the maturity of the follicle and oocyte at the time of ovulation. Metabolic programming may induce gender-specific loss of embryos by Day 30 and affects embryonic development directly, without significant effects on placental size. In contrast, inadvertent crowding of embryos in utero, particularly evident in a sub-population of mature sows with high ovulation rates and moderate to high embryonic survival to Day 30, significantly limits placental development of crowded litters. However, even at Day 30, moderate crowding in utero also appears to affect myogenesis in the embryo in a gender-specific manner. In the absence of compensatory placental growth after Day 30, classic measures of IUGR are evident in surviving fetuses at Day 90 and at term.

Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells.

PubMed

Cencioni, Chiara; Spallotta, Francesco; Savoia, Matteo; Kuenne, Carsten; Guenther, Stefan; Re, Agnese; Wingert, Susanne; Rehage, Maike; Sürün, Duran; Siragusa, Mauro; Smith, Jacob G; Schnütgen, Frank; von Melchner, Harald; Rieger, Michael A; Martelli, Fabio; Riccio, Antonella; Fleming, Ingrid; Braun, Thomas; Zeiher, Andreas M; Farsetti, Antonella; Gaetano, Carlo

2018-03-29

Nitric oxide (NO) synthesis is a late event during differentiation of mouse embryonic stem cells (mESC) and occurs after release from serum and leukemia inhibitory factor (LIF). Here we show that after release from pluripotency, a subpopulation of mESC, kept in the naive state by 2i/LIF, expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes NO. This eNOS/NO-positive subpopulation (ESNO+) expresses mesendodermal markers and is more efficient in the generation of cardiovascular precursors than eNOS/NO-negative cells. Mechanistically, production of endogenous NO triggers rapid Hdac2 S-nitrosylation, which reduces association of Hdac2 with the transcriptional repression factor Zeb1, allowing mesendodermal gene expression. In conclusion, our results suggest that the interaction between Zeb1, Hdac2, and eNOS is required for early mesendodermal differentiation of naive mESC.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ayeb, M.E.; Bahraoui, E.M.; Granier, C.

Two antibody subpopulations directed against Anemonia sulcata toxin I or II have been purified by immunoaffinity chromatography. These antibodies are specific for a single antigenic region and were used in a structure-antigenicity relationship study using homologous toxins and chemically modified derivatives of A. sulcata toxin II. Asp-7 and/or Asp=9 and Gln-47 of toxin II were found to be implicated in the antigenic region recognized by the two antibody subpopulations. On the contrary, Arg-14, Lys-35, -36, and -46, and ..cap alpha..-NH/sub 2/ of the glycine residue of A. sulcata toxin II are not involved in the corresponding antigenic region. When assayedmore » for interaction with the sodium channel, the antigenic region of toxin II, including Asp-9 and Gln-47, appeared fully accessible to its specific antibodies, suggesting that it is not involved in the binding of the toxin to its receptor.« less

Genetic differentiation of sockeye salmon subpopulations from a geologically young Alaskan lake system

USGS Publications Warehouse

Burger, C.V.; Spearman, William J.; Cronin, M.A.

1997-01-01

The Tustumena lake drainage in southcentral Alaska is glacially turbid and geologically young (<2,000 years old). Previous field studies identified at least three subpopulations of sockeye salmon Oncorhynchus nerka at Tustumena Lake, based on the distribution and timing of spawners. The subpopulations included early-run salmon that spawned in six clearwater tributaries of the lake (mid August), lake shoreline spawners (late August), and late-run fish that spawned in the lake's outlet, the Kasilof River (late September). Our objective was to determine the degree of genetic differentiation among these subpopulations based on restriction enzyme analyses of the cytochrome b gene of mitochondrial DNA and analyses of four polymorphic allozyme loci. Mitochondrial DNA haplotype frequencies for outlet-spawning sockeye salmon differed significantly from those of all other subpopulations. The most common (36%) haplotype in the outlet subpopulation did not occur elsewhere, thus suggesting little or no gene flow between outlet spawners and other spatially close subpopulations at Tustumena Lake. Allele frequencies at two allozyme loci also indicated a degree of differentiation of the outlet subpopulation from the shoreline and tributary subpopulations. Allele frequencies for three tributary subpopulations were temporally stable over approximately 20 years (based on a comparison to previously published results) despite initiation of a hatchery program in two of the tributaries during the intervening period. Collectively, our results are consistent with the hypothesis that significant genetic differentiation has occurred within the Tustumena Lake drainage since deglaciation approximately 2,000 years ago.

The cochaperone BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1.

PubMed

Kathage, Barbara; Gehlert, Sebastian; Ulbricht, Anna; Lüdecke, Laura; Tapia, Victor E; Orfanos, Zacharias; Wenzel, Daniela; Bloch, Wilhelm; Volkmer, Rudolf; Fleischmann, Bernd K; Fürst, Dieter O; Höhfeld, Jörg

2017-01-01

The cochaperone BAG3 is a central protein homeostasis factor in mechanically strained mammalian cells. It mediates the degradation of unfolded and damaged forms of the actin-crosslinker filamin through chaperone-assisted selective autophagy (CASA). In addition, BAG3 stimulates filamin transcription in order to compensate autophagic disposal and to maintain the actin cytoskeleton under strain. Here we demonstrate that BAG3 coordinates protein synthesis and autophagy through spatial regulation of the mammalian target of rapamycin complex 1 (mTORC1). The cochaperone utilizes its WW domain to contact a proline-rich motif in the tuberous sclerosis protein TSC1 that functions as an mTORC1 inhibitor in association with TSC2. Interaction with BAG3 results in a recruitment of TSC complexes to actin stress fibers, where the complexes act on a subpopulation of mTOR-positive vesicles associated with the cytoskeleton. Local inhibition of mTORC1 is essential to initiate autophagy at sites of filamin unfolding and damage. At the same time, BAG3-mediated sequestration of TSC1/TSC2 relieves mTORC1 inhibition in the remaining cytoplasm, which stimulates protein translation. In human muscle, an exercise-induced association of TSC1 with the cytoskeleton coincides with mTORC1 activation in the cytoplasm. The spatial regulation of mTORC1 exerted by BAG3 apparently provides the basis for a simultaneous induction of autophagy and protein synthesis to maintain the proteome under mechanical strain. Copyright © 2016 Elsevier B.V. All rights reserved.

Insight into the Peopling of Mainland Southeast Asia from Thai Population Genetic Structure

PubMed Central

Chaichoompu, Kridsadakorn; Ngamphiw, Chumpol; Assawamakin, Anunchai; Nuinoon, Manit; Sripichai, Orapan; Svasti, Saovaros; Fucharoen, Suthat; Praphanphoj, Verayuth; Tongsima, Sissades

2013-01-01

There is considerable ethno-linguistic and genetic variation among human populations in Asia, although tracing the origins of this diversity is complicated by migration events. Thailand is at the center of Mainland Southeast Asia (MSEA), a region within Asia that has not been extensively studied. Genetic substructure may exist in the Thai population, since waves of migration from southern China throughout its recent history may have contributed to substantial gene flow. Autosomal SNP data were collated for 438,503 markers from 992 Thai individuals. Using the available self-reported regional origin, four Thai subpopulations genetically distinct from each other and from other Asian populations were resolved by Neighbor-Joining analysis using a 41,569 marker subset. Using an independent Principal Components-based unsupervised clustering approach, four major MSEA subpopulations were resolved in which regional bias was apparent. A major ancestry component was common to these MSEA subpopulations and distinguishes them from other Asian subpopulations. On the other hand, these MSEA subpopulations were admixed with other ancestries, in particular one shared with Chinese. Subpopulation clustering using only Thai individuals and the complete marker set resolved four subpopulations, which are distributed differently across Thailand. A Sino-Thai subpopulation was concentrated in the Central region of Thailand, although this constituted a minority in an otherwise diverse region. Among the most highly differentiated markers which distinguish the Thai subpopulations, several map to regions known to affect phenotypic traits such as skin pigmentation and susceptibility to common diseases. The subpopulation patterns elucidated have important implications for evolutionary and medical genetics. The subpopulation structure within Thailand may reflect the contributions of different migrants throughout the history of MSEA. The information will also be important for genetic association studies to account for population-structure confounding effects. PMID:24223962

Identification of sperm subpopulations with defined motility characteristics in ejaculates from Ile de France rams.

PubMed

Bravo, J A; Montanero, J; Calero, R; Roy, T J

2011-11-01

The aims of this study were to identify different motile sperm subpopulations in fresh ejaculates from six Ile de France rams, by using a computer-assisted sperm motility analysis (CASA) system, and to evaluate the effects of individual ram and season on population distribution. Overall sperm motility and individual kinematic parameters of motile spermatozoa were evaluated for 125,312 spermatozoa, defined by curvilinear velocity (VCL), linear velocity (VSL), average path velocity (VAP), linearity coefficient (LIN), straightness coefficient (STR), wobble coefficient (WOB), mean amplitude of lateral head displacement (ALH) and frequency of head displacement (BCF). A multivariate cluster analysis was carried out to classify these spermatozoa into a reduced number of subpopulations according to their movement patterns. The statistical analysis clustered the whole motile sperm population into five separate groups: subpopulation 1, constituted by rapid, progressive and non sinuous spermatozoa (VCL=126.41 μm/s, STR=92.87% and LIN=86.47%); subpopulation 2, characterized by progressive spermatozoa with moderate velocity (VCL=74.74 μm/s and STR=84.03%); subpopulation 3, represented by rapid, progressive and sinuous spermatozoa (VCL=130.45 μm/s, STR=76.02% and LIN=47.68%); subpopulation 4 represents rapid nonprogressive spermatozoa (VCL=128.69 μm/s and STR=44.09%); subpopulation 5 includes poorly motile, nonprogressive spermatozoa with a very irregular trajectory (VCL=36.81 μm/s and STR=47.04%). Our results show the existence of five subpopulations of motile spermatozoa in ram ejaculates. The frequency distribution of spermatozoa within subpopulations was quite similar for the six rams, and the five subpopulations turned out to be very stable along seasons. Copyright © 2011 Elsevier B.V. All rights reserved.

Optimal allocation of conservation effort among subpopulations of a threatened species: how important is patch quality?

PubMed

Chauvenet, Aliénor L M; Baxter, Peter W J; McDonald-Madden, Eve; Possingham, Hugh P

2010-04-01

Money is often a limiting factor in conservation, and attempting to conserve endangered species can be costly. Consequently, a framework for optimizing fiscally constrained conservation decisions for a single species is needed. In this paper we find the optimal budget allocation among isolated subpopulations of a threatened species to minimize local extinction probability. We solve the problem using stochastic dynamic programming, derive a useful and simple alternative guideline for allocating funds, and test its performance using forward simulation. The model considers subpopulations that persist in habitat patches of differing quality, which in our model is reflected in different relationships between money invested and extinction risk. We discover that, in most cases, subpopulations that are less efficient to manage should receive more money than those that are more efficient to manage, due to higher investment needed to reduce extinction risk. Our simple investment guideline performs almost as well as the exact optimal strategy. We illustrate our approach with a case study of the management of the Sumatran tiger, Panthera tigris sumatrae, in Kerinci Seblat National Park (KSNP), Indonesia. We find that different budgets should be allocated to the separate tiger subpopulations in KSNP. The subpopulation that is not at risk of extinction does not require any management investment. Based on the combination of risks of extinction and habitat quality, the optimal allocation for these particular tiger subpopulations is an unusual case: subpopulations that occur in higher-quality habitat (more efficient to manage) should receive more funds than the remaining subpopulation that is in lower-quality habitat. Because the yearly budget allocated to the KSNP for tiger conservation is small, to guarantee the persistence of all the subpopulations that are currently under threat we need to prioritize those that are easier to save. When allocating resources among subpopulations of a threatened species, the combined effects of differences in habitat quality, cost of action, and current subpopulation probability of extinction need to be integrated. We provide a useful guideline for allocating resources among isolated subpopulations of any threatened species.

Connectivity among subpopulations of Louisiana black bears as estimated by a step selection function

USGS Publications Warehouse

Clark, Joseph D.; Jared S. Laufenberg,; Maria Davidson,; Jennifer L. Murrow,

2015-01-01

Habitat fragmentation is a fundamental cause of population decline and increased risk of extinction for many wildlife species; animals with large home ranges and small population sizes are particularly sensitive. The Louisiana black bear (Ursus americanus luteolus) exists only in small, isolated subpopulations as a result of land clearing for agriculture, but the relative potential for inter-subpopulation movement by Louisiana black bears has not been quantified, nor have characteristics of effective travel routes between habitat fragments been identified. We placed and monitored global positioning system (GPS) radio collars on 8 female and 23 male bears located in 4 subpopulations in Louisiana, which included a reintroduced subpopulation located between 2 of the remnant subpopulations. We compared characteristics of sequential radiolocations of bears (i.e., steps) with steps that were possible but not chosen by the bears to develop step selection function models based on conditional logistic regression. The probability of a step being selected by a bear increased as the distance to natural land cover and agriculture at the end of the step decreased and as distance from roads at the end of a step increased. To characterize connectivity among subpopulations, we used the step selection models to create 4,000 hypothetical correlated random walks for each subpopulation representing potential dispersal events to estimate the proportion that intersected adjacent subpopulations (hereafter referred to as successful dispersals). Based on the models, movement paths for males intersected all adjacent subpopulations but paths for females intersected only the most proximate subpopulations. Cross-validation and genetic and independent observation data supported our findings. Our models also revealed that successful dispersals were facilitated by a reintroduced population located between 2 distant subpopulations. Successful dispersals for males were dependent on natural land cover in private ownership. The addition of hypothetical 1,000-m- or 3,000-m-wide corridors between the 4 study areas had minimal effects on connectivity among subpopulations. For females, our model suggested that habitat between subpopulations would probably have to be permanently occupied for demographic rescue to occur. Thus, the establishment of stepping-stone populations, such as the reintroduced population that we studied, may be a more effective conservation measure than long corridors without a population presence in between. 

RT-SHIV subpopulation dynamics in infected macaques during anti-HIV therapy

PubMed Central

2009-01-01

Background To study the dynamics of wild-type and drug-resistant HIV-1 RT variants, we developed a methodology that follows the fates of individual genomes over time within the viral quasispecies. Single genome sequences were obtained from 3 pigtail macaques infected with a recombinant simian immunodeficiency virus containing the RT coding region from HIV-1 (RT-SHIV) and treated with short-course efavirenz monotherapy 13 weeks post-infection followed by daily combination antiretroviral therapy (ART) beginning at week 17. Bioinformatics tools were constructed to trace individual genomes from the beginning of infection to the end of the treatment. Results A well characterized challenge RT-SHIV inoculum was used to infect three monkeys. The RT-SHIV inoculum had 9 variant subpopulations and the dominant subpopulation accounted for 80% of the total genomes. In two of the three monkeys, the inoculated wild-type virus was rapidly replaced by new wild type variants. By week 13, the original dominant subpopulation in the inoculum was replaced by new dominant subpopulations, followed by emergence of variants carrying known NNRTI resistance mutations. However, during ART, virus subpopulations containing resistance mutations did not outgrow the wide-type subpopulations until a minor subpopulation carrying linked drug resistance mutations (K103N/M184I) emerged. We observed that persistent viremia during ART is primarily made up of wild type subpopulations. We also found that subpopulations carrying the V75L mutation, not known to be associated with NNRTI resistance, emerged initially in week 13 in two macaques. Eventually, all subpopulations from these two macaques carried the V75L mutation. Conclusion This study quantitatively describes virus evolution and population dynamics patterns in an animal model. The fact that wild type subpopulations remained as dominant subpopulations during ART treatment suggests that the presence or absence of at least some known drug resistant mutations may not greatly affect virus replication capacity in vivo. Additionally, the emergence and prevalence of V75L indicates that this mutation may provide the virus a selective advantage, perhaps escaping the host immure system surveillance. Our new method to quantitatively analyze viral population dynamics enabled us to observe the relative competitiveness and adaption of different viral variants and provided a valuable tool for studying HIV subpopulation emergence, persistence, and decline during ART. PMID:19889213

Modification of the interleukin-6 response to air pollution by interleukin-6 and fibrinogen polymorphisms.

PubMed

Ljungman, Petter; Bellander, Tom; Schneider, Alexandra; Breitner, Susanne; Forastiere, Francesco; Hampel, Regina; Illig, Thomas; Jacquemin, Bénédicte; Katsouyanni, Klea; von Klot, Stephanie; Koenig, Wolfgang; Lanki, Timo; Nyberg, Fredrik; Pekkanen, Juha; Pistelli, Riccardo; Pitsavos, Christos; Rosenqvist, Mårten; Sunyer, Jordi; Peters, Annette

2009-09-01

Evidence suggests that cardiovascular effects of air pollution are mediated by inflammation and that air pollution can induce genetic expression of the interleukin-6 gene (IL6). We investigated whether IL6 and fibrinogen gene variants can affect plasma IL-6 responses to air pollution in patients with cardiovascular disease. We repeatedly determined plasma IL-6 in 955 myocardial infarction survivors from six European cities (n = 5,539). We conducted city-specific analyses using additive mixed models adjusting for patient characteristics, time trend, and weather to assess the impact of air pollutants on plasma IL-6. We pooled city-specific estimates using meta-analysis methodology. We selected three IL6 single-nucleotide polymorphisms (SNPs) and one SNP each from the fibrinogen alpha-chain gene (FGA) and beta-chain gene (FGB) for gene-environment analyses. We found the most consistent modifications for variants in IL6 rs2069832 and FBG rs1800790 after exposure to carbon monoxide (CO; 24-hr average; p-values for interaction, 0.034 and 0.019, respectively). Nitrogen dioxide effects were consistently modified, but p-values for interaction were larger (0.09 and 0.19, respectively). The strongest effects were seen 6-11 hr after exposure, when, for example, the overall effect of a 2.2% increase in IL-6 per 0.64 mg/m(3) CO was modified to a 10% (95% confidence interval, 4.6-16%) increase in IL-6 (p-value for interaction = 0.002) for minor homozygotes of FGB rs1800790. The effect of gaseous traffic-related air pollution on inflammation may be stronger in genetic subpopulations with ischemic heart disease. This information could offer an opportunity to identify postinfarction patients who would benefit more than others from a cleaner environment and antiinflammatory treatment.

Triatominae-Trypanosoma cruzi/T. rangeli: Vector-parasite interactions.

PubMed

Vallejo, G A; Guhl, F; Schaub, G A

2009-01-01

Of the currently known 140 species in the family Reduviidae, subfamily Triatominae, those which are most important as vectors of the aetiologic agent of Chagas disease, Trypanosoma cruzi, belong to the tribes Triatomini and Rhodniini. The latter not only transmit T. cruzi but also Trypanosoma rangeli, which is considered apathogenic for the mammalian host but can be pathogenic for the vectors. Using different molecular methods, two main lineages of T. cruzi have been classified, T. cruzi I and T. cruzi II. Within T. cruzi II, five subdivisions are recognized, T. cruzi IIa-IIe, according to the variability of the ribosomal subunits 24Salpha rRNA and 18S rRNA. In T. rangeli, differences in the organization of the kinetoplast DNA separate two forms denoted T. rangeli KP1+ and KP1-, although differences in the intergenic mini-exon gene and of the small subunit rRNA (SSU rRNA) suggest four subpopulations denoted T. rangeli A, B, C and D. The interactions of these subpopulations of the trypanosomes with different species and populations of Triatominae determine the epidemiology of the human-infecting trypanosomes in Latin America. Often, specific subpopulations of the trypanosomes are transmitted by specific vectors in a particular geographic area. Studies centered on trypanosome-triatomine interaction may allow identification of co-evolutionary processes, which, in turn, could consolidate hypotheses of the evolution and the distribution of T. cruzi/T. rangeli-vectors in America, and they may help to identify the mechanisms that either facilitate or impede the transmission of the parasites in different vector species. Such mechanisms seem to involve intestinal bacteria, especially the symbionts which are needed by the triatomines to complete nymphal development and to produce eggs. Development of the symbionts is regulated by the vector. T. cruzi and T. rangeli interfere with this system and induce the production of antibacterial substances. Whereas T. cruzi is only subpathogenic for the insect host, T. rangeli strongly affects species of the genus Rhodnius and this pathogenicity seems based on a reduction of the number of symbionts.

Modulation of the proteome of peripheral blood mononuclear cells from HIV-1 infected patients by drugs of abuse

PubMed Central

Reynolds, Jessica L.; Mahajan, Supriya D.; Aalinkeel, Ravikunar; Nair, Bindukumar; Sykes, Donald E.; Agosto-Mujica, Arnadri; Hsiao, Chiu Bin; Schwartz, Stanley A.

2010-01-01

We used proteomic analyses to assess how drug abuse modulates immunologic responses to infections with the human immunodeficiency virus type 1 (HIV-1). Two dimensional (2D) difference gel electrophoresis was utilized to determine changes in the proteome of peripheral blood mononuclear cells (PBMC) isolated from HIV-1 positive donors that occurred after treatment with cocaine or methamphetamine. Both drugs differentially regulated the expression of several functional classes of proteins. We further isolated specific subpopulations of PBMC to determine which subpopulations were selectively affected by treatment with drugs of abuse. Monocytes, B cells and T cells were positively or negatively selected from PBMC isolated from HIV-1 positive donors. Our results demonstrate that cocaine and methamphetamine modulate gene expression primarily in monocytes and T cells, the primary targets of HIV-1 infection. Proteomic data were validated with quantitative, real-time PCR. These studies elucidate the molecular mechanisms underlying the effects of drugs of abuse on HIV-1 infections. Several functionally relevant classes of proteins were identified as potential mediators of HIV-1 pathogenesis and disease progression associated with drug abuse. PMID:19543960

Maternal antibody reactivity to lymphocytes of offspring with autism.

PubMed

Bressler, Joseph P; Gillin, Pam K; O'Driscoll, Cliona; Kiihl, Samara; Solomon, Megan; Zimmerman, Andrew W

2012-11-01

The study examined whether maternal serum antibodies from mothers of autistic children preferentially bind to lymphocytes of their autistic children compared with unaffected siblings. In a previous study, maternal serum antibodies from mothers mediated cytotoxicity with complement to lymphocytes of their autistic children. Here, maternal serum antibody binding was examined by flow cytometry. We compared levels of mothers' serum binding against peripheral blood monocytes of their autistic children vs unaffected siblings. Because the level of binding to peripheral blood monocytes could be low, binding was examined in specific lymphocyte subpopulations. In 19 samples, the mean level of maternal serum immunoglobulin G binding to CD4 and CD8 T cells, B cells, natural killer cells, and macrophages was not significantly different from the mean level of binding to unaffected siblings. The percentages of different subpopulations were not significantly different between autistic children and unaffected siblings, although a trend (P < 0.1) emerged, i.e., autistic children displayed a higher percentage of natural killer cells and a lower percentage of B cells. These findings cast doubt on a direct effect of maternal antibodies, but do not preclude potential intrauterine pathogenic immune mechanisms in autism. Copyright © 2012 Elsevier Inc. All rights reserved.

Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion.

PubMed

Qualls-Creekmore, Emily; Yu, Sangho; Francois, Marie; Hoang, John; Huesing, Clara; Bruce-Keller, Annadora; Burk, David; Berthoud, Hans-Rudolf; Morrison, Christopher D; Münzberg, Heike

2017-06-21

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA GABA neurons that coexpress the neuropeptide galanin (LHA Gal ). These LHA Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA Gal neurons may represent a subpopulation of LHA GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA Gal or LHA GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA Gal or LHA GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA GABA neurons increased overall chow consumption. Additionally, LHA Gal or LHA GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA GABA neurons induced compulsive-like locomotor behavior; while LHA Gal neurons induced locomotor activity without compulsivity. Thus, LHA Gal neurons define a subpopulation of LHA GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified. SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHA GABA neurons is heterogeneous and largely undefined. Here we introduce LHA Gal neurons as a subset of LHA GABA neurons that lack direct innervation of the ventral tegmental area (VTA). LHA Gal neurons are sufficient to drive motivated feeding and locomotor activity similar to LHA GABA neurons, but without inducing compulsive-like behaviors, which we propose to require direct VTA innervation. Our study integrates galanin-expressing LHA neurons into our current understanding of the neuronal circuits and molecular mechanisms of the LHA that contribute to motivated feeding behaviors. Copyright © 2017 the authors 0270-6474/17/376053-13$15.00/0.

Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism

PubMed Central

Adams, Kristin N.; Takaki, Kevin; Connolly, Lynn E.; Wiedenhoft, Heather; Winglee, Kathryn; Humbert, Olivier; Edelstein, Paul H.; Cosma, Christine L.; Ramakrishnan, Lalita

2011-01-01

SUMMARY Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multi-drug tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This newly discovered tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug, or more specific inhibitors, to standard antitubercular therapy may shorten the duration of curative treatment. PMID:21376383

Single-platelet nanomechanics measured by high-throughput cytometry

NASA Astrophysics Data System (ADS)

Myers, David R.; Qiu, Yongzhi; Fay, Meredith E.; Tennenbaum, Michael; Chester, Daniel; Cuadrado, Jonas; Sakurai, Yumiko; Baek, Jong; Tran, Reginald; Ciciliano, Jordan C.; Ahn, Byungwook; Mannino, Robert G.; Bunting, Silvia T.; Bennett, Carolyn; Briones, Michael; Fernandez-Nieves, Alberto; Smith, Michael L.; Brown, Ashley C.; Sulchek, Todd; Lam, Wilbur A.

2017-02-01

Haemostasis occurs at sites of vascular injury, where flowing blood forms a clot, a dynamic and heterogeneous fibrin-based biomaterial. Paramount in the clot's capability to stem haemorrhage are its changing mechanical properties, the major drivers of which are the contractile forces exerted by platelets against the fibrin scaffold. However, how platelets transduce microenvironmental cues to mediate contraction and alter clot mechanics is unknown. This is clinically relevant, as overly softened and stiffened clots are associated with bleeding and thrombotic disorders. Here, we report a high-throughput hydrogel-based platelet-contraction cytometer that quantifies single-platelet contraction forces in different clot microenvironments. We also show that platelets, via the Rho/ROCK pathway, synergistically couple mechanical and biochemical inputs to mediate contraction. Moreover, highly contractile platelet subpopulations present in healthy controls are conspicuously absent in a subset of patients with undiagnosed bleeding disorders, and therefore may function as a clinical diagnostic biophysical biomarker.

Periodic synchronization and chimera in conformist and contrarian oscillators

NASA Astrophysics Data System (ADS)

Hong, Hyunsuk

2014-06-01

We consider a system of phase oscillators that couple with both attractive and repulsive interaction under a pinning force and explore collective behavior of the system. The oscillators can be divided into two subpopulations of "conformist" oscillators with attractive interaction and "contrarian" ones with repulsive interaction. We find that the interplay between the pinning force and the opposite relationship of the conformist and contrarian oscillators induce peculiar dynamic states: periodic synchronization, breathing chimera, and fully pinned state depending on the fraction of the conformists. Using the Watanabe-Strogatz transformation, we reduce the dynamics into a low-dimensional one and find that the above dynamic states are generated from the reduced dynamics.

New Model for Population-Subpopulation Differences

DTIC Science & Technology

2007-02-01

EDGEWOOD CHEMICAL BIOLOGICAL CENTER U.S. ARMY RESEARCH, DEVELOPMENT AND ENGINEERING COMMAND ECBC-TR-534 NEW MODEL FOR POPULATION-SUBPOPULATION...DATES COVERED (From - To) XX-02-2007 Final Nov 2005 - Nov 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER New Model for Population-Subpopulation...susceptibilities for both the general population and the military subpopulation were modeled by a lognormal distribution. The assumption of a lognormal distribution

Radiation Response of Cancer Stem-Like Cells From Established Human Cell Lines After Sorting for Surface Markers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Assar, Osama; Muschel, Ruth J.; Mantoni, Tine S.

2009-11-15

Purpose: A subpopulation of cancer stem-like cells (CSLC) is hypothesized to exist in different cancer cell lines and to mediate radioresistance in solid tumors. Methods and Materials: Cells were stained for CSLC markers and sorted (fluorescence-activated cell sorter/magnetic beads) to compare foci and radiosensitivity of phosphorylated histone H2AX at Ser 139 (gamma-H2AX) in sorted vs. unsorted populations in eight cell lines from different organs. CSLC properties were examined using anchorage-independent growth and levels of activated Notch1. Validation consisted of testing tumorigenicity and postirradiation enrichment of CSLC in xenograft tumors. Results: The quantity of CSLC was generally in good agreement withmore » primary tumors. CSLC from MDA-MB-231 (breast) and Panc-1 and PSN-1 (both pancreatic) cells had fewer residual gamma-H2AX foci than unsorted cells, pointing to radioresistance of CSLC. However, only MDA-MB-231 CSLC were more radioresistant than unsorted cells. Furthermore, MDA-MB-231 CSLC showed enhanced anchorage-independent growth and overexpression of activated Notch1 protein. The expression of cancer stem cell surface markers in the MDA-MB-231 xenograft model was increased after exposure to fractionated radiation. In contrast to PSN-1 cells, a growth advantage for MDA-MB-231 CSLC xenograft tumors was found compared to tumors arising from unsorted cells. Conclusions: CSLC subpopulations showed no general radioresistant phenotype, despite the quantities of CSLC subpopulations shown to correspond relatively well in other reports. Likewise, CSLC characteristics were found in some but not all of the tested cell lines. The reported problems in testing for CSLC in cell lines may be overcome by additional techniques, beyond sorting for markers.« less

Connexin36 Expression in Primary Afferent Neurons in Relation to the Axon Reflex and Modality Coding of Somatic Sensation.

PubMed

Nagy, J I; Lynn, B D; Senecal, J M M; Stecina, K

2018-05-07

Electrical coupling mediated by connexin36-containing gap junctions that form electrical synapses is known to be prevalent in the central nervous system, but such coupling was long ago reported also to occur between cutaneous sensory fibers. Here, we provide evidence supporting the capability of primary afferent fibers to engage in electrical coupling. In transgenic mice with enhanced green fluorescent protein (eGFP) serving as a reporter for connexin36 expression, immunofluorescence labeling of eGFP was found in subpopulations of neurons in lumbar dorsal root and trigeminal sensory ganglia, and in fibers within peripheral nerves and tissues. Immunolabeling of connexin36 was robust in the sciatic nerve, weaker in sensory ganglia than in peripheral nerve, and absent in these tissues from Cx36 null mice. Connexin36 mRNA was detected in ganglia from wild-type mice, but not in those from Cx36 null mice. Labeling of eGFP was localized within a subpopulation of ganglion cells containing substance P and calcitonin gene-releasing peptide, and in peripheral fibers containing these peptides. Expression of eGFP was also found in various proportions of sensory ganglion neurons containing transient receptor potential (TRP) channels, including TRPV1 and TRPM8. Ganglion cells labeled for isolectin B4 and tyrosine hydroxylase displayed very little co-localization with eGFP. Our results suggest that previously observed electrical coupling between peripheral sensory fibers occurs via electrical synapses formed by Cx36-containing gap junctions, and that some degree of selectivity in the extent of electrical coupling may occur between fibers belonging to subpopulations of sensory neurons identified according to their sensory modality responsiveness. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Daily Sampling of an HIV-1 Patient with Slowly Progressing Disease Displays Persistence of Multiple env Subpopulations Consistent with Neutrality

PubMed Central

Wilbe Ramsay, Karin; Alaeus, Annette; Albert, Jan; Leitner, Thomas

2011-01-01

The molecular evolution of HIV-1 is characterized by frequent substitutions, indels and recombination events. In addition, a HIV-1 population may adapt through frequency changes of its variants. To reveal such population dynamics we analyzed HIV-1 subpopulation frequencies in an untreated patient with stable, low plasma HIV-1 RNA levels and close to normal CD4+ T-cell levels. The patient was intensively sampled during a 32-day period as well as approximately 1.5 years before and after this period (days −664, 1, 2, 3, 11, 18, 25, 32 and 522). 77 sequences of HIV-1 env (approximately 3100 nucleotides) were obtained from plasma by limiting dilution with 7–11 sequences per time point, except day −664. Phylogenetic analysis using maximum likelihood methods showed that the sequences clustered in six distinct subpopulations. We devised a method that took into account the relatively coarse sampling of the population. Data from days 1 through 32 were consistent with constant within-patient subpopulation frequencies. However, over longer time periods, i.e. between days 1…32 and 522, there were significant changes in subpopulation frequencies, which were consistent with evolutionarily neutral fluctuations. We found no clear signal of natural selection within the subpopulations over the study period, but positive selection was evident on the long branches that connected the subpopulations, which corresponds to >3 years as the subpopulations already were established when we started the study. Thus, selective forces may have been involved when the subpopulations were established. Genetic drift within subpopulations caused by de novo substitutions could be resolved after approximately one month. Overall, we conclude that subpopulation frequencies within this patient changed significantly over a time period of 1.5 years, but that this does not imply directional or balancing selection. We show that the short-term evolution we study here is likely representative for many patients of slow and normal disease progression. PMID:21829600

Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways.

PubMed

Haverkamp, Jessica M; Smith, Amber M; Weinlich, Ricardo; Dillon, Christopher P; Qualls, Joseph E; Neale, Geoffrey; Koss, Brian; Kim, Young; Bronte, Vincenzo; Herold, Marco J; Green, Douglas R; Opferman, Joseph T; Murray, Peter J

2014-12-18

Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Integration of genetic and demographic data to assess population risk in a continuously distributed species

USGS Publications Warehouse

Fedy, Bradley C.; Row, Jeffery R.; Oyler-McCance, Sara J.

2017-01-01

The identification and demographic assessment of biologically meaningful populations is fundamental to species’ ecology and management. Although genetic tools are used frequently to identify populations, studies often do not incorporate demographic data to understand their respective population trends. We used genetic data to define subpopulations in a continuously distributed species. We assessed demographic independence and variation in population trends across the distribution. Additionally, we identified potential barriers to gene flow among subpopulations. We sampled greater sage-grouse (Centrocercus urophasianus) leks from across their range (≈175,000 Km2) in Wyoming and amplified DNA at 14 microsatellite loci for 1761 samples. Subsequently, we assessed population structure in unrelated individuals (n = 872) by integrating results from multiple Bayesian clustering approaches and used the boundaries to inform our assessment of long-term population trends and lek activity over the period of 1995–2013. We identified four genetic clusters of which two northern ones showed demographic independence from the others. Trends in population size for the northwest subpopulation were statistically different from the other three genetic clusters and the northeast and southwest subpopulations demonstrated a general trend of increasing proportion of inactive leks over time. Population change from 1996 to 2012 suggested population growth in the southern subpopulations and decline, or neutral, change in the northern subpopulations. We suggest that sage-grouse subpopulations in northern Wyoming are at greater risk of extirpation than the southern subpopulations due to smaller census and effective population sizes and higher variability within subpopulations. Our research is an example of incorporating genetic and demographic data and provides guidance on the identification of subpopulations of conservation concern.

Development of a pan-Arctic monitoring plan for polar bears: Background paper

USGS Publications Warehouse

Vongraven, Dag; Peacock, Lily

2011-01-01

Polar bears (Ursus maritimus), by their very nature, and the extreme, remote environment in which they live, are inherently difficult to study and monitor. Monitoring polar bear populations is both arduous and costly and, to be effective, must be a long-term commitment. There are few jurisdictional governments and management boards with a mandate for polar bear research and management, and many have limited resources. Although population monitoring of polar bears has been a focus to some degree within most jurisdictions around the Arctic, of the 19 subpopulations recognised by the IUCN/Species Survival Commission Polar Bear Specialist Group (PBSG), adequate scientific trend data exist for only three of the subpopulations, fair trend data for five and poor or no trend data for the remaining 11 subpopulations (PBSG 2010a). There are especially critical knowledge gaps for the subpopulations in East Greenland, in the Russian Kara and Laptev seas, and in the Chukchi Sea, which is shared between Russia and the United States. The range covered by these subpopulations represents a third of the total area (approx. 23 million km2) of polar bears’ current range, and more than half if the Arctic Basin is included. If we use popular terms, we know close to nothing about polar bears in this portion of their range.As summer sea-ice extent, and to a lesser degree, spring-time extent, continues to retreat, outpacing model forecasts (Stroeve et al. 2007, Pedersen et al. 2009), polar bears face the challenge of adapting to rapidly changing habitats. There is a need to use current and synthesised information across the Arctic, and to develop new methods that will facilitate monitoring to generate new knowledge at a pan-Arctic scale. The circumpolar dimension can be lost when efforts are channelled into regional monitoring. Developing and implementing a plan that harmonises local, regional and global efforts will increase our power to detect and understand important trends for polar bears, with particular emphasis on how climate warming may differentially affect populations and habitats. Current knowledge is inadequate for a comprehensive understanding of the present and future impact of climate warming and its interaction with other stressors. The cumulative effects are unknown (Laidre et al. 2008). An integrated pan-Arctic research and monitoring plan will improve the ability to detect future trends, identify the most vulnerable subpopulations and guide effective conservation. There is a need to direct attention and resources where data are deficient to understand the mechanisms that drive trends, and to facilitate more effective and timely conservation response.

Emotional contagion and proto-organizing in human interaction dynamics

PubMed Central

Hazy, James K.; Boyatzis, Richard E.

2015-01-01

This paper combines the complexity notions of phase transitions and tipping points with recent advances in cognitive neuroscience to propose a general theory of human proto-organizing. It takes as a premise that a necessary prerequisite for organizing, or “proto-organizing,” occurs through emotional contagion in subpopulations of human interaction dynamics in complex ecosystems. Emotional contagion is posited to engender emotional understanding and identification with others, a social process that acts as a mechanism that enables (or precludes) cooperative responses to opportunities and risks. Propositions are offered and further research is suggested. PMID:26124736

Tumorigenesis: it takes a village.

PubMed

Tabassum, Doris P; Polyak, Kornelia

2015-08-01

Although it is widely accepted that most cancers exhibit some degree of intratumour heterogeneity, we are far from understanding the dynamics that operate among subpopulations within tumours. There is growing evidence that cancer cells behave as communities, and increasing attention is now being directed towards the cooperative behaviour of subclones that can influence disease progression. As expected, these interactions can add a greater layer of complexity to therapeutic interventions in heterogeneous tumours, often leading to a poor prognosis. In this Review, we highlight studies that demonstrate such interactions in cancer and postulate ways to overcome them with better-designed therapeutic strategies.

Evaluating water management scenarios to support habitat management for the Cape Sable seaside sparrow

USGS Publications Warehouse

Beerens, James M.; Romañach, Stephanie S.; McKelvy, Mark

2016-06-22

The endangered Cape Sable seaside sparrow (Ammodramus maritimus mirabilis) is endemic to south Florida and a key indicator species of marl prairie, a highly diverse freshwater community in the Florida Everglades. Maintenance and creation of suitable habitat is seen as the most important pathway to the persistence of the six existing sparrow subpopulations; however, major uncertainties remain in how to increase suitable habitat within and surrounding these subpopulations, which are vulnerable to environmental stochasticity. Currently, consistently suitable conditions for the Cape Sable seaside sparrow are only present in two of these subpopulations (B and E). The water management scenarios evaluated herein were intended to lower water levels and improve habitat conditions in subpopulation A and D, raise water levels to improve habitat conditions in subpopulations C and F, and minimize impacts to subpopulations B and E. Our objective in this analysis was to compare these scenarios utilizing a set of metrics (short- to long-time scales) that relate habitat suitability to hydrologic conditions. Although hydrologic outputs are similar across scenarios in subpopulation A, scenario R2H reaches the hydroperiod and depth suitability targets more than the other scenarios relative to ECB, while minimizing negative consequences to subpopulation E. However, although R2H hydroperiods are longer than those for ECB during the wet season in subpopulations C and F, depths during the breeding season are predicted to decrease in suitability (less than -50 cm) relative to existing conditions.

Morphometric and kinematic sperm subpopulations in split ejaculates of normozoospermic men

PubMed Central

Santolaria, Pilar; Soler, Carles; Recreo, Pilar; Carretero, Teresa; Bono, Araceli; Berné, José M; Yániz, Jesús L

2016-01-01

This study was designed to analyze the sperm kinematic and morphometric subpopulations in the different fractions of the ejaculate in normozoospermic men. Ejaculates from eight normozoospermic men were collected by masturbation in three fractions after 3–5 days of sexual abstinence. Analyses of sperm motility by computer-assisted sperm analysis (CASA-Mot), and of sperm morphometry by computer-assisted sperm morphometry analysis (CASA-Morph) using fluorescence were performed. Clustering and discriminant procedures were performed to identify sperm subpopulations in the kinematic and morphometric data obtained. Clustering procedures resulted in the classification of spermatozoa into three kinematic subpopulations (slow with low ALH [35.6% of all motile spermatozoa], with circular trajectories [32.0%], and rapid with high ALH [32.4%]), and three morphometric subpopulations (large-round [33.9% of all spermatozoa], elongated [32.0%], and small [34.10%]). The distribution of kinematic sperm subpopulations was different among ejaculate fractions (P < 0.001), with higher percentages of spermatozoa exhibiting slow movements with low ALH in the second and third portions, and with a more homogeneous distribution of kinematic sperm subpopulations in the first portion. The distribution of morphometric sperm subpopulations was also different among ejaculate fractions (P < 0.001), with more elongated spermatozoa in the first, and of small spermatozoa in the third, portion. It is concluded that important variations in the distribution of kinematic and morphometric sperm subpopulations exist between ejaculate fractions, with possible functional implications. PMID:27624985

Iron triggers λSo prophage induction and release of extracellular DNA in Shewanella oneidensis MR-1 biofilms.

PubMed

Binnenkade, Lucas; Teichmann, Laura; Thormann, Kai M

2014-09-01

Prophages are ubiquitous elements within bacterial chromosomes and affect host physiology and ecology in multiple ways. We have previously demonstrated that phage-induced lysis is required for extracellular DNA (eDNA) release and normal biofilm formation in Shewanella oneidensis MR-1. Here, we investigated the regulatory mechanisms of prophage λSo spatiotemporal induction in biofilms. To this end, we used a functional fluorescence fusion to monitor λSo activation in various mutant backgrounds and in response to different physiological conditions. λSo induction occurred mainly in a subpopulation of filamentous cells in a strictly RecA-dependent manner, implicating oxidative stress-induced DNA damage as the major trigger. Accordingly, mutants affected in the oxidative stress response (ΔoxyR) or iron homeostasis (Δfur) displayed drastically increased levels of phage induction and abnormal biofilm formation, while planktonic cells were not or only marginally affected. To further investigate the role of oxidative stress, we performed a mutant screen and identified two independent amino acid substitutions in OxyR (T104N and L197P) that suppress induction of λSo by hydrogen peroxide (H2O2). However, λSo induction was not suppressed in biofilms formed by both mutants, suggesting a minor role of intracellular H2O2 in this process. In contrast, addition of iron to biofilms strongly enhanced λSo induction and eDNA release, while both processes were significantly suppressed at low iron levels, strongly indicating that iron is the limiting factor. We conclude that uptake of iron during biofilm formation triggers λSo-mediated lysis of a subpopulation of cells, likely by an increase in iron-mediated DNA damage sensed by RecA. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Identification of cells initiating human melanomas

PubMed Central

Schatton, Tobias; Murphy, George F.; Frank, Natasha Y.; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M.; Weishaupt, Carsten; Fuhlbrigge, Robert C.; Kupper, Thomas S.; Sayegh, Mohamed H.; Frank, Markus H.

2012-01-01

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3–6. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5− bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ sub-populations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5− progeny, whereas ABCB5− tumour populations give rise, at lower rates, exclusively to ABCB5− cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy. PMID:18202660

Rapid Induction of High-Level Carbapenem Resistance in Heteroresistant KPC-Producing Klebsiella pneumoniae

PubMed Central

Adams-Sapper, Sheila; Nolen, Shantell; Donzelli, Grace Fox; Lal, Mallika; Chen, Kunihiko; Justo da Silva, Livia Helena; Moreira, Beatriz M.

2015-01-01

Enterobacteriaceae strains producing the Klebsiella pneumoniae carbapenemase (KPC) have disseminated worldwide, causing an urgent threat to public health. KPC-producing strains often exhibit low-level carbapenem resistance, which may be missed by automated clinical detection systems. In this study, eight Klebsiella pneumoniae strains with heterogeneous resistance to imipenem were used to elucidate the factors leading from imipenem susceptibility to high-level resistance as defined by clinical laboratory testing standards. Time-kill analysis with an inoculum as low as 3 × 106 CFU/ml and concentrations of imipenem 8- and 16-fold higher than the MIC resulted in the initial killing of 99.9% of the population. However, full recovery of the population occurred by 20 h of incubation in the same drug concentrations. Population profiles showed that recovery was mediated by a heteroresistant subpopulation at a frequency of 2 × 10−7 to 3 × 10−6. Samples selected 2 h after exposure to imipenem were as susceptible as the unexposed parental strain and produced the major outer membrane porin OmpK36. However, between 4 to 8 h after exposure, OmpK36 became absent, and the imipenem MIC increased at least 32-fold. Individual colonies isolated from cultures after 20 h of exposure revealed both susceptible and resistant subpopulations. Once induced, however, the high-level imipenem resistance was maintained, and OmpK36 remained unexpressed even without continued carbapenem exposure. This study demonstrates the essential coordination between blaKPC and ompK36 expression mediating high-level imipenem resistance from a population of bacteria that initially exhibits a carbapenem-susceptibility phenotype. PMID:25801565

Liquid-phase electron microscopy of molecular drug response in breast cancer cells reveals irresponsive cell subpopulations related to lack of HER2 homodimers.

PubMed

Peckys, Diana B; Korf, Ulrike; Wiemann, Stefan; de Jonge, Niels

2017-08-09

The development of drug resistance in cancer poses a major clinical problem. An example is human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer often treated with anti-HER2 antibody therapies, such as trastuzumab. Since drug resistance is rooted mainly in tumor cell heterogeneity, we examined the drug effect in different subpopulations of SKBR3 breast cancer cells, and compared the results with a drug resistant cell line, HCC1954. Correlative light microscopy and liquid-phase scanning transmission electron microscopy (STEM) were used to quantitatively analyze HER2 responses upon drug binding, whereby many tens of whole cells were imaged. Trastuzumab was found to selectively cross-link and down regulate HER2 homodimers from the plasma membranes of bulk cancer cells. In contrast, HER2 resided mainly as monomers in rare subpopulations of resting- and cancer stem cells (CSCs), and these monomers were not internalized after drug binding. The HER2 distribution was hardly influenced by trastuzumab for the HCC1954 cells. These findings show that resting cells and CSCs are irresponsive to the drug, and thus point towards a molecular explanation behind the origin of drug resistance. This analytical method is broadly applicable to study membrane protein interactions in the intact plasma membrane, while accounting for cell heterogeneity. © 2017 by The American Society for Cell Biology.

Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number.

PubMed

Podhorecka, Monika; Goracy, Aneta; Szymczyk, Agnieszka; Kowal, Malgorzata; Ibanez, Blanca; Jankowska-Lecka, Olga; Macheta, Arkadiusz; Nowaczynska, Aleksandra; Drab-Urbanek, Elzbieta; Chocholska, Sylwia; Jawniak, Dariusz; Hus, Marek

2017-05-23

B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration.The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively.The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.

Costs and benefits of group living with disease: a case study of pneumonia in bighorn lambs (Ovis canadensis).

PubMed

Manlove, Kezia R; Cassirer, E Frances; Cross, Paul C; Plowright, Raina K; Hudson, Peter J

2014-12-22

Group living facilitates pathogen transmission among social hosts, yet temporally stable host social organizations can actually limit transmission of some pathogens. When there are few between-subpopulation contacts for the duration of a disease event, transmission becomes localized to subpopulations. The number of per capita infectious contacts approaches the subpopulation size as pathogen infectiousness increases. Here, we illustrate that this is the case during epidemics of highly infectious pneumonia in bighorn lambs (Ovis canadensis). We classified individually marked bighorn ewes into disjoint seasonal subpopulations, and decomposed the variance in lamb survival to weaning into components associated with individual ewes, subpopulations, populations and years. During epidemics, lamb survival varied substantially more between ewe-subpopulations than across populations or years, suggesting localized pathogen transmission. This pattern of lamb survival was not observed during years when disease was absent. Additionally, group sizes in ewe-subpopulations were independent of population size, but the number of ewe-subpopulations increased with population size. Consequently, although one might reasonably assume that force of infection for this highly communicable disease scales with population size, in fact, host social behaviour modulates transmission such that disease is frequency-dependent within populations, and some groups remain protected during epidemic events. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Costs and benefits of group living with disease: a case study of pneumonia in bighorn lambs (Ovis canadensis)

PubMed Central

Manlove, Kezia R.; Cassirer, E. Frances; Cross, Paul C.; Plowright, Raina K.; Hudson, Peter J.

2014-01-01

Group living facilitates pathogen transmission among social hosts, yet temporally stable host social organizations can actually limit transmission of some pathogens. When there are few between-subpopulation contacts for the duration of a disease event, transmission becomes localized to subpopulations. The number of per capita infectious contacts approaches the subpopulation size as pathogen infectiousness increases. Here, we illustrate that this is the case during epidemics of highly infectious pneumonia in bighorn lambs (Ovis canadensis). We classified individually marked bighorn ewes into disjoint seasonal subpopulations, and decomposed the variance in lamb survival to weaning into components associated with individual ewes, subpopulations, populations and years. During epidemics, lamb survival varied substantially more between ewe-subpopulations than across populations or years, suggesting localized pathogen transmission. This pattern of lamb survival was not observed during years when disease was absent. Additionally, group sizes in ewe-subpopulations were independent of population size, but the number of ewe-subpopulations increased with population size. Consequently, although one might reasonably assume that force of infection for this highly communicable disease scales with population size, in fact, host social behaviour modulates transmission such that disease is frequency-dependent within populations, and some groups remain protected during epidemic events. PMID:25377464

Costs and benefits of group living with disease: a case study of pneumonia in bighorn lambs (Ovis canadensis)

USGS Publications Warehouse

Manlove, Kezia R.; Cassirer, E. Frances; Cross, Paul C.; Plowright, Raina K.; Hudson, Peter J.

2014-01-01

Group living facilitates pathogen transmission among social hosts, yet temporally stable host social organizations can actually limit transmission of some pathogens. When there are few between-subpopulation contacts for the duration of a disease event, transmission becomes localized to subpopulations. The number of per capita infectious contacts approaches the subpopulation size as pathogen infectiousness increases. Here, we illustrate that this is the case during epidemics of highly infectious pneumonia in bighorn lambs (Ovis canadensis). We classified individually marked bighorn ewes into disjoint seasonal subpopulations, and decomposed the variance in lamb survival to weaning into components associated with individual ewes, subpopulations, populations and years. During epidemics, lamb survival varied substantially more between ewe-subpopulations than across populations or years, suggesting localized pathogen transmission. This pattern of lamb survival was not observed during years when disease was absent. Additionally, group sizes in ewe-subpopulations were independent of population size, but the number of ewe-subpopulations increased with population size. Consequently, although one might reasonably assume that force of infection for this highly communicable disease scales with population size, in fact, host social behaviour modulates transmission such that disease is frequency-dependent within populations, and some groups remain protected during epidemic events.

Estimates of vital rates for a declining loggerhead turtle (Caretta caretta) subpopulation: implications for management

USGS Publications Warehouse

Lamont, Margaret M.; Fujisaki, Ikuko; Carthy, Raymond R.

2014-01-01

Because subpopulations can differ geographically, genetically and/or phenotypically, using data from one subpopulation to derive vital rates for another, while often unavoidable, is not optimal. We used a two-state open robust design model to analyze a 14-year dataset (1998–2011) from the St. Joseph Peninsula, Florida (USA; 29.748°, −85.400°) which is the densest loggerhead (Caretta caretta) nesting beach in the Northern Gulf of Mexico subpopulation. For these analyses, 433 individuals were marked of which only 7.2 % were observed re-nesting in the study area in subsequent years during the study period. Survival was estimated at 0.86 and is among the highest estimates for all subpopulations in the Northwest Atlantic population. The robust model estimated a nesting assemblage size that ranged from 32 to 230 individuals each year with an annual average of 110. The model estimates indicated an overall population decline of 17 %. The results presented here for this nesting group represent the first estimates for this subpopulation. These data provide managers with information specific to this subpopulation that can be used to develop recovery plans and conduct subpopulation-specific modeling exercises explicit to the challenges faced by turtles nesting in this region.

Chlorinated, brominated, and perfluorinated contaminants in livers of polar bears from Alaska.

PubMed

Kannan, Kurunthachalam; Yun, Se Hun; Evans, Thomas J

2005-12-01

The existence of two subpopulations of polar bears in Alaska, the Beaufort Sea and the Chukchi Sea populations, has been documented. In this study, differences in concentrations and profiles of organochlorine pesticides, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and perfluorinated acids were examined in livers of polar bears from the two subpopulations in Alaska. Concentrations of most of the organohalogens analyzed were greater in the Beaufort Sea subpopulation than in the Chukchi Sea subpopulation, except for HCHs and perfluorononanoic acid (PFNA), which were high in samples from the Chukchi Sea subpopulation. Concentrations of chlordanes, PCBs, and perfluorooctanesulfonate (PFOS) were significantly different between the two subpopulations. Chlordane was the predominant contaminant in the Beaufort Sea population, and PFOS was the major contaminant in the Chukchi Sea population. Polar bears from the Beaufort Sea showed significantly higher proportions of more highly chlorinated PCBs than those from the Chukchi Sea. Concentrations of several perfluorinated acids were significantly correlated. Overall, the concentrations and profiles of organohalogens analyzed in the two subpopulations of polar bears suggest differences in the sources of exposures between the two regions of Alaska.

Gene Environment Interactions in Women With Breast and Secondary Lung Cancer

DTIC Science & Technology

2005-07-01

information that may be useful in defining subpopulations sensitive to radiation therapy . 15. SUBJECT TERMS Breast cancer, lung cancer, secondary...risk levels to women choosing a breast cancer therapy . Additionally, this research may provide new data on the susceptibilities of women with...secondary lung cancer risk that increased 2-3 fold for nonsmokers and 30 fold in smokers who receive radiation therapy (4,5). Overall, radiotherapy

Super-resolution imaging and tracking of protein-protein interactions in sub-diffraction cellular space

NASA Astrophysics Data System (ADS)

Liu, Zhen; Xing, Dong; Su, Qian Peter; Zhu, Yun; Zhang, Jiamei; Kong, Xinyu; Xue, Boxin; Wang, Sheng; Sun, Hao; Tao, Yile; Sun, Yujie

2014-07-01

Imaging the location and dynamics of individual interacting protein pairs is essential but often difficult because of the fluorescent background from other paired and non-paired molecules, particularly in the sub-diffraction cellular space. Here we develop a new method combining bimolecular fluorescence complementation and photoactivated localization microscopy for super-resolution imaging and single-molecule tracking of specific protein-protein interactions. The method is used to study the interaction of two abundant proteins, MreB and EF-Tu, in Escherichia coli cells. The super-resolution imaging shows interesting distribution and domain sizes of interacting MreB-EF-Tu pairs as a subpopulation of total EF-Tu. The single-molecule tracking of MreB, EF-Tu and MreB-EF-Tu pairs reveals intriguing localization-dependent heterogonous dynamics and provides valuable insights to understanding the roles of MreB-EF-Tu interactions.

Super-resolution imaging and tracking of protein–protein interactions in sub-diffraction cellular space

PubMed Central

Liu, Zhen; Xing, Dong; Su, Qian Peter; Zhu, Yun; Zhang, Jiamei; Kong, Xinyu; Xue, Boxin; Wang, Sheng; Sun, Hao; Tao, Yile; Sun, Yujie

2014-01-01

Imaging the location and dynamics of individual interacting protein pairs is essential but often difficult because of the fluorescent background from other paired and non-paired molecules, particularly in the sub-diffraction cellular space. Here we develop a new method combining bimolecular fluorescence complementation and photoactivated localization microscopy for super-resolution imaging and single-molecule tracking of specific protein–protein interactions. The method is used to study the interaction of two abundant proteins, MreB and EF-Tu, in Escherichia coli cells. The super-resolution imaging shows interesting distribution and domain sizes of interacting MreB–EF-Tu pairs as a subpopulation of total EF-Tu. The single-molecule tracking of MreB, EF-Tu and MreB–EF-Tu pairs reveals intriguing localization-dependent heterogonous dynamics and provides valuable insights to understanding the roles of MreB–EF-Tu interactions. PMID:25030837

Epidemic spreading between two coupled subpopulations with inner structures

NASA Astrophysics Data System (ADS)

Ruan, Zhongyuan; Tang, Ming; Gu, Changgui; Xu, Jinshan

2017-10-01

The structure of underlying contact network and the mobility of agents are two decisive factors for epidemic spreading in reality. Here, we study a model consisting of two coupled subpopulations with intra-structures that emphasizes both the contact structure and the recurrent mobility pattern of individuals simultaneously. We show that the coupling of the two subpopulations (via interconnections between them and round trips of individuals) makes the epidemic threshold in each subnetwork to be the same. Moreover, we find that the interconnection probability between two subpopulations and the travel rate are important factors for spreading dynamics. In particular, as a function of interconnection probability, the epidemic threshold in each subpopulation decreases monotonously, which enhances the risks of an epidemic. While the epidemic threshold displays a non-monotonic variation as travel rate increases. Moreover, the asymptotic infected density as a function of travel rate in each subpopulation behaves differently depending on the interconnection probability.

Intracellular Delivery System for Antibody–Peptide Drug Conjugates

PubMed Central

Berguig, Geoffrey Y; Convertine, Anthony J; Frayo, Shani; Kern, Hanna B; Procko, Erik; Roy, Debashish; Srinivasan, Selvi; Margineantu, Daciana H; Booth, Garrett; Palanca-Wessels, Maria Corinna; Baker, David; Hockenbery, David; Press, Oliver W; Stayton, Patrick S

2015-01-01

Antibodies armed with biologic drugs could greatly expand the therapeutic potential of antibody–drug conjugates for cancer therapy, broadening their application to disease targets currently limited by intracellular delivery barriers. Additional selectivity and new therapeutic approaches could be realized with intracellular protein drugs that more specifically target dysregulated pathways in hematologic cancers and other malignancies. A multifunctional polymeric delivery system for enhanced cytosolic delivery of protein drugs has been developed that incorporates endosomal-releasing activity, antibody targeting, and a biocompatible long-chain ethylene glycol component for optimized safety, pharmacokinetics, and tumor biodistribution. The pH-responsive polymeric micelle carrier, with an internalizing anti-CD22 monoclonal targeting antibody, effectively delivered a proapoptotic Bcl-2 interacting mediator (BIM) peptide drug that suppressed tumor growth for the duration of treatment and prolonged survival in a xenograft mouse model of human B-cell lymphoma. Antitumor drug activity was correlated with a mechanistic induction of the Bcl-2 pathway biomarker cleaved caspase-3 and a marked decrease in the Ki-67 proliferation biomarker. Broadening the intracellular target space by more effective delivery of protein/peptide drugs could expand the repertoire of antibody–drug conjugates to currently undruggable disease-specific targets and permit tailored drug strategies to stratified subpopulations and personalized medicines. PMID:25669432

Bet-hedging in bacteriocin producing Escherichia coli populations: the single cell perspective

NASA Astrophysics Data System (ADS)

Bayramoglu, Bihter; Toubiana, David; van Vliet, Simon; Inglis, R. Fredrik; Shnerb, Nadav; Gillor, Osnat

2017-02-01

Production of public goods in biological systems is often a collaborative effort that may be detrimental to the producers. It is therefore sustainable only if a small fraction of the population shoulders the cost while the majority reap the benefits. We modelled this scenario using Escherichia coli populations producing colicins, an antibiotic that kills producer cells’ close relatives. Colicin expression is a costly trait, and it has been proposed that only a small fraction of the population actively expresses the antibiotic. Colicinogenic populations were followed at the single-cell level using time-lapse microscopy, and showed two distinct, albeit dynamic, subpopulations: the majority silenced colicin expression, while a small fraction of elongated, slow-growing cells formed colicin-expressing hotspots, placing a significant burden on expressers. Moreover, monitoring lineages of individual colicinogenic cells showed stochastic switching between expressers and non-expressers. Hence, colicin expressers may be engaged in risk-reducing strategies—or bet-hedging—as they balance the cost of colicin production with the need to repel competitors. To test the bet-hedging strategy in colicin-mediated interactions, competitions between colicin-sensitive and producer cells were simulated using a numerical model, demonstrating a finely balanced expression range that is essential to sustaining the colicinogenic population.

Decipher the dynamic coordination between enzymatic activity and structural modulation at focal adhesions in living cells

NASA Astrophysics Data System (ADS)

Lu, Shaoying; Seong, Jihye; Wang, Yi; Chang, Shiou-Chi; Eichorst, John Paul; Ouyang, Mingxing; Li, Julie Y.-S.; Chien, Shu; Wang, Yingxiao

2014-07-01

Focal adhesions (FAs) are dynamic subcellular structures crucial for cell adhesion, migration and differentiation. It remains an enigma how enzymatic activities in these local complexes regulate their structural remodeling in live cells. Utilizing biosensors based on fluorescence resonance energy transfer (FRET), we developed a correlative FRET imaging microscopy (CFIM) approach to quantitatively analyze the subcellular coordination between the enzymatic Src activation and the structural FA disassembly. CFIM reveals that the Src kinase activity only within the microdomain of lipid rafts at the plasma membrane is coupled with FA dynamics. FA disassembly at cell periphery was linearly dependent on this raft-localized Src activity, although cells displayed heterogeneous levels of response to stimulation. Within lipid rafts, the time delay between Src activation and FA disassembly was 1.2 min in cells seeded on low fibronectin concentration ([FN]) and 4.3 min in cells on high [FN]. CFIM further showed that the level of Src-FA coupling, as well as the time delay, was regulated by cell-matrix interactions, as a tight enzyme-structure coupling occurred in FA populations mediated by integrin αvβ3, but not in those by integrin α5β1. Therefore, different FA subpopulations have distinctive regulation mechanisms between their local kinase activity and structural FA dynamics.

New Strategies to Develop Novel Pain Therapies: Addressing Thermoreceptors from Different Points of View

PubMed Central

Fernández-Carvajal, Asia; Fernández-Ballester, Gregorio; Devesa, Isabel; González-Ros, José Manuel; Ferrer-Montiel, Antonio

2011-01-01

One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as nociceptors. Pharmacological blockade and genetic deletion of thermoTRP have validated these channels as therapeutic targets for pain intervention. Several thermoTRP modulators have progressed towards clinical development, although most failed because of the appearance of unpredicted side effects. Thus, there is yet a need to develop novel channel modulators with improved therapeutic index. Here, we review the current state-of-the art and illustrate new pharmacological paradigms based on TRPV1 that include: (i) the identification of activity-dependent modulators of this thermoTRP channel; (ii) the design of allosteric modulators that interfere with protein-protein interaction involved in the functional coupling of stimulus sensing and gate opening; and (iii) the development of compounds that abrogate the inflammation-mediated increase of receptor expression in the neuronal surface. These new sites of action represent novel strategies to modulate pathologically active TRPV1, while minimizing an effect on the TRPV1 subpopulation involved in physiological and protective roles, thus increasing their potential therapeutic use. PMID:24288041

Desynchronizing electrical and sensory coordinated reset neuromodulation

PubMed Central

Popovych, Oleksandr V.; Tass, Peter A.

2012-01-01

Coordinated reset (CR) stimulation is a desynchronizing stimulation technique based on timely coordinated phase resets of sub-populations of a synchronized neuronal ensemble. It has initially been computationally developed for electrical deep brain stimulation (DBS), to enable an effective desynchronization and unlearning of pathological synchrony and connectivity (anti-kindling). Here we computationally show for ensembles of spiking and bursting model neurons interacting via excitatory and inhibitory adaptive synapses that a phase reset of neuronal populations as well as a desynchronization and an anti-kindling can robustly be achieved by direct electrical stimulation or indirect (synaptically-mediated) excitatory and inhibitory stimulation. Our findings are relevant for DBS as well as for sensory stimulation in neurological disorders characterized by pathological neuronal synchrony. Based on the obtained results, we may expect that the local effects in the vicinity of a depth electrode (realized by direct stimulation of the neurons' somata or stimulation of axon terminals) and the non-local CR effects (realized by stimulation of excitatory or inhibitory efferent fibers) of deep brain CR neuromodulation may be similar or even identical. Furthermore, our results indicate that an effective desynchronization and anti-kindling can even be achieved by non-invasive, sensory CR neuromodulation. We discuss the concept of sensory CR neuromodulation in the context of neurological disorders. PMID:22454622

Desynchronizing electrical and sensory coordinated reset neuromodulation.

PubMed

Popovych, Oleksandr V; Tass, Peter A

2012-01-01

Coordinated reset (CR) stimulation is a desynchronizing stimulation technique based on timely coordinated phase resets of sub-populations of a synchronized neuronal ensemble. It has initially been computationally developed for electrical deep brain stimulation (DBS), to enable an effective desynchronization and unlearning of pathological synchrony and connectivity (anti-kindling). Here we computationally show for ensembles of spiking and bursting model neurons interacting via excitatory and inhibitory adaptive synapses that a phase reset of neuronal populations as well as a desynchronization and an anti-kindling can robustly be achieved by direct electrical stimulation or indirect (synaptically-mediated) excitatory and inhibitory stimulation. Our findings are relevant for DBS as well as for sensory stimulation in neurological disorders characterized by pathological neuronal synchrony. Based on the obtained results, we may expect that the local effects in the vicinity of a depth electrode (realized by direct stimulation of the neurons' somata or stimulation of axon terminals) and the non-local CR effects (realized by stimulation of excitatory or inhibitory efferent fibers) of deep brain CR neuromodulation may be similar or even identical. Furthermore, our results indicate that an effective desynchronization and anti-kindling can even be achieved by non-invasive, sensory CR neuromodulation. We discuss the concept of sensory CR neuromodulation in the context of neurological disorders.

Restricted T cell receptor repertoire in CLL-like monoclonal B cell lymphocytosis and early stage CLL.

PubMed

Blanco, Gonzalo; Vardi, Anna; Puiggros, Anna; Gómez-Llonín, Andrea; Muro, Manuel; Rodríguez-Rivera, María; Stalika, Evangelia; Abella, Eugenia; Gimeno, Eva; López-Sánchez, Manuela; Senín, Alicia; Calvo, Xavier; Abrisqueta, Pau; Bosch, Francesc; Ferrer, Ana; Stamatopoulos, Kostas; Espinet, Blanca

2018-01-01

Analysis of the T cell receptor (TR) repertoire of chronic lymphocytic leukemia-like monoclonal B cell lymphocytosis (CLL-like MBL) and early stage CLL is relevant for understanding the dynamic interaction of expanded B cell clones with bystander T cells. Here we profiled the T cell receptor β chain (TRB) repertoire of the CD4 + and CD8 + T cell fractions from 16 CLL-like MBL and 13 untreated, Binet stage A/Rai stage 0 CLL patients using subcloning analysis followed by Sanger sequencing. The T cell subpopulations of both MBL and early stage CLL harbored restricted TRB gene repertoire, with CD4 + T cell clonal expansions whose frequency followed the numerical increase of clonal B cells. Longitudinal analysis in MBL cases revealed clonal persistence, alluding to persistent antigen stimulation. In addition, the identification of shared clonotypes among different MBL/early stage CLL cases pointed towards selection of the T cell clones by common antigenic elements. T cell clonotypes previously described in viral infections and immune disorders were also detected. Altogether, our findings evidence that antigen-mediated TR restriction occurs early in clonal evolution leading to CLL and may further increase together with B cell clonal expansion, possibly suggesting that the T cell selecting antigens are tumor-related.

Coenzyme Q10 supplementation downregulates the increase of monocytes expressing toll-like receptor 4 in response to 6-day intensive training in kendo athletes.

PubMed

Shimizu, Kazuhiro; Kon, Michihiro; Tanimura, Yuko; Hanaoka, Yukichi; Kimura, Fuminori; Akama, Takao; Kono, Ichiro

2015-06-01

This study examined changes in toll-like receptor 4 (TLR-4)-expressing monocytes and lymphocyte subpopulations in response to continuous intensive exercise training in athletes, as well as the effect of coenzyme Q10 (CoQ10) supplementation on these changes. Eighteen male elite kendo athletes in Japan were randomly assigned to a CoQ10-supplementation group (n = 9) or a placebo-supplementation group (n = 9) using a double-blind method. Subjects in the CoQ10 group took 300 mg CoQ10 per day for 20 days. Subjects in the placebo group took the same dosage of placebo. All subjects practiced kendo 5.5 h per day for 6 consecutive days during the study period. Blood samples were collected 2 weeks before training, on the first day (day 1), third day (day 3), and fifth day of training (day 5), and 1 week after the training period (post-training) to ascertain TLR-4(+)/CD14(+) monocyte and lymphocyte subpopulations (CD3(+), CD4(+), CD8(+), CD28(+)/CD4(+), CD28(+)/CD8(+), and CD56(+)/CD3(-) cells) using flow cytometry analysis. The group × time interaction for TLR-4(+)/CD14(+) cells did not reach significance (p = 0.08). Within the CoQ10 group, the absolute number of TLR-4(+)/CD14(+) cells was significantly higher only at day 5. The placebo group showed a significant increase in the absolute number of TLR-4(+)/CD14(+) cells at day 3, day 5, and post-training (p < 0.05). There was no significant group × time interaction for any lymphocyte subpopulation. CD3(+), CD8(+), and CD56(+)/CD3(-) cells were significantly reduced at day 3 in both groups (p < 0.05). In conclusion, CoQ10 supplementation might downregulate the increase of TLR-4-expressing monocytes in response to continuous strenuous exercise training in kendo athletes.

The DenA/DEN1 Interacting Phosphatase DipA Controls Septa Positioning and Phosphorylation-Dependent Stability of Cytoplasmatic DenA/DEN1 during Fungal Development

PubMed Central

Schinke, Josua; Kolog Gulko, Miriam; Christmann, Martin; Valerius, Oliver; Stumpf, Sina Kristin; Stirz, Margarita; Braus, Gerhard H.

2016-01-01

DenA/DEN1 and the COP9 signalosome (CSN) represent two deneddylases which remove the ubiquitin-like Nedd8 from modified target proteins and are required for distinct fungal developmental programmes. The cellular DenA/DEN1 population is divided into a nuclear and a cytoplasmatic subpopulation which is especially enriched at septa. DenA/DEN1 stability control mechanisms are different for the two cellular subpopulations and depend on different physical interacting proteins and the C-terminal DenA/DEN1 phosphorylation pattern. Nuclear DenA/DEN1 is destabilized during fungal development by five of the eight CSN subunits which target nuclear DenA/DEN1 for degradation. DenA/DEN1 becomes stabilized as a phosphoprotein at S243/S245 during vegetative growth, which is necessary to support further asexual development. After the initial phase of development, the newly identified cytoplasmatic DenA/DEN1 interacting phosphatase DipA and an additional developmental specific C-terminal phosphorylation site at serine S253 destabilize DenA/DEN1. Outside of the nucleus, DipA is co-transported with DenA/DEN1 in the cytoplasm between septa and nuclei. Deletion of dipA resulted in increased DenA/DEN1 stability in a strain which is unresponsive to illumination. The mutant strain is dysregulated in cytokinesis and impaired in asexual development. Our results suggest a dual phosphorylation-dependent DenA/DEN1 stability control with stabilizing and destabilizing modifications and physical interaction partner proteins which function as control points in the nucleus and the cytoplasm. PMID:27010942

Case-crossover analysis of heat-coded deaths and vulnerable subpopulations: Oklahoma, 1990-2011

NASA Astrophysics Data System (ADS)

Moore, Brianna F.; Brooke Anderson, G.; Johnson, Matthew G.; Brown, Sheryll; Bradley, Kristy K.; Magzamen, Sheryl

2017-11-01

The extent of the association between temperature and heat-coded deaths, for which heat is the primary cause of death, remains largely unknown. We explored the association between temperature and heat-coded deaths and potential interactions with various demographic and environmental factors. A total of 335 heat-coded deaths that occurred in Oklahoma from 1990 through 2011 were identified using heat-related International Classification of Diseases codes, cause-of-death nomenclature, and narrative descriptions. Conditional logistic regression models examined the association between temperature and heat index on heat-coded deaths. Interaction by demographic factors (age, sex, marital status, living alone, outdoor/heavy labor occupations) and environmental factors (ozone, PM10, PM2.5) was also explored. Temperatures ≥99 °F (the median value) were associated with approximately five times higher odds of a heat-coded death as compared to temperatures <99 °F (adjusted OR = 4.9, 95% CI 3.3, 7.2). The effect estimates were attenuated when exposure to heat was characterized by heat index. The interaction results suggest that effect of temperature on heat-coded deaths may depend on sex and occupation. For example, the odds of a heat-coded death among outdoor/heavy labor workers exposed to temperatures ≥99 °F was greater than expected based on the sum of the individual effects (observed OR = 14.0, 95% CI 2.7, 72.0; expected OR = 4.1 [2.8 + 2.3-1.0]). Our results highlight the extent of the association between temperature and heat-coded deaths and emphasize the need for a comprehensive, multisource definition of heat-coded deaths. Furthermore, based on the interaction results, we recommend that states implement or expand heat safety programs to protect vulnerable subpopulations, such as outdoor workers.

Toxic epidermal necrolysis in a child 6 months post-hematopoietic stem cell transplantation.

PubMed

Oba, Utako; Yamada, Hiroshi; Suenobu, So-Ichi; Nakamura, Yusuke; Ito, Akiko; Hatano, Yutaka; Itonaga, Nobuyoshi; Ohshima, Kouichi; Koga, Yuhki; Ohga, Shouichi; Ihara, Kenji

2017-08-01

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B-cell acute lymphoblastic leukemia (pre-B-ALL) in second complete remission. Although we did not evaluate the T-cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic and epigenetic divergence between disturbed and undisturbed subpopulations of a Mediterranean shrub: a 20-year field experiment.

PubMed

Herrera, Carlos M; Bazaga, Pilar

2016-06-01

Little is known on the potential of ecological disturbance to cause genetic and epigenetic changes in plant populations. We take advantage of a long-term field experiment initiated in 1986 to study the demography of the shrub Lavandula latifolia , and compare genetic and epigenetic characteristics of plants in two adjacent subplots, one experimentally disturbed and one left undisturbed, 20 years after disturbance. Experimental setup was comparable to an unreplicated 'Before-After-Control-Impact' (BACI) design where a single pair of perturbed and control areas were compared. When sampled in 2005, plants in the two subplots had roughly similar ages, but they had established in contrasting environments: dense conspecific population ('Undisturbed' subpopulation) versus open area with all conspecifics removed ('Disturbed' subpopulation). Plants were characterized genetically and epigenetically using amplified fragment length polymorphism (AFLP) and two classes of methylation-sensitive AFLP (MSAP) markers. Subpopulations were similar in genetic diversity but differed in epigenetic diversity and multilocus genetic and epigenetic characteristics. Epigenetic divergence between subpopulations was statistically unrelated to genetic divergence. Bayesian clustering revealed an abrupt linear boundary between subpopulations closely coincident with the arbitrary demarcation line between subplots drawn 20 years back, which supports that genetic and epigenetic divergence between subpopulations was caused by artificial disturbance. There was significant fine-scale spatial structuring of MSAP markers in both subpopulations, which in the Undisturbed one was indistinguishable from that of AFLP markers. Genetic differences between subpopulations could be explained by divergent selection alone, while the concerted action of divergent selection and disturbance-driven appearance of new methylation variants in the Disturbed subpopulation is proposed to explain epigenetic differences. This study provides the first empirical evidence to date suggesting that relatively mild disturbances could leave genetic and epigenetic signatures on the next adult generation of long-lived plants.

Antigen Cross-Presentation of Immune Complexes

PubMed Central

Platzer, Barbara; Stout, Madeleine; Fiebiger, Edda

2014-01-01

The ability of dendritic cells (DCs) to cross-present tumor antigens has long been a focus of interest to physicians, as well as basic scientists, that aim to establish efficient cell-based cancer immune therapy. A prerequisite for exploiting this pathway for therapeutic purposes is a better understanding of the mechanisms that underlie the induction of tumor-specific cytotoxic T-lymphocyte (CTL) responses when initiated by DCs via cross-presentation. The ability of humans DC to perform cross-presentation is of utmost interest, as this cell type is a main target for cell-based immunotherapy in humans. The outcome of a cross-presentation event is guided by the nature of the antigen, the form of antigen uptake, and the subpopulation of DCs that performs presentation. Generally, CD8α+ DCs are considered to be the most potent cross-presenting DCs. This paradigm, however, only applies to soluble antigens. During adaptive immune responses, immune complexes form when antibodies interact with their specific epitopes on soluble antigens. Immunoglobulin G (IgG) immune complexes target Fc-gamma receptors on DCs to shuttle exogenous antigens efficiently into the cross-presentation pathway. This receptor-mediated cross-presentation pathway is a well-described route for the induction of strong CD8+ T cell responses. IgG-mediated cross-presentation is intriguing because it permits the CD8− DCs, which are commonly considered to be weak cross-presenters, to efficiently cross-present. Engaging multiple DC subtypes for cross-presentation might be a superior strategy to boost CTL responses in vivo. We here summarize our current understanding of how DCs use IgG-complexed antigens for the efficient induction of CTL responses. Because of its importance for human cell therapy, we also review the recent advances in the characterization of cross-presentation properties of human DC subsets. PMID:24744762

Interactions between dietary oil treatments and genetic variants modulate fatty acid ethanolamides in plasma and body weight composition.

PubMed

Pu, Shuaihua; Eck, Peter; Jenkins, David J A; Connelly, Philip W; Lamarche, Benoît; Kris-Etherton, Penny M; West, Sheila G; Liu, Xiaoran; Jones, Peter J H

2016-03-28

Fatty acid ethanolamides (FAE), a group of lipid mediators derived from long-chain fatty acids (FA), mediate biological activities including activation of cannabinoid receptors, stimulation of fat oxidation and regulation of satiety. However, how circulating FAE levels are influenced by FA intake in humans remains unclear. The objective of the present study was to investigate the response of six major circulating FAE to various dietary oil treatments in a five-period, cross-over, randomised, double-blind, clinical study in volunteers with abdominal obesity. The treatment oils (60 g/12 552 kJ per d (60 g/3000 kcal per d)) provided for 30 d were as follows: conventional canola oil, high oleic canola oil, high oleic canola oil enriched with DHA, flax/safflower oil blend and corn/safflower oil blend. Two SNP associated with FAE degradation and synthesis were studied. Post-treatment results showed overall that plasma FAE levels were modulated by dietary FA and were positively correlated with corresponding plasma FA levels; minor allele (A) carriers of SNP rs324420 in gene fatty acid amide hydrolase produced higher circulating oleoylethanolamide (OEA) (P=0·0209) and docosahexaenoylethanolamide (DHEA) levels (P=0·0002). In addition, elevated plasma DHEA levels in response to DHA intake tended to be associated with lower plasma OEA levels and an increased gynoid fat mass. In summary, data suggest that the metabolic and physiological responses to dietary FA may be influenced via circulating FAE. Genetic analysis of rs324420 might help identify a sub-population that appears to benefit from increased consumption of DHA and oleic acid.

CHILDREN AS A SENSITIVE SUBPOPULATION FOR THE RISK ASSESSMENT PROCESS

EPA Science Inventory

Children as a sensitive subpopulation for the risk assessment process
Abstract
For cancer risk assessment purposes, it is necessary to consider how to incorporate sensitive subpopulations into the process to ensure that they are appropriately protected. Children represent o...

Reproducibility and Reliability: How To Define the Population of Trees That Represent Site Quality For Longleaf Pine Plantations

Treesearch

J.C.G. Goelz; Daniel J. Leduc

2004-01-01

We compared 13 definitions for the subpopulation of “site trees.” Each subpopulation was defined (1) once at base age or at each measurement; (2) by crown class, diameter, or height; and (3) by the number of trees per acre. These subpopulations were applied to base ages of 25 and 50. For base age 25, the subpopulations defined at base age were superior to those defined...

Identification and Description of Healthcare Customer Communication Patterns Among Individuals with Diabetes in Clalit Health Services: A Retrospective Database Study.

PubMed

Benis, Arriel; Harel, Nissim; Barkan, Refael; Sela, Tomer; Feldman, Becca

2017-01-01

HMOs record medical data and their interactions with patients. Using this data we strive to identify sub-populations of healthcare customers based on their communication patterns and characterize these sub-populations by their socio-demographic, medical, treatment effectiveness, and treatment adherence profiles. This work will be used to develop tools and interventions aimed at improving patient care. The process included: (1) Extracting socio-demographic, clinical, laboratory, and communication data of 309,460 patients with diabetes in 2015, aged 32+ years, having 7+ years of the disease treated by Clalit Healthcare Services; (2) Reducing dimensions of continuous variables; (3) Finding the K communication-patterns clusters; (4) Building a hierarchical clustering and its associated heatmap to summarize the discovered clusters; (5) Analyzing the clusters found; (6) Validating results epidemiologically. Such a process supports understanding different communication-channel usage and the implementation of personalized services focusing on patients' needs and preferences.

Location restrictions on smoking: assessing their differential impacts and consequences in the workplace.

PubMed

Bell, Kirsten; McCullough, Lucy; Devries, Karen; Jategaonkar, Natasha; Greaves, Lorraine; Richardson, Lindsay

2009-01-01

To analyze existing evidence on the impact of two types of location restrictions on smoking: workplace bans and bans in hospitality settings, and to assess the extent to which they differentially affect subpopulations. A review of international studies on location restrictions on smoking published between 1990-2007. Although workplace smoking bans reduce exposure to second-hand smoke (SHS) at work, their effects on overall cigarette consumption and smoking prevalence may be uneven across the population. Bans in hospitality settings reduce SHS exposure among workers, but have potentially uneven effects based on the interactions between gender, socio-economic status (SES) and ethnicity. The unintended consequences of smoking bans are also more likely to be experienced by low SES groups. Although location restrictions on smoking reduce SHS exposure and may serve to positively impact smoking behaviours, there is preliminary evidence that they may have a reduced impact on subpopulations such as low-income groups, although further research is needed.

Local excitation-inhibition ratio for synfire chain propagation in feed-forward neuronal networks

NASA Astrophysics Data System (ADS)

Guo, Xinmeng; Yu, Haitao; Wang, Jiang; Liu, Jing; Cao, Yibin; Deng, Bin

2017-09-01

A leading hypothesis holds that spiking activity propagates along neuronal sub-populations which are connected in a feed-forward manner, and the propagation efficiency would be affected by the dynamics of sub-populations. In this paper, how the interaction between local excitation and inhibition effects on synfire chain propagation in feed-forward network (FFN) is investigated. The simulation results show that there is an appropriate excitation-inhibition (EI) ratio maximizing the performance of synfire chain propagation. The optimal EI ratio can significantly enhance the selectivity of FFN to synchronous signals, which thereby increases the stability to background noise. Moreover, the effect of network topology on synfire chain propagation is also investigated. It is found that synfire chain propagation can be maximized by an optimal interlayer linking probability. We also find that external noise is detrimental to synchrony propagation by inducing spiking jitter. The results presented in this paper may provide insights into the effects of network dynamics on neuronal computations.

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab.

PubMed

Fujii, Rika; Friedman, Eitan R; Richards, Jacob; Tsang, Kwong Y; Heery, Christopher R; Schlom, Jeffrey; Hodge, James W

2016-06-07

Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

PubMed Central

Fujii, Rika; Friedman, Eitan R.; Richards, Jacob; Tsang, Kwong Y.; Heery, Christopher R.; Schlom, Jeffrey; Hodge, James W.

2016-01-01

Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC. PMID:27172898

Coexisting synchronous and asynchronous states in locally coupled array of oscillators by partial self-feedback control

NASA Astrophysics Data System (ADS)

Bera, Bidesh K.; Ghosh, Dibakar; Parmananda, Punit; Osipov, G. V.; Dana, Syamal K.

2017-07-01

We report the emergence of coexisting synchronous and asynchronous subpopulations of oscillators in one dimensional arrays of identical oscillators by applying a self-feedback control. When a self-feedback is applied to a subpopulation of the array, similar to chimera states, it splits into two/more sub-subpopulations coexisting in coherent and incoherent states for a range of self-feedback strength. By tuning the coupling between the nearest neighbors and the amount of self-feedback in the perturbed subpopulation, the size of the coherent and the incoherent sub-subpopulations in the array can be controlled, although the exact size of them is unpredictable. We present numerical evidence using the Landau-Stuart system and the Kuramoto-Sakaguchi phase model.

Isolated in an ocean of grass: low levels of gene flow between termite subpopulations.

PubMed

Schmidt, Anna M; Jacklyn, Peter; Korb, Judith

2013-04-01

Habitat fragmentation is one of the most important causes of biodiversity loss, but many species are distributed in naturally patchy habitats. Such species are often organized in highly dynamic metapopulations or in patchy populations with high gene flow between subpopulations. Yet, there are also species that exist in stable patchy habitats with small subpopulations and presumably low dispersal rates. Here, we present population genetic data for the 'magnetic' termite Amitermes meridionalis, which show that short distances between subpopulations do not hinder exceptionally strong genetic differentiation (FST : 0.339; RST : 0.636). Despite the strong genetic differentiation between subpopulations, we did not find evidence for genetic impoverishment. We propose that loss of genetic diversity might be counteracted by a long colony life with low colony turnover. Indeed, we found evidence for the inheritance of colonies by so-called 'replacement reproductives'. Inhabiting a mound for several generations might result in loss of gene diversity within a colony but maintenance of gene diversity at the subpopulation level. © 2013 Blackwell Publishing Ltd.

A Multipopulation Coevolutionary Strategy for Multiobjective Immune Algorithm

PubMed Central

Shi, Jiao; Gong, Maoguo; Ma, Wenping; Jiao, Licheng

2014-01-01

How to maintain the population diversity is an important issue in designing a multiobjective evolutionary algorithm. This paper presents an enhanced nondominated neighbor-based immune algorithm in which a multipopulation coevolutionary strategy is introduced for improving the population diversity. In the proposed algorithm, subpopulations evolve independently; thus the unique characteristics of each subpopulation can be effectively maintained, and the diversity of the entire population is effectively increased. Besides, the dynamic information of multiple subpopulations is obtained with the help of the designed cooperation operator which reflects a mutually beneficial relationship among subpopulations. Subpopulations gain the opportunity to exchange information, thereby expanding the search range of the entire population. Subpopulations make use of the reference experience from each other, thereby improving the efficiency of evolutionary search. Compared with several state-of-the-art multiobjective evolutionary algorithms on well-known and frequently used multiobjective and many-objective problems, the proposed algorithm achieves comparable results in terms of convergence, diversity metrics, and running time on most test problems. PMID:24672330

Cancer stem cell as therapeutic target for melanoma treatment.

PubMed

Alamodi, Abdulhadi A; Eshaq, Abdulaziz M; Hassan, Sofie-Yasmin; Al Hmada, Youssef; El Jamal, Siraj M; Fothan, Ahmed M; Arain, Omair M; Hassan, Sarah-Lilly; Haikel, Youssef; Megahed, Mosaad; Hassan, Mohamed

2016-12-01

Human malignant melanoma is a highly aggressive skin tumor that is characterized by its extraordinary heterogeneity, propensity for dissemination to distant organs and resistance to cytotoxic agents. Although chemo- and immune-based therapies have been evaluated in clinical trials, most of these therapeutics do not show significant benefit for patients with advanced disease. Treatment failure in melanoma patients is attributed mainly to the development of tumor heterogeneity resulting from the formation of genetically divergent subpopulations. These subpopulations are composed of cancer stem-like cells (CSCs) as a small fraction and non-cancer stem cells that form the majority of the tumor mass. In recent years, CSCs gained more attention and suggested as valuable experimental model system for tumor study. In melanoma, intratumoral heterogeneity, progression and drug resistance result from the unique characteristics of melanoma stem cells (MSCs). These MSCs are characterized by their distinct protein signature and tumor growth-driving pathways, whose activation is mediated by driver mutation-dependent signal. The molecular features of MSCs are either in a causal or consequential relationship to melanoma progression, drug resistance and relapse. Here, we review the current scientific evidence that supports CSC hypothesis and the validity of MSCs-dependent pathways and their key molecules as potential therapeutic target for melanoma treatment.

The caudo-ventral pallium is a novel pallial domain expressing Gdf10 and generating Ebf3-positive neurons of the medial amygdala.

PubMed

Ruiz-Reig, Nuria; Andres, Belen; Lamonerie, Thomas; Theil, Thomas; Fairén, Alfonso; Studer, Michèle

2018-06-04

In rodents, the medial nucleus of the amygdala receives direct inputs from the accessory olfactory bulbs and is mainly implicated in pheromone-mediated reproductive and defensive behaviors. The principal neurons of the medial amygdala are GABAergic neurons generated principally in the caudo-ventral medial ganglionic eminence and preoptic area. Beside GABAergic neurons, the medial amygdala also contains glutamatergic Otp-expressing neurons cells generated in the lateral hypothalamic neuroepithelium and a non-well characterized Pax6-positive population. In the present work, we describe a novel glutamatergic Ebf3-expressing neuronal subpopulation distributed within the periphery of the postero-ventral medial amygdala. These neurons are generated in a pallial domain characterized by high expression of Gdf10. This territory is topologically the most caudal tier of the ventral pallium and accordingly, we named it Caudo-Ventral Pallium (CVP). In the absence of Pax6, the CVP is disrupted and Ebf3-expressing neurons fail to be generated. Overall, this work proposes a novel model of the neuronal composition of the medial amygdala and unravels for the first time a new novel pallial subpopulation originating from the CVP and expressing the transcription factor Ebf3.

Higher leukocyte subpopulation counts in healthy smoker industrial workers than in nonsmoker industrial workers: possible health consequences.

PubMed

Mansoor, M Azam; Stakkestad, Jacob A; Drabløs, Per Arne

2013-01-01

Cigarette smoke contains free radicals, which cause injury to endothelial cells and oxidize bioactive components in the blood. Neutrophils, a subpopulation of leukocytes, contain the enzyme myeloperoxidase that mediates production of hypochlorous acid during oxidative stress. In this study, we investigated whether smoker industrial workers had significantly higher neutrophil counts than nonsmoker industrial workers. We collected blood samples from 183 apparently healthy male and 30 female industrial workers. We obtained blood cell counts, measured the concentration of plasma aminothiols and determined the concentration of serum and erythrocyte folate and serum vitamin B12 in the samples. Smoker industrial workers had significantly higher neutrophil, lymphocyte, monocyte, eosinophil and basophil counts than nonsmoker industrial workers (p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001 and p = 0.01, respectively). Mean corpuscular volume and mean corpuscular hemoglobin in smoker industrial workers were higher than in nonsmoker industrial workers (p = 0.001 and p = 0.03). Our study demonstrates that smoker industrial workers have higher neutrophil counts than nonsmoker industrial workers. Therefore, our observations suggest that smokers may become more easily prone to chronic inflammation than nonsmokers. About 84% of the study participants were male subjects; therefore, our findings may be more representative for men than women. Copyright © 2013 S. Karger AG, Basel.

Information to cerebellum on spinal motor networks mediated by the dorsal spinocerebellar tract

PubMed Central

Stecina, Katinka; Fedirchuk, Brent; Hultborn, Hans

2013-01-01

The main objective of this review is to re-examine the type of information transmitted by the dorsal and ventral spinocerebellar tracts (DSCT and VSCT respectively) during rhythmic motor actions such as locomotion. Based on experiments in the 1960s and 1970s, the DSCT was viewed as a relay of peripheral sensory input to the cerebellum in general, and during rhythmic movements such as locomotion and scratch. In contrast, the VSCT was seen as conveying a copy of the output of spinal neuronal circuitry, including those circuits generating rhythmic motor activity (the spinal central pattern generator, CPG). Emerging anatomical and electrophysiological information on the putative subpopulations of DSCT and VSCT neurons suggest differentiated functions for some of the subpopulations. Multiple lines of evidence support the notion that sensory input is not the only source driving DSCT neurons and, overall, there is a greater similarity between DSCT and VSCT activity than previously acknowledged. Indeed the majority of DSCT cells can be driven by spinal CPGs for locomotion and scratch without phasic sensory input. It thus seems natural to propose the possibility that CPG input to some of these neurons may contribute to distinguishing sensory inputs that are a consequence of the active locomotion from those resulting from perturbations in the external world. PMID:23613538

VEGFR-1 Expressed by Malignant Melanoma-Initiating Cells Is Required for Tumor Growth

PubMed Central

Frank, Natasha Y.; Schatton, Tobias; Kim, Soo; Zhan, Qian; Wilson, Brian J.; Ma, Jie; Saab, Karim R.; Osherov, Veronika; Widlund, Hans R.; Gasser, Martin; Waaga-Gasser, Ana-Maria; Kupper, Thomas S.; Murphy, George F.; Frank, Markus H.

2011-01-01

Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5+ melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31− vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5+ MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5+ tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5+ subpopulations that constitutively expressed VEGFR-1 but not in ABCB5− bulk populations that were predominantly VEGFR-1−. In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5+ VM morphology and inhibited ABCB5+ VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by >90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. PMID:21212411

VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth.

PubMed

Frank, Natasha Y; Schatton, Tobias; Kim, Soo; Zhan, Qian; Wilson, Brian J; Ma, Jie; Saab, Karim R; Osherov, Veronika; Widlund, Hans R; Gasser, Martin; Waaga-Gasser, Ana-Maria; Kupper, Thomas S; Murphy, George F; Frank, Markus H

2011-02-15

Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5(+) melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31(-) vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5(+) MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5(+) tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5(+) subpopulations that constitutively expressed VEGFR-1 but not in ABCB5(-) bulk populations that were predominantly VEGFR-1(-). In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5(+) VM morphology and inhibited ABCB5(+) VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by > 90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. ©2011 AACR.

Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells

PubMed Central

Miao, Xin; Koch, Gilbert; Ait-Oudhia, Sihem; Straubinger, Robert M.; Jusko, William J.

2016-01-01

Combinations of gemcitabine and trabectedin exert modest synergistic cytotoxic effects on two pancreatic cancer cell lines. Here, systems pharmacodynamic (PD) models that integrate cellular response data and extend a prototype model framework were developed to characterize dynamic changes in cell cycle phases of cancer cell subpopulations in response to gemcitabine and trabectedin as single agents and in combination. Extensive experimental data were obtained for two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3), including cell proliferation rates over 0–120 h of drug exposure, and the fraction of cells in different cell cycle phases or apoptosis. Cell cycle analysis demonstrated that gemcitabine induced cell cycle arrest in S phase, and trabectedin induced transient cell cycle arrest in S phase that progressed to G2/M phase. Over time, cells in the control group accumulated in G0/G1 phase. Systems cell cycle models were developed based on observed mechanisms and were used to characterize both cell proliferation and cell numbers in the sub G1, G0/G1, S, and G2/M phases in the control and drug-treated groups. The proposed mathematical models captured well both single and joint effects of gemcitabine and trabectedin. Interaction parameters were applied to quantify unexplainable drug-drug interaction effects on cell cycle arrest in S phase and in inducing apoptosis. The developed models were able to identify and quantify the different underlying interactions between gemcitabine and trabectedin, and captured well our large datasets in the dimensions of time, drug concentrations, and cellular subpopulations. PMID:27895579

Evidence for the separate human T-lymphocyte subpopulations that collaborate with autologous monocyte/macrophages in the elaboration of colony-stimulating activity and those that suppress this collaboration.

PubMed

Verma, D S; Johnston, D A; McCredie, K B

1983-11-01

We investigated the interaction of monocyte/macrophages and autologous T lymphocytes in the methanol extraction residue (MER) of BCG-induced production of granulocyte-macrophage colony-stimulating activity (CSA). Coincubation of monocyte/macrophages and T lymphocytes at a 1:3 ratio produces an optimum collaboration; a change to a 1:9 ratio diminished this collaboration. Coincubation of monocyte/macrophages and T lymphocytes primed with lithium carbonate (2 meq/liter) for 40 hr synergistically increased CSA elaboration and prevented the decline in CSA noted for the 1:9 monocyte/macrophage: T lymphocyte ratio. In contrast, concanavalin-A-primed T lymphocytes did not enhance CSA elaboration at any monocyte/macrophage:T lymphocyte ratio except, occasionally, at 1:9. However, this was overcome if the T lymphocytes were primed with both concanavalin-A and lithium carbonate before their coincubation with monocyte/macrophages. Further cell-mixing experiments revealed that concanavalin-A-primed T lymphocytes contained a subpopulation that suppressed monocyte/macrophage and T-lymphocyte collaboration. Activation of suppressor T lymphocytes could be effectively prevented by lithium carbonate and, in a dose-dependent manner, by irradiation. Also, suppressor T lymphocytes not only diminished the elaboration of colony-stimulating factor(s), but also elaborated an inhibitor of granulocyte-macrophage colony-forming cells. We further demonstrated that the respective hemopoietic helper and suppressor T-lymphocyte activities could be enriched with OKT8- (or OKT4+) and OKT8+ subpopulations.

Osteoarthritis subpopulations and implications for clinical trial design

PubMed Central

2011-01-01

Treatment guidelines for osteoarthritis have stressed the need for research on clinical predictors of response to different treatments. However, identifying such clinical predictors of response is less easy than it seems, and there is not a given classification of osteoarthritis subpopulations. This review article highlights the key methodical issues when analyzing and designing clinical studies to detect important subgroups with respect to treatment effect. In addition, we discuss the main osteoarthritis subpopulations and give examples of how specific treatment effects in these subpopulations have been assessed. PMID:21470393

Automatic Classification of Cellular Expression by Nonlinear Stochastic Embedding (ACCENSE).

PubMed

Shekhar, Karthik; Brodin, Petter; Davis, Mark M; Chakraborty, Arup K

2014-01-07

Mass cytometry enables an unprecedented number of parameters to be measured in individual cells at a high throughput, but the large dimensionality of the resulting data severely limits approaches relying on manual "gating." Clustering cells based on phenotypic similarity comes at a loss of single-cell resolution and often the number of subpopulations is unknown a priori. Here we describe ACCENSE, a tool that combines nonlinear dimensionality reduction with density-based partitioning, and displays multivariate cellular phenotypes on a 2D plot. We apply ACCENSE to 35-parameter mass cytometry data from CD8(+) T cells derived from specific pathogen-free and germ-free mice, and stratify cells into phenotypic subpopulations. Our results show significant heterogeneity within the known CD8(+) T-cell subpopulations, and of particular note is that we find a large novel subpopulation in both specific pathogen-free and germ-free mice that has not been described previously. This subpopulation possesses a phenotypic signature that is distinct from conventional naive and memory subpopulations when analyzed by ACCENSE, but is not distinguishable on a biaxial plot of standard markers. We are able to automatically identify cellular subpopulations based on all proteins analyzed, thus aiding the full utilization of powerful new single-cell technologies such as mass cytometry.

Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP.

PubMed

Lazar, Ann A; Bonetti, Marco; Cole, Bernard F; Yip, Wai-Ki; Gelber, Richard D

2016-04-01

Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial. We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling. The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation. © The Author(s) 2015.

Decomposition of the Total Effect in the Presence of Multiple Mediators and Interactions.

PubMed

Bellavia, Andrea; Valeri, Linda

2018-06-01

Mediation analysis allows decomposing a total effect into a direct effect of the exposure on the outcome and an indirect effect operating through a number of possible hypothesized pathways. Recent studies have provided formal definitions of direct and indirect effects when multiple mediators are of interest and have described parametric and semiparametric methods for their estimation. Investigating direct and indirect effects with multiple mediators, however, can be challenging in the presence of multiple exposure-mediator and mediator-mediator interactions. In this paper we derive a decomposition of the total effect that unifies mediation and interaction when multiple mediators are present. We illustrate the properties of the proposed framework in a secondary analysis of a pragmatic trial for the treatment of schizophrenia. The decomposition is employed to investigate the interplay of side effects and psychiatric symptoms in explaining the effect of antipsychotic medication on quality of life in schizophrenia patients. Our result offers a valuable tool to identify the proportions of total effect due to mediation and interaction when more than one mediator is present, providing the finest decomposition of the total effect that unifies multiple mediators and interactions.

Solvable model for chimera states of coupled oscillators.

PubMed

Abrams, Daniel M; Mirollo, Rennie; Strogatz, Steven H; Wiley, Daniel A

2008-08-22

Networks of identical, symmetrically coupled oscillators can spontaneously split into synchronized and desynchronized subpopulations. Such chimera states were discovered in 2002, but are not well understood theoretically. Here we obtain the first exact results about the stability, dynamics, and bifurcations of chimera states by analyzing a minimal model consisting of two interacting populations of oscillators. Along with a completely synchronous state, the system displays stable chimeras, breathing chimeras, and saddle-node, Hopf, and homoclinic bifurcations of chimeras.

Curvature-Mediated Assembly of Janus Nanoparticles on Membrane Vesicles.

PubMed

Bahrami, Amir Houshang; Weikl, Thomas R

2018-02-14

Besides direct particle-particle interactions, nanoparticles adsorbed to biomembranes experience indirect interactions that are mediated by the membrane curvature arising from particle adsorption. In this Letter, we show that the curvature-mediated interactions of adsorbed Janus particles depend on the initial curvature of the membrane prior to adsorption, that is, on whether the membrane initially bulges toward or away from the particles in our simulations. The curvature-mediated interaction can be strongly attractive for Janus particles adsorbed to the outside of a membrane vesicle, which initially bulges away from the particles. For Janus particles adsorbed to the vesicle inside, in contrast, the curvature-mediated interactions are repulsive. We find that the area fraction of the adhesive Janus particle surface is an important control parameter for the curvature-mediated interaction and assembly of the particles, besides the initial membrane curvature.

Psychometric Consequences of Subpopulation Item Parameter Drift

ERIC Educational Resources Information Center

Huggins-Manley, Anne Corinne

2017-01-01

This study defines subpopulation item parameter drift (SIPD) as a change in item parameters over time that is dependent on subpopulations of examinees, and hypothesizes that the presence of SIPD in anchor items is associated with bias and/or lack of invariance in three psychometric outcomes. Results show that SIPD in anchor items is associated…

Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically defined disease in post-menopausal women

USDA-ARS?s Scientific Manuscript database

The association of coronary heart disease (CHD) with subpopulations of triglyceride (TG)-rich lipoproteins and high-density lipoproteins (HDL) is established in men, but has not been well characterized in women. Plasma HDL subpopulation concentrations, quantified by 2-dimensional gel electrophoresis...

Access to Health Care Among Latinos of Mexican Descent in "Colonias" in Two Texas Counties

ERIC Educational Resources Information Center

Ortiz, Larry; Arizmendi, Lydia; Cornelius, Llewellyn J.

2004-01-01

Critical to resolving the problem of health disparities among Latinos is examining the needs within ethnic subpopulations. This paper focused on the unique challenges encountered by one ethnic subpopulation -- Latinos of Mexican descent living in colonias. Findings reaffirm the importance of looking within ethnic subpopulations to understand the…

Respiratory and physiological characteristics in subpopulations of Great Basin cheatgrass

Treesearch

V. Wallace McCarlie; Lee D. Hansen; Bruce N. Smith

2001-01-01

Cheatgrass (Bromus tectorum L.) is a dominant weed that has increased the frequency of wildfire in the Great Basin since its introduction approximately 106 years ago. Characteristics of respiratory metabolism were examined in eleven subpopulations from different habitats. Seeds from each subpopulation were germinated (4mm radicle) and metabolic heat rates (q) and...

Effect of sexual steroids on boar kinematic sperm subpopulations.

PubMed

Ayala, E M E; Aragón, M A

2017-11-01

Here, we show the effects of sexual steroids, progesterone, testosterone, or estradiol on motility parameters of boar sperm. Sixteen commercial seminal doses, four each of four adult boars, were analyzed using computer assisted sperm analysis (CASA). Mean values of motility parameters were analyzed by bivariate and multivariate statistics. Principal component analysis (PCA), followed by hierarchical clustering, was applied on data of motility parameters, provided automatically as intervals by the CASA system. Effects of sexual steroids were described in the kinematic subpopulations identified from multivariate statistics. Mean values of motility parameters were not significantly changed after addition of sexual steroids. Multivariate graphics showed that sperm subpopulations were not sensitive to the addition of either testosterone or estradiol, but sperm subpopulations responsive to progesterone were found. Distribution of motility parameters were wide in controls but sharpened at distinct concentrations of progesterone. We conclude that kinematic sperm subpopulations responsive to progesterone are present in boar semen, and these subpopulations are masked in evaluations of mean values of motility parameters. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

Associating seasonal range characteristics with survival of female white-tailed deer

USGS Publications Warehouse

Klaver, R.W.; Jenks, J.A.; Deperno, C.S.; Griffin, S.L.

2008-01-01

Delineating populations is critical for understanding population dynamics and managing habitats. Our objective was to delineate subpopulations of migratory female white-tailed deer (Odocoileus virginianus) in the central Black Hills, South Dakota and Wyoming, USA, on summer and winter ranges. We used fuzzy classification to assign radiocollared deer to subpopulations based on spatial location, characterized subpopulations by trapping sites, and explored relationships among survival of subpopulations and habitat variables. In winter, Kaplan-Meier estimates for subpopulations indicated 2 groups: high (S = 0.991 ?? 0.005 [x- ?? SE]) and low (S = 0.968 ?? 0.007) weekly survivorship. Survivorship increased with basal area per hectare of trees, average diameter at breast height of trees, percent cover of slash, and total point-center quarter distance of trees. Cover of grass and forbs were less for the high survivorship than the lower survivorship group. In summer, deer were spaced apart with mixed associations among subpopulations. Habitat manipulations that promote or maintain large trees (i.e., basal area = 14.8 m2/ha and average dbh of trees = 8.3 cm) would seem to improve adult survival of deer in winter.

Discrete microfluidics for the isolation of circulating tumor cell subpopulations targeting fibroblast activation protein alpha and epithelial cell adhesion molecule.

PubMed

Witek, Małgorzata A; Aufforth, Rachel D; Wang, Hong; Kamande, Joyce W; Jackson, Joshua M; Pullagurla, Swathi R; Hupert, Mateusz L; Usary, Jerry; Wysham, Weiya Z; Hilliard, Dawud; Montgomery, Stephanie; Bae-Jump, Victoria; Carey, Lisa A; Gehrig, Paola A; Milowsky, Matthew I; Perou, Charles M; Soper, John T; Whang, Young E; Yeh, Jen Jen; Martin, George; Soper, Steven A

2017-01-01

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges.

Separation and characterization of high-density lipoprotein subpopulations by gel permeation chromatography.

PubMed

Clifton, P M; MacKinnon, A M; Barter, P J

1987-02-20

High-density lipoproteins (HDL) contain at least five distinct subpopulations when analyzed by gradient gel electrophoresis. This report represents the first description of a simple technique for isolating these subpopulations of HDL in quantities sufficient to enable characterization in terms of particle size, apolipoprotein AI and apolipoprotein AII content and chemical composition. Lipoproteins were separated and subfractionated on a column of Superose 6B using a fast protein liquid chromatography system. Five normal subjects were studied: HDL2b and HDL3a were isolated as essentially single subpopulations from all subjects, while HDL2a could be isolated from only three of the subjects. HDL3b was isolated in a relatively impure form (70%) from all subjects. Identical subpopulations were identified in each subject by gradient gel electrophoresis of unseparated HDL.

Seasonal genetic partitioning in the neotropical malaria vector, Anopheles darlingi

PubMed Central

2014-01-01

Background Anopheles darlingi is the main malaria mosquito vector in the Amazonia region. In spite of being considered a riverine, forest-dwelling species, this mosquito is becoming more abundant in peri-urban areas, increasing malaria risk. This has been associated with human-driven environmental changes such as deforestation. Methods Microsatellites were used to characterize A. darlingi from seven localities along the Madeira River, Rondônia (Brazil), collected in the early and late periods of the rainy season. Results Two genetically distinct subpopulations were detected: one (subpopulation A) was associated with the late rainfall period and seems to be ecologically closer to the typical forest A. darlingi; the other (subpopulation B) was associated with the early rainfall period and is probably more adapted to drier conditions by exploiting permanent anthropogenic breeding sites. Results suggest also a pattern of asymmetric introgression, with more subpopulation A alleles introgressed into subpopulation B. Both subpopulations (and admixed mosquitoes) presented similar malaria infection rates, highlighting the potential for perennial malaria transmission in the region. Conclusions The co-occurrence of two genetically distinct subpopulations of A. darlingi adapted to different periods of rainfall may promote a more perennial transmission of malaria throughout the year. These findings, in a context of strong environmental impact due to deforestation and dam construction, have serious implications for malaria epidemiology and control in the Amazonian region. PMID:24885508

Stress and Alcohol Use in Rural Chinese Residents: A Moderated Mediation Model Examining the Roles of Resilience and Negative Emotions

PubMed Central

Wang, Yan; Chen, Xinguang

2015-01-01

Objective Little research has been done on alcohol use and dependence among rural residents in China, a sub-population that might be under increased stress due to the rapid modernization and urbanization processes. We aimed to assess rural residents’ levels of stress, negative emotions, resilience, alcohol use/dependence and the complex relationships among them. Methods Survey data from a large random sample (n = 1145, mean age = 35.9, SD = 7.7, 50.7% male) of rural residents in Wuhan, China were collected using Audio Computer-Assisted Self-Interview. Results The sample had high prevalence of frequently perceived stress (47%) and high prevalence of ever (54.4%), past 30-day (40.4%), and binge drinking (13.8%). Approximately 11% met the criterion for intermediate to severe alcohol dependence. Mediation analysis indicated that the association between perceived stress (predictor) and alcohol dependence (outcome) was fully mediated by anxiety (indirect effect = .203, p < .01) and depression (indict effect =.158, p < .05); moderation analysis indicated that association between stress and two negative emotions (mediators) was significantly modified by resilience (moderator); an integrative moderated mediation analysis indicated that the indirect effect from stress to alcohol dependence through negative emotions was also moderated by resilience. Conclusions Negative emotions play a key role in bridging stress and alcohol dependence, while resilience significantly buffers the impact of stress on depression, reducing the risk of alcohol dependence. Resilience training may be an effective component for alcohol intervention in rural China. PMID:26342628

Methods and Measures: Growth Mixture Modeling--A Method for Identifying Differences in Longitudinal Change among Unobserved Groups

ERIC Educational Resources Information Center

Ram, Nilam; Grimm, Kevin J.

2009-01-01

Growth mixture modeling (GMM) is a method for identifying multiple unobserved sub-populations, describing longitudinal change within each unobserved sub-population, and examining differences in change among unobserved sub-populations. We provide a practical primer that may be useful for researchers beginning to incorporate GMM analysis into their…

How and for whom does web-based acceptance and commitment therapy work? Mediation and moderation analyses of web-based ACT for depressive symptoms.

PubMed

Pots, Wendy T M; Trompetter, Hester R; Schreurs, Karlein M G; Bohlmeijer, Ernst T

2016-05-23

Acceptance and Commitment Therapy (ACT) has been demonstrated to be effective in reducing depressive symptoms. However, little is known how and for whom therapeutic change occurs, specifically in web-based interventions. This study focuses on the mediators, moderators and predictors of change during a web-based ACT intervention. Data from 236 adults from the general population with mild to moderate depressive symptoms, randomized to either web-based ACT (n = 82) or one of two control conditions (web-based Expressive Writing (EW; n = 67) and a waiting list (n = 87)), were analysed. Single and multiple mediation analyses, and exploratory linear regression analyses were performed using PROCESS and linear regression analyses, to examine mediators, moderators and predictors on pre- to post- and follow-up treatment change of depressive symptoms. The treatment effect of ACT versus the waiting list was mediated by psychological flexibility and two mindfulness facets. The treatment effect of ACT versus EW was not significantly mediated. The moderator analyses demonstrated that the effects of web-based ACT did not vary according to baseline patient characteristics when compared to both control groups. However, higher baseline depressive symptoms and positive mental health and lower baseline anxiety were identified as predictors of outcome across all conditions. Similar results are found for follow-up. The findings of this study corroborate the evidence that psychological flexibility and mindfulness are distinct process mechanisms that mediate the effects of web-based ACT intervention. The results indicate that there are no restrictions to the allocation of web-based ACT intervention and that web-based ACT can work for different subpopulations. Netherlands Trial Register NTR2736 . Registered 6 February 2011.

Polar Bear Conservation Status in Relation to Projected Sea-ice Conditions

NASA Astrophysics Data System (ADS)

Regehr, E. V.

2015-12-01

The status of the world's 19 subpopulations of polar bears (Ursus maritimus) varies as a function of sea-ice conditions, ecology, management, and other factors. Previous methods to project the response of polar bears to loss of Arctic sea ice—the primary threat to the species—include expert opinion surveys, Bayesian Networks providing qualitative stressor assessments, and subpopulations-specific demographic analyses. Here, we evaluated the global conservation status of polar bears using a data-based sensitivity analysis. First, we estimated generation length for subpopulations with available data (n=11). Second, we developed standardized sea-ice metrics representing habitat availability. Third, we projected global population size under alternative assumptions for relationships between sea ice and subpopulation abundance. Estimated generation length (median = 11.4 years; 95%CI = 9.8 to 13.6) and sea-ice change (median = loss of 1.26 ice-covered days per year; 95%CI = 0.70 to 3.37) varied across subpopulations. Assuming a one-to-one proportional relationship between sea ice and abundance, the median percent change in global population size over three polar bear generations was -30% (95%CI = -35% to -25%). Assuming a linear relationship between sea ice and normalized estimates of subpopulation abundance, median percent change was -4% (95% CI = -62% to +50%) or -43% (95% CI = -76% to -20%), depending on how subpopulations were grouped and how inference was extended from relatively well-studied subpopulations (n=7) to those with little or no data. Our findings suggest the potential for large reductions in polar bear numbers over the next three polar bear generations if sea-ice loss due to climate change continues as forecasted.

Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model.

PubMed

VanScoy, Brian; McCauley, Jennifer; Bhavnani, Sujata M; Ellis-Grosse, Evelyn J; Ambrose, Paul G

2016-09-01

Understanding the relationship between antibiotic exposure and amplification of bacterial subpopulations with reduced drug susceptibility over time is important for evaluating the adequacy of dosing regimens. We utilized a hollow-fiber infection model to identify the fosfomycin intravenous dosing regimens that prevented the amplification of Escherichia coli bacterial subpopulations with reduced fosfomycin susceptibility. The challenge isolate was E. coli ATCC 25922 (agar MIC with glucose-6-phosphate, 1 mg/liter; agar MIC without glucose-6-phosphate, 32 mg/liter). The fosfomycin dosing regimens studied were 1 to 12 g every 8 h for 10 days to approximate that planned for clinical use. The studies included a no-treatment control regimen. Two bacterial subpopulations were identified, one with reduced susceptibility with agar MIC values ranging from 32 to 128 mg/liter and the other resistant with agar MIC values of 256 to >1,024 mg/liter on plates containing 5× and 256× the baseline MIC value, respectively. An inverted-U-shaped function best described the relationship between the amplification of the two bacterial subpopulations and drug exposure. The lowest fosfomycin dosing regimen that did not amplify a bacterial subpopulation with reduced susceptibility was 4 g administered every 8 h. Nearly immediate amplification of bacterial subpopulations with reduced susceptibility was observed with fosfomycin dosing regimens consisting of 1 to 2 g every 8 h. These data will be useful to support the selection of fosfomycin dosing regimens that minimize the potential for on-therapy amplification of bacterial subpopulations with reduced susceptibility. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Sperm kinematic, head morphometric and kinetic-morphometric subpopulations in the blue fox (Alopex lagopus).

PubMed

Soler, Carles; Contell, Jesús; Bori, Lorena; Sancho, María; García-Molina, Almudena; Valverde, Anthony; Segarvall, Jan

2017-01-01

This work provides information on the blue fox ejaculated sperm quality needed for seminal dose calculations. Twenty semen samples, obtained by masturbation, were analyzed for kinematic and morphometric parameters by using CASA-Mot and CASA-Morph system and principal component (PC) analysis. For motility, eight kinematic parameters were evaluated, which were reduced to PC1, related to linear variables, and PC2, related to oscillatory movement. The whole population was divided into three independent subpopulations: SP1, fast cells with linear movement; SP2, slow cells and nonoscillatory motility; and SP3, medium speed cells and oscillatory movement. In almost all cases, the subpopulation distribution by animal was significantly different. Head morphology analysis generated four size and four shape parameters, which were reduced to PC1, related to size, and PC2, related to shape of the cells. Three morphometric subpopulations existed: SP1: large oval cells; SP2: medium size elongated cells; and SP3: small and short cells. The subpopulation distribution differed between animals. Combining the kinematic and morphometric datasets produced PC1, related to morphometric parameters, and PC2, related to kinematics, which generated four sperm subpopulations - SP1: high oscillatory motility, large and short heads; SP2: medium velocity with small and short heads; SP3: slow motion small and elongated cells; and SP4: high linear speed and large elongated cells. Subpopulation distribution was different in all animals. The establishment of sperm subpopulations from kinematic, morphometric, and combined variables not only improves the well-defined fox semen characteristics and offers a good conceptual basis for fertility and sperm preservation techniques in this species, but also opens the door to use this approach in other species, included humans.

Sperm kinematic, head morphometric and kinetic-morphometric subpopulations in the blue fox (Alopex lagopus)

PubMed Central

Soler, Carles; Contell, Jesús; Bori, Lorena; Sancho, María; García-Molina, Almudena; Valverde, Anthony; Segarvall, Jan

2017-01-01

This work provides information on the blue fox ejaculated sperm quality needed for seminal dose calculations. Twenty semen samples, obtained by masturbation, were analyzed for kinematic and morphometric parameters by using CASA-Mot and CASA-Morph system and principal component (PC) analysis. For motility, eight kinematic parameters were evaluated, which were reduced to PC1, related to linear variables, and PC2, related to oscillatory movement. The whole population was divided into three independent subpopulations: SP1, fast cells with linear movement; SP2, slow cells and nonoscillatory motility; and SP3, medium speed cells and oscillatory movement. In almost all cases, the subpopulation distribution by animal was significantly different. Head morphology analysis generated four size and four shape parameters, which were reduced to PC1, related to size, and PC2, related to shape of the cells. Three morphometric subpopulations existed: SP1: large oval cells; SP2: medium size elongated cells; and SP3: small and short cells. The subpopulation distribution differed between animals. Combining the kinematic and morphometric datasets produced PC1, related to morphometric parameters, and PC2, related to kinematics, which generated four sperm subpopulations – SP1: high oscillatory motility, large and short heads; SP2: medium velocity with small and short heads; SP3: slow motion small and elongated cells; and SP4: high linear speed and large elongated cells. Subpopulation distribution was different in all animals. The establishment of sperm subpopulations from kinematic, morphometric, and combined variables not only improves the well-defined fox semen characteristics and offers a good conceptual basis for fertility and sperm preservation techniques in this species, but also opens the door to use this approach in other species, included humans. PMID:27751987

A cluster analysis method for identification of subpopulations of cells in flow cytometric list-mode arrays

NASA Technical Reports Server (NTRS)

Li, Z. K.

1985-01-01

A specialized program was developed for flow cytometric list-mode data using an heirarchical tree method for identifying and enumerating individual subpopulations, the method of principal components for a two-dimensional display of 6-parameter data array, and a standard sorting algorithm for characterizing subpopulations. The program was tested against a published data set subjected to cluster analysis and experimental data sets from controlled flow cytometry experiments using a Coulter Electronics EPICS V Cell Sorter. A version of the program in compiled BASIC is usable on a 16-bit microcomputer with the MS-DOS operating system. It is specialized for 6 parameters and up to 20,000 cells. Its two-dimensional display of Euclidean distances reveals clusters clearly, as does its 1-dimensional display. The identified subpopulations can, in suitable experiments, be related to functional subpopulations of cells.

Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells.

PubMed

Buettner, Florian; Natarajan, Kedar N; Casale, F Paolo; Proserpio, Valentina; Scialdone, Antonio; Theis, Fabian J; Teichmann, Sarah A; Marioni, John C; Stegle, Oliver

2015-02-01

Recent technical developments have enabled the transcriptomes of hundreds of cells to be assayed in an unbiased manner, opening up the possibility that new subpopulations of cells can be found. However, the effects of potential confounding factors, such as the cell cycle, on the heterogeneity of gene expression and therefore on the ability to robustly identify subpopulations remain unclear. We present and validate a computational approach that uses latent variable models to account for such hidden factors. We show that our single-cell latent variable model (scLVM) allows the identification of otherwise undetectable subpopulations of cells that correspond to different stages during the differentiation of naive T cells into T helper 2 cells. Our approach can be used not only to identify cellular subpopulations but also to tease apart different sources of gene expression heterogeneity in single-cell transcriptomes.

Single cell RNA sequencing of stem cell-derived retinal ganglion cells.

PubMed

Daniszewski, Maciej; Senabouth, Anne; Nguyen, Quan H; Crombie, Duncan E; Lukowski, Samuel W; Kulkarni, Tejal; Sluch, Valentin M; Jabbari, Jafar S; Chamling, Xitiz; Zack, Donald J; Pébay, Alice; Powell, Joseph E; Hewitt, Alex W

2018-02-13

We used single cell sequencing technology to characterize the transcriptomes of 1,174 human embryonic stem cell-derived retinal ganglion cells (RGCs) at the single cell level. The human embryonic stem cell line BRN3B-mCherry (A81-H7), was differentiated to RGCs using a guided differentiation approach. Cells were harvested at day 36 and prepared for single cell RNA sequencing. Our data indicates the presence of three distinct subpopulations of cells, with various degrees of maturity. One cluster of 288 cells showed increased expression of genes involved in axon guidance together with semaphorin interactions, cell-extracellular matrix interactions and ECM proteoglycans, suggestive of a more mature RGC phenotype.

Genetic diversity and population structure of African village dogs based on microsatellite and immunity-related molecular markers.

PubMed

Vychodilova, Leona; Necesankova, Michaela; Albrechtova, Katerina; Hlavac, Jan; Modry, David; Janova, Eva; Vyskocil, Mirko; Mihalca, Andrei D; Kennedy, Lorna J; Horin, Petr

2018-01-01

The village and street dogs represent a unique model of canine populations. In the absence of selective breeding and veterinary care, they are subject mostly to natural selection. Their analyses contribute to understanding general mechanisms governing the genetic diversity, evolution and adaptation. In this study, we analyzed the genetic diversity and population structure of African village dogs living in villages in three different geographical areas in Northern Kenya. Data obtained for neutral microsatellite molecular markers were compared with those computed for potentially non-neutral markers of candidate immunity-related genes. The neutral genetic diversity was similar to other comparable village dog populations studied so far. The overall genetic diversity in microsatellites was higher than the diversity of European pure breeds, but it was similar to the range of diversity observed in a group composed of many European breeds, indicating that the African population has maintained a large proportion of the genetic diversity of the canine species as a whole. Microsatellite marker diversity indicated that the entire population is subdivided into three genetically distinct, although closely related subpopulations. This genetical partitioning corresponded to their geographical separation and the observed gene flow well correlated with the communication patterns among the three localities. In contrast to neutral microsatellites, the genetic diversity in immunity-related candidate SNP markers was similar across all three subpopulations and to the European group. It seems that the genetic structure of this particular population of Kenyan village dogs is mostly determined by geographical and anthropogenic factors influencing the gene flow between various subpopulations rather than by biological factors, such as genetic contribution of original migrating populations and/or the pathogen-mediated selection. On the other hand, the study of oldest surviving dogs suggested a biological mechanism, i.e. a possible advantage of the overal heterozygosity marked by the the microsatellite loci analyzed.

Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance.

PubMed

Wartenberg, Martin; Cibin, Silvia; Zlobec, Inti; Vassella, Erik; Eppenberger-Castori, Serenella M M; Terracciano, Luigi; Eichmann, Micha; Worni, Mathias; Gloor, Beat; Perren, Aurel; Karamitopoulou, Eva

2018-04-16

Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC-cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. A well-characterized PDAC-cohort (n=110) underwent next-generation sequencing with a hotspot cancer panel, while Next-generation Tissue-Microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM) and DNA mismatch-repair proteins. Previous data on FOXP3 were integrated. Immune-cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8. 2017), survival and epithelial-mesenchymal-transition (EMT)-like tumor budding.  Results: Three PDAC-subtypes were identified: the "immune-escape" (54%), poor in T- and B-cells and enriched in FOXP3+Tregs, with high-grade budding, frequent CDKN2A- , SMAD4- and PIK3CA-mutations and poor outcome; the "immune-rich" (35%), rich in T- and B-cells and poorer in FOXP3+Tregs, with infrequent budding, lower CDKN2A- and PIK3CA-mutation rate and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11, ATM) and the best outcome; and the "immune-exhausted" (11%) with immunogenic microenvironment and two subpopulations: one with PD-L1-expression and high PIK3CA-mutation rate and a microsatellite-unstable subpopulation with high prevalence of JAK3-mutations. The combination of low budding, low stromal FOXP3-counts, presence of TLTs and absence of CDKN2A-mutations confers significant survival advantage in PDAC-patients. Immune host responses correlate with tumor characteristics leading to morphologically recognizable PDAC-subtypes with prognostic/predictive significance. Copyright ©2018, American Association for Cancer Research.

Differential sensitivity to cadmium of immunomarkers measured in hemocyte subpopulations of zebra mussel Dreissena polymorpha.

PubMed

Evariste, Lauris; Rioult, Damien; Brousseau, Pauline; Geffard, Alain; David, Elise; Auffret, Michel; Fournier, Michel; Betoulle, Stéphane

2017-03-01

Increasing discharge of industrial wastes into the environment results in pollution transfer towards hydrosystems. These activities release heavy metals such as cadmium, known as persistent pollutant that is accumulated by molluscs and exercise immunotoxicological effects. Among molluscs, the zebra mussel, Dreissena polymorpha constitutes a suitable support for freshwater ecotoxicological studies. In molluscs, homeostasis maintain is ensured in part by hemocytes that are composed of several cell populations involved in multiple physiological processes such as cell-mediated immune response or metal metabolism. Thus, hemocytes constitute a target of concern to study adverse effects of heavy metals. The objectives of this work were to determine whether immune-related endpoints assessed were of different sensitivity to cadmium and whether hemocyte functionalities were differentially affected depending on hemocyte subpopulation considered. Hemocytes were exposed ex vivo to concentrations of cadmium ranging from 10 -6 M to 10 -3 M for 21h prior flow cytometric analysis of cellular markers. Measured parameters (viability, phagocytosis, oxidative activity, lysosomal content) decreased in a dose-dependent manner with sensitivity differences depending on endpoint and cell type considered. Our results indicated that phagocytosis related endpoints were the most sensitive studied mechanisms to cadmium compared to other markers with EC 50 of 3.71±0.53×10 -4 M for phagocytic activity and 2.79±0.19×10 -4 M considering mean number of beads per phagocytic cell. Lysosomal content of granulocytes was less affected compared to other cell types, indicating lower sensitivity to cadmium. This suggests that granulocyte population is greatly involved in metal metabolism. Mitochondrial activity was reduced only in blast-like hemocytes that are considered to be cell precursors. Impairment of these cell functionalities may potentially compromise functions ensured by differentiated cells. We concluded that analysis of hemocyte activities should be performed at sub-population scale for more accurate results in ecotoxicological studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Glycophenotype of breast and prostate cancer stem cells treated with thieno[2,3-b]pyridine anticancer compound.

PubMed

Mastelić, Angela; Čikeš Čulić, Vedrana; Režić Mužinić, Nikolina; Vuica-Ross, Milena; Barker, David; Leung, Euphemia Y; Reynisson, Jóhannes; Markotić, Anita

2017-01-01

Tumor progression may be driven by a small subpopulation of cancer stem cells (CSCs characterized by CD44 + /CD24 - phenotype). We investigated the influence of a newly developed thienopyridine anticancer compound (3-amino-5-oxo- N -naphthyl-5,6,7, 8-tetrahydrothieno[2,3- b ]quinoline-2-carboxamide, 1 ) on the growth, survival and glycophenotype (CD15s and GM3 containing neuraminic acid substituted with acetyl residue, NeuAc) of breast and prostate cancer stem/progenitor-like cell population. MDA-MB-231 and Du-145 cells were incubated with compound 1 alone or in combination with paclitaxel. The cellular metabolic activity was determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The type of cell death induced by 48-h treatment was assessed using a combination of Annexin-V-FITC and propidium iodide staining. Flow cytometric analysis was performed to detect the percentage of CD44 + /CD24 - cells, and GM3 and CD15s positive CSCs, as well as the expression of GM3 and CD15s per one CSC, in both cell lines. Compound 1 produces a dose- and time-dependent cytotoxicity, mediated mainly by apoptosis in breast cancer cells, and slightly (2.3%) but statistically significant lowering breast CSC subpopulation. GM3 expression per one breast CSC was increased, and the percentage of prostate GM3 + CSC subpopulation was decreased in cells treated with compound 1 compared with non-treated cells. The percentage of CD15s + CSCs was lower in both cell lines after treatment with compound 1 . Considering that triple-negative breast cancers are characterized by an increased percentage of breast CSCs and knowing their association with an increased risk of metastasis and mortality, compound 1 is a potentially effective drug for triple-negative breast cancer treatment.

Med5(Nut1) and Med17(Srb4) Are Direct Targets of Mediator Histone H4 Tail Interactions

PubMed Central

Liu, Zhongle; Myers, Lawrence C.

2012-01-01

The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone tail peptides substituted with an amino acid analog that is a UV activatible crosslinker, we have identified specific subunits within Mediator that participate in histone tail interactions. Using Mediator purified from mutant yeast strains we have evaluated the impact of these subunits on histone tail binding. This analysis has identified the Med5 subunit of Mediator as a target for histone tail interactions and suggests that the previously observed effect of med5 mutations on telomeric heterochromatin and silencing is direct. PMID:22693636

Mediator binds to boundaries of chromosomal interaction domains and to proteins involved in DNA looping, RNA metabolism, chromatin remodeling, and actin assembly

PubMed Central

Chereji, Răzvan V.; Bharatula, Vasudha; Elfving, Nils; Blomberg, Jeanette; Larsson, Miriam; Morozov, Alexandre V.; Broach, James R.

2017-01-01

Abstract Mediator is a multi-unit molecular complex that plays a key role in transferring signals from transcriptional regulators to RNA polymerase II in eukaryotes. We have combined biochemical purification of the Saccharomyces cerevisiae Mediator from chromatin with chromatin immunoprecipitation in order to reveal Mediator occupancy on DNA genome-wide, and to identify proteins interacting specifically with Mediator on the chromatin template. Tandem mass spectrometry of proteins in immunoprecipitates of mediator complexes revealed specific interactions between Mediator and the RSC, Arp2/Arp3, CPF, CF 1A and Lsm complexes in chromatin. These factors are primarily involved in chromatin remodeling, actin assembly, mRNA 3′-end processing, gene looping and mRNA decay, but they have also been shown to enter the nucleus and participate in Pol II transcription. Moreover, we have found that Mediator, in addition to binding Pol II promoters, occupies chromosomal interacting domain (CID) boundaries and that Mediator in chromatin associates with proteins that have been shown to interact with CID boundaries, such as Sth1, Ssu72 and histone H4. This suggests that Mediator plays a significant role in higher-order genome organization. PMID:28575439

Plasma amino acid profiles in healthy East Asian subpopulations living in Japan.

PubMed

Nakamura, Hidehiro; Nishikata, Natsumi; Kawai, Nobuhiro; Imaizumi, Akira; Miyano, Hiroshi; Mori, Maiko; Yamamoto, Hiroshi; Noguchi, Yasushi

2016-01-01

Profiles of plasma free amino acids (PFAAs) have been utilized as biomarkers to detect various diseases. However, few studies have investigated whether ethnicity or specific subpopulations within East Asia influence PFAA concentrations. A total of 95 healthy volunteers living in Japan, including 31 Japanese individuals, 36 Korean individuals and 28 Chinese individuals, were enrolled. Participants' PFAA levels were measured by high-performance liquid chromatography mass spectrometry, and the effects of factors such as sex, age, body mass index (BMI) and subpopulation on PFAA profiles were analyzed. With the exception of glutamine and α-aminobutyric acid, there were no significant differences among the three examined subpopulations with respect to either the means or the distributions of PFAA concentrations. A multiple regression analysis revealed that most of the PFAA concentrations were significantly related to sex. Ornithine concentrations, glutamate concentrations, and glutamine and α-aminobutyric acid concentrations were significantly associated with age, BMI, and Chinese subpopulation, respectively. The study results indicate that the contributions of subpopulation within East Asia to PFAA profiles are small, particularly relative to the contributions provided by sex. © 2015 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc.

Quantitative analysis of immune cell subset infiltration of supraspinatus muscle after severe rotator cuff injury.

PubMed

Krieger, J R; Tellier, L E; Ollukaren, M T; Temenoff, J S; Botchwey, E A

2017-06-01

Rotator cuff tears cause muscle degeneration that is characterized by myofiber atrophy, fatty infiltration, and fibrosis and is minimally responsive to current treatment options. The underlying pathogenesis of rotator cuff muscle degeneration remains to be elucidated, and increasing evidence implicates immune cell infiltration as a significant factor. Because immune cells are comprised of highly heterogeneous subpopulations that exert divergent effects on injured tissue, understanding trafficking and accumulation of immune subpopulations may hold the key to more effective therapies. The present study quantifies subpopulations of immune cells infiltrating the murine supraspinatus muscle after severe rotator cuff injury that includes tenotomy and denervation. Rotator cuff injury stimulates dramatic infiltration of mononuclear phagocytes, enriches mononuclear phagocytes in non-classical subpopulations, and enriches T lymphocytes in T H and T reg subpopulations. The combination of tenotomy plus denervation significantly increases mononuclear phagocyte infiltration, enriches macrophages in the non-classical subpopulation, and decreases T lymphocyte enrichment in T H cells compared to tenotomy alone. Depletion of circulating monocytes via liposomal clodronate accelerates supraspinatus atrophy after tenotomy and denervation. The study may aid rational design of immunologically smart therapies that harness immune cells to enhance outcomes after rotator cuff tears.

Langerhans' cell expression of the selectin ligand, sialyl Lewis x.

PubMed Central

Ross, E L; Barker, J N; Allen, M H; Chu, A C; Groves, R W; MacDonald, D M

1994-01-01

Cellular adhesion molecules play a central role in leucocyte migration through peripheral blood and tissues. A crucial stage in these events in selectin-mediated adhesion involving E-selectin expressed on activated endothelium interacting with a range of carbohydrate ligands expressed by specific subpopulations of leucocytes. As such mechanisms may be relevant to bone marrow-derived dendritic epidermal Langerhans' cell (LC) migration, expression of these carbohydrate ligands was assessed immunocytochemically in whole skin biopsies and in epidermal cell suspensions obtained from adult humans. Double-labelling experiments revealed that sialyl Lewis x, recognized by the monoclonal antibody CSLEX1, was expressed on epidermal LC (n = 9). Furthermore, expression was enhanced at 24 hr following epicutaneous application of antigen and in the inflammatory disorder psoriasis (n = 10). E-selectin was concomitantly strongly expressed on dermal endothelium in psoriasis and allergic contact dermatitis. Intradermal injection of the T-cell-derived cytokine interferon-gamma (IFN-gamma) led to increased LC expression of sialyl Lewis x. In epidermal cell suspensions, in contrast to keratinocytes, CD1a+ cells expressed sialyl Lewis x, intensity of which was enhanced after 4 days in culture. CSLEX1 staining could be abolished and CD15 (non-sialated Lewis x) expression induced by saponification and treatment with neuraminidase. Expression of other selectin ligands was also examined. While the cutaneous lymphocyte antigen defined by the monoclonal antibody HECA-452 reacted with a small minority of LC, sialyl Lewis a and sulphatide were not expressed under any experimental conditions. These studies indicate that E-selectin-sialyl Lewis x interactions are potentially important in LC migration, both into and out of skin. Images Figure 2 Figure 3 Figure 5 Figure 6 PMID:7512530

Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

PubMed

Berko, Esther R; Suzuki, Masako; Beren, Faygel; Lemetre, Christophe; Alaimo, Christine M; Calder, R Brent; Ballaban-Gil, Karen; Gounder, Batya; Kampf, Kaylee; Kirschen, Jill; Maqbool, Shahina B; Momin, Zeineen; Reynolds, David M; Russo, Natalie; Shulman, Lisa; Stasiek, Edyta; Tozour, Jessica; Valicenti-McDermott, Maria; Wang, Shenglong; Abrahams, Brett S; Hargitai, Joseph; Inbar, Dov; Zhang, Zhengdong; Buxbaum, Joseph D; Molholm, Sophie; Foxe, John J; Marion, Robert W; Auton, Adam; Greally, John M

2014-01-01

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Quantitative Protein Sulfenic Acid Analysis Identifies Platelet Releasate-Induced Activation of Integrin β2 on Monocytes via NADPH Oxidase.

PubMed

Li, Ru; Klockenbusch, Cordula; Lin, Liwen; Jiang, Honghui; Lin, Shujun; Kast, Juergen

2016-12-02

Physiological stimuli such as thrombin, or pathological stimuli such as lysophosphatidic acid (LPA), activate platelets. The activated platelets bind to monocytes through P-selectin-PSGL-1 interactions but also release the contents of their granules, commonly called "platelet releasate". It is known that monocytes in contact with platelet releasate produce reactive oxygen species (ROS). Reversible cysteine oxidation by ROS is considered to be a potential regulator of protein function. In a previous study, we used THP-1 monocytic cells exposed to LPA- or thrombin-induced platelet releasate and a modified biotin switch assay to unravel the biological processes that are influenced by reversible cysteine oxidation. To gain a better understanding of the redox regulation of monocytes in atherosclerosis, we have now altered the modified biotin switch to selectively quantify protein sulfenic acid, a subpopulation of reversible cysteine oxidation. Using arsenite as reducing agent in the modified biotin switch assay, we were able to quantify 1161 proteins, in which more than 100 sulfenic acid sites were identified. Bioinformatics analysis of the quantified sulfenic acid sites highlighted the relevant, previously missed biological process of monocyte transendothelial migration, which included integrin β 2 . Flow cytometry validated the activation of LFA-1 (α L β 2 ) and Mac-1 (α M β 2 ), two subfamilies of integrin β 2 complexes, on human primary monocytes following platelet releasate treatment. The activation of LFA-1 was mediated by ROS from NADPH oxidase (NOX) activation. Production of ROS and activation of LFA-1 in human primary monocytes were independent of P-selectin-PSGL-1 interaction. Our results proved the modified biotin switch assay to be a powerful tool with the ability to reveal new regulatory mechanisms and identify new therapeutic targets.

Microarray and Proteomic Analysis of Breast Cancer Cell and Osteoblast Co-cultures

PubMed Central

Morrison, Charlotte; Mancini, Stephanie; Cipollone, Jane; Kappelhoff, Reinhild; Roskelley, Calvin; Overall, Christopher

2011-01-01

Dynamic reciprocal interactions between a tumor and its microenvironment impact both the establishment and progression of metastases. These interactions are mediated, in part, through proteolytic sculpting of the microenvironment, particularly by the matrix metalloproteinases, with both tumors and stroma contributing to the proteolytic milieu. Because bone is one of the predominant sites of breast cancer metastases, we used a co-culture system in which a subpopulation of the highly invasive human breast cancer cell line MDA-MB-231, with increased propensity to metastasize to bone, was overlaid onto a monolayer of differentiated osteoblast MC3T3-E1 cells in a mineralized osteoid matrix. CLIP-CHIP® microarrays identified changes in the complete protease and inhibitor expression profile of the breast cancer and osteoblast cells that were induced upon co-culture. A large increase in osteoblast-derived MMP-13 mRNA and protein was observed. Affymetrix analysis and validation showed induction of MMP-13 was initiated by soluble factors produced by the breast tumor cells, including oncostatin M and the acute response apolipoprotein SAA3. Significant changes in the osteoblast secretomes upon addition of MMP-13 were identified by degradomics from which six novel MMP-13 substrates with the potential to functionally impact breast cancer metastasis to bone were identified and validated. These included inactivation of the chemokines CCL2 and CCL7, activation of platelet-derived growth factor-C, and cleavage of SAA3, osteoprotegerin, CutA, and antithrombin III. Hence, the influence of breast cancer metastases on the bone microenvironment that is executed via the induction of osteoblast MMP-13 with the potential to enhance metastases growth by generating a microenvironmental amplifying feedback loop is revealed. PMID:21784845

Evaluating Protein Structure and Dynamics Using Co-Solvents, Photochemical Triggers, and Site-Specific Spectroscopic Probes

NASA Astrophysics Data System (ADS)

Abaskharon, Rachel M.

As ubiquitous and diverse biopolymers, proteins are dynamic molecules that are constantly engaging in inter- and intramolecular interactions responsible for their structure, fold, and function. Because of this, gaining a comprehensive understanding of the factors that control protein conformation and dynamics remains elusive as current experimental techniques often lack the ability to initiate and probe a specific interaction or conformational transition. For this reason, this thesis aims to develop methods to control and monitor protein conformations, conformational transitions, and dynamics in a site-specific manner, as well as to understand how specific and non-specific interactions affect the protein folding energy landscape. First, by using the co-solvent, trifluoroethanol (TFE), we show that the rate at which a peptide folds can be greatly impacted and thus controlled by the excluded volume effect. Secondly, we demonstrate the utility of several light-responsive molecules and reactions as methods to manipulate and investigate protein-folding processes. Using an azobenzene linker as a photo-initiator, we are able to increase the folding rate of a protein system by an order of magnitude by channeling a sub-population through a parallel, faster folding pathway. Additionally, we utilize a tryptophan-mediated electron transfer process to a nearby disulfide bond to strategically unfold a protein molecule with ultraviolet light. We also demonstrate the potential of two ruthenium polypyridyl complexes as ultrafast phototriggers of protein reactions. Finally, we develop several site-specific spectroscopic probes of protein structure and environment. Specifically, we demonstrate that a 13C-labeled aspartic acid residue constitutes a useful site-specific infrared probe for investigating salt-bridges and hydration dynamics of proteins, particularly in proteins containing several acidic amino acids. We also show that a proline-derivative, 4-oxoproline, possesses novel infrared properties that can be exploited to monitor the cis-trans isomerization process of individual proline residues in proteins.

Personalized medicine, availability, and group disparity: an inquiry into how physicians perceive and rate the elements and barriers of personalized medicine.

PubMed

Petersen, Katelin E; Prows, Cynthia A; Martin, Lisa J; Maglo, Koffi N

2014-01-01

The success of personalized medicine depends on factors influencing the availability and implementation of its new tools to individualize clinical care. However, little is known about physicians' views of the availability of personalized medicine across racial/ethnic groups and the relationship between perceived availability and clinical implementation. This study examines physicians' perceptions of key elements/tools and potential barriers to personalized medicine in connection with their perceptions of the availability of the latter across subpopulations. Study subjects consisted of physicians recruited from Cincinnati Children's Hospital Medical Center and UC Health. An electronic survey conducted from September 2012 to November 2012 recruited 104 physicians. Wilcoxon rank sum analysis compared groups. Physicians were divided about whether personalized medicine contributes to health equality, as 37.4% of them believe that personalized medicine is currently available only for some subpopulations. They also rated the importance of racial/ethnic background almost as high as the importance of genetic information in the delivery of personalized medicine. Actual elements of personalized medicine rated highest include family history, drug-drug interaction alerts in medical records, and biomarker measurements to guide therapy. Costs of gene-based therapies and genetic testing were rated the most significant barriers. The ratings of several elements and barriers were associated with perceived availability of personalized medicine across subpopulations. While physicians hold differing views about the availability and implementation of personalized medicine, they likewise establish complex relationships between race/ethnicity and personalized medicine that may carry serious implications for its clinical success. © 2014 S. Karger AG, Basel.

Sea ice-associated diet change increases the levels of chlorinated and brominated contaminants in polar bears.

PubMed

Mckinney, Melissa A; Peacock, Elizabeth; Letcher, Robert J

2009-06-15

Two global environmental issues, climate change and contamination by persistent organic pollutants, represent major concerns for arctic ecosystems. Yet, it is unclear how these two stressors interact in the Arctic. For instance, the influence of climate-associated changes in food web structure on exposure to pollutants within arctic ecosystems is presently unknown. Here, we report on recent changes in feeding ecology (1991-2007) in polar bears (Ursus maritimus) from the western Hudson Bay subpopulation that have resulted in increases in the tissue concentrations of several chlorinated and brominated contaminants. Differences in timing of the annual sea ice breakup explained a significant proportion of the diet variation among years. As expected from climate change predictions, this diet change was consistent with an increase in the consumed proportions of open water-associated seal species compared to ice-associated seal species in years of earlier sea ice breakup. Our results demonstrate that climate change is a modulating influence on contaminants in this polar bear subpopulation and may pose an additional and previously unidentified threat to northern ecosystems through altered exposures to contaminants.

PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena

PubMed Central

Hughes, Shannon K.; Oudin, Madeleine J.; Tadros, Jenny; Neil, Jason; Del Rosario, Amanda; Joughin, Brian A.; Ritsma, Laila; Wyckoff, Jeff; Vasile, Eliza; Eddy, Robert; Philippar, Ulrike; Lussiez, Alisha; Condeelis, John S.; van Rheenen, Jacco; White, Forest; Lauffenburger, Douglas A.; Gertler, Frank B.

2015-01-01

During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express MenaINV, which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs is unknown. Here we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling. On EGF stimulation, complexes containing Mena and PTP1B are recruited to the EGFR, causing receptor dephosphorylation and leading to decreased motility responses. Mena also interacts with the 5′ inositol phosphatase SHIP2, which is important for the recruitment of the Mena-PTP1B complex to the EGFR. When MenaINV is expressed, PTP1B recruitment to the EGFR is impaired, providing a mechanism for growth factor sensitization to EGF, as well as HGF and IGF, and increased resistance to EGFR and Met inhibitors in signaling and motility assays. In sum, we demonstrate that Mena plays an important role in regulating growth factor–induced signaling. Disruption of this attenuation by MenaINV sensitizes tumor cells to low–growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes. PMID:26337385

Forms of Mediation: The Case of Interpreter-Mediated Interactions in Medical Systems

ERIC Educational Resources Information Center

Baraldi, Claudio

2009-01-01

This paper analyses the forms of mediation in interlinguistic interactions performed in Italian healthcare services and in contexts of migration. The literature encourages dialogic transformative mediation, empowering participants' voices and changing cultural presuppositions in social systems. It may be doubtful, however, whether mediation can…

Compulsory citizenship behavior and organizational citizenship behavior: the role of organizational identification and perceived interactional justice.

PubMed

Zhao, Hongdan; Peng, Zhenglong; Chen, Hsiu-Kuei

2014-01-01

This article examines the psychological mechanism underlying the relationship between compulsory citizenship behavior (CCB) and organizational citizenship behavior (OCB) by developing a moderated mediation model. The model focuses on the mediating role of organizational identification and the moderating role of interactional justice in influencing the mediation. Using a time-lagged research design, the authors collected two waves of data from 388 supervisor-subordinate dyads in 67 teams to test the moderated mediation model. Results revealed that CCB negatively influenced OCB via impairing organizational identification. Moreover, interactional justice moderated the strength of the indirect effect of CCB on OCB (through organizational identification), such that the mediated relationship was stronger under low interactional justice than under high interactional justice.

Serotonin promotes feminization of the sexually dimorphic nucleus of the preoptic area, but not the calbindin cell group.

PubMed

Madden, Amanda M K; Paul, Alexandria T; Pritchard, Rory A; Michel, Rebecca; Zup, Susan L

2016-11-01

Testosterone and its metabolites masculinize the brain during a critical perinatal window, including the relative volume of sexually dimorphic brain areas such as the sexually dimorphic nucleus of the preoptic area (SDN), which is larger in males than females. Serotonin (5HT) may mediate this hormone action, since 5HT given during the second week of life decreases (i.e., feminizes) SDN volume in males and testosterone-treated females. Although previous work indicates that the 5HT 2A/2C receptor is sufficient to induce feminization, it is unclear whether other serotonin receptors are required and which subpopulation(s) of SDN cells are specifically organized by 5HT. Therefore, we injected male and female Sprague-Dawley rat pups with saline, a nonselective 5HTR agonist, a 5HT 2A/2C agonist, or a 5HT 2A/2C antagonist over several timecourses in early life, and measured the Nissl-SDN as well as a calbindin+ subdivision of the SDN, the CALB-SDN. When examined on postnatal day 18 or early adulthood, the size of the Nissl-SDN was feminized in males treated with any of the serotonergic drugs, eliminating the typical sex difference. In contrast, the sex difference in CALB-SDN size was maintained regardless of serotoninergic drug treatment. This pattern suggests that although gonadal hormones shape the whole SDN, individual cellular phenotypes respond to different intermediary signals to become sexually dimorphic. Specifically, 5HT mediates sexual differentiation of non-calbindin population(s) within the SDN. The results also caution against using measurement of the CALB-SDN in isolation, as the absence of an effect on the CALB-SDN does not preclude an effect on the overall nucleus. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1241-1253, 2016. © 2016 Wiley Periodicals, Inc.

The cell-mediated immune response to ectromelia virus infection. Secondary response in vitro: specificity, nature of effector and responder cells and requirements for induction of antigenic changes in stimulator cells.

PubMed

Pang, T; Blanden, R V

1976-06-01

An in vitro culture method was used to study secondary cell-mediated responses to ectromelia virus infection in mice. Infected, syngeneic spleen cells or peritoneal cells were efficient "stimulator" cells when cultured with "responder" cells obtained from mice infected with ectromelia 4-6 weeks previously. The kinetics of generation of cytotoxic cells in cultures were determined; a peak occurred on days 4-5. A separation procedure performed on the cytotoxic cells showed that activity was associated mainly with the Ig-negative subpopulation (T cell-rich) and that H-2 compatibility between cytotoxic cells and target cells was required. The secondary response was virus-specific, at the level of both induction and target cell lysis, at least so far as ectromelia and lymphocytic choriomeningitis (LCM) viruses are concerned. Seperation of responder cells prior to culture showed that a potent secondary response was generated with the Ig-negative (T cell-rich) subpopulation and only a weak response was observed when the responder cells were Ig-positive (rich in B cells). Infected stimulator cells did not appear to secrete significant amounts of soluble antigen into the medium over 4 days of culture. Thus, antigenic patterns effective in memory T cell stimulation may be largely associated with the surfaces of infected cells.Pretreatment of ectromelia virus with UV- or gamma-irradiation did not impair its ability to induce antigenic changes in stimulator cells. Stimulator cells treated with UV-or gamma-irradiated virus for 1 h and then immediately with pactamycin to inhibit further viral protein synthesis and replication were efficient stimulators, thus indicating that antigenic changes are induced very rapidly on the surface of stimulator cells after uptake of virus. These treatments are being used to further characterize the cellular requirements in the stimulator population.

Expression of chemokine CXCL10 in dendritic-cell-like S100β-positive cells in rat anterior pituitary gland.

PubMed

Horiguchi, Kotaro; Fujiwara, Ken; Higuchi, Masashi; Yoshida, Saishu; Tsukada, Takehiro; Ueharu, Hiroki; Chen, Mo; Hasegawa, Rumi; Takigami, Shu; Ohsako, Shunji; Yashiro, Takashi; Kato, Takako; Kato, Yukio

2014-09-01

Chemokines are mostly small secreted polypeptides whose signals are mediated by seven trans-membrane G-protein-coupled receptors. Their functions include the control of leukocytes and the intercellular mediation of cell migration, proliferation, and adhesion in several tissues. We have previously revealed that the CXC chemokine ligand 12 (CXCL12) and its receptor 4 (CXCR4) are expressed in the anterior pituitary gland, and that the CXCL12/CXCR4 axis evokes the migration and interconnection of S100β-protein-positive cells (S100β-positive cells), which do not produce classical anterior pituitary hormones. However, little is known of the cells producing the other CXCLs and CXCRs or of their characteristics in the anterior pituitary. We therefore examined whether CXCLs and CXCRs occurred in the rat anterior pituitary lobe. We used reverse transcription plus the polymerase chain reaction to analyze the expression of Cxcl and Cxcr and identified the cells that expressed Cxcl by in situ hybridization. Transcripts of Cxcl10 and its receptor (Cxcr3 and toll-like receptor 4, Tlr4) were clearly detected: cells expressing Cxcl10 and Tlr4 were identified amongst S100β-positive cells and those expressing Cxcr3 amongst adrenocorticotropic hormone (ACTH)-producing cells. We also investigated Cxcl10 expression in subpopulations of S100β-positive cells. We separated cultured S100β-positive cells into the round-type (dendritic-cell-like) and process-type (astrocyte- or epithelial-cell-like) by their adherent activity to laminin, a component of the extracellular matrix; CXCL10 was expressed only in round-type S100β-positive cells. Thus, CXCL10 produced by a subpopulation of S100β-positive cells probably exerts an autocrine/paracrine effect on S100β-positive cells and ACTH-producing cells in the anterior lobe.

Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome Immunopathology.

PubMed

Szabo, Peter A; Goswami, Ankur; Mazzuca, Delfina M; Kim, Kyoungok; O'Gorman, David B; Hess, David A; Welch, Ian D; Young, Howard A; Singh, Bhagirath; McCormick, John K; Haeryfar, S M Mansour

2017-04-01

Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4 + effector memory T (T EM ) cells that secrete IL-17A, but not IFN-γ, was responsible for early IL-17A production. We found mouse "T EM -17" cells to be enriched within the intestinal epithelium and among lamina propria lymphocytes. Furthermore, interfering with IL-17A receptor signaling in human PBMCs attenuated the expression of numerous inflammatory mediators implicated in the TSS-associated cytokine storm. IL-17A receptor blockade also abrogated the secondary effect of SAg-stimulated PBMCs on human dermal fibroblasts as judged by C/EBP δ expression. Finally, the early IL-17A response to SAgs was pathogenic because in vivo neutralization of IL-17A in humanized mice ameliorated hepatic and intestinal damage and reduced mortality. Together, our findings identify CD4 + T EM cells as a key effector of TSS and reveal a novel role for IL-17A in TSS immunopathogenesis. Our work thus elucidates a pathogenic, as opposed to protective, role for IL-17A during Gram-positive bacterial infections. Accordingly, the IL-17-IL-17R axis may provide an attractive target for the management of SAg-mediated illnesses. Copyright © 2017 by The American Association of Immunologists, Inc.

Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells

PubMed Central

Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M.; Delcroix, Gaëtan J.-R.; Gomez, Lourdes A.; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A.

2016-01-01

Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis.

PubMed

Grund, Thomas; Goyon, Stephanie; Li, Yuting; Eliava, Marina; Liu, Haikun; Charlet, Alexandre; Grinevich, Valery; Neumann, Inga D

2017-12-13

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca 2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus. SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca 2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system. Copyright © 2017 the authors 0270-6474/17/3712215-12$15.00/0.

Using a spatially structured life cycle model to assess the influence of multiple stressors on an exploited coastal-nursery-dependent population

NASA Astrophysics Data System (ADS)

Archambault, B.; Rivot, E.; Savina, M.; Le Pape, O.

2018-02-01

Exploited coastal-nursery-dependent fish species are subject to various stressors occurring at specific stages of the life cycle: climate-driven variability in hydrography determines the success of the first eggs/larvae stages; coastal nursery habitat suitability controls juvenile growth and survival; and fisheries target mostly adults. A life cycle approach was used to quantify the relative influence of these stressors on the Eastern English Channel (EEC) population of the common sole (Solea solea), a coastal-nursery-dependent flatfish population which sustains important fisheries. The common sole has a complex life cycle: after eggs hatch, larvae spend several weeks drifting in open water. Survivors go on to metamorphose into benthic fish. Juveniles spend the first two years of their life in coastal and estuarine nurseries. Close to maturation, they migrate to deeper areas, where different subpopulations supplied by different nurseries reproduce and are exploited by fisheries. A spatially structured age-and stage-based hierarchical Bayesian model integrating various aspects of ecological knowledge, data sources and expert knowledge was built to quantitatively describe this complex life cycle. The model included the low connectivity among three subpopulations in the EEC, the influence of hydrographic variability, the availability of suitable juvenile habitat and fisheries. Scenarios were designed to quantify the effects of interacting stressors on population renewal. Results emphasized the importance of coastal nursery habitat availability and quality for the population renewal. Realistic restoration scenarios of the highly degraded Seine estuary produced a two-third increase in catch potential for the adjacent subpopulation. Fisheries, however, remained the main source of population depletion. Setting fishing mortality to the maximum sustainable yield led to substantial increases in biomass (+100%) and catch (+33%) at the EEC scale. The approach also showed how climate-driven variability in hydrography is likely to interact with human pressures, e.g., overfishing increased the sensitivity to unfavourable conditions. Our results provided insights into the dynamics of numerous exploited coastal-nursery-dependent species while paving the way toward more robust advice for sustainable management of these resources.

The Gulliver Effect: The Impact of Error in an Elephantine Subpopulation on Estimates for Lilliputian Subpopulations

ERIC Educational Resources Information Center

Micceri, Theodore; Parasher, Pradnya; Waugh, Gordon W.; Herreid, Charlene

2009-01-01

An extensive review of the research literature and a study comparing over 36,000 survey responses with archival true scores indicated that one should expect a minimum of at least three percent random error for the least ambiguous of self-report measures. The Gulliver Effect occurs when a small proportion of error in a sizable subpopulation exerts…

Desmoglein 3-specific T regulatory 1 cells consist of two subpopulations with differential expression of the transcription factor Foxp3

PubMed Central

Veldman, Christian; Pahl, Andreas; Hertl, Michael

2009-01-01

Pemphigus vulgaris (PV) is an autoimmune bullous skin disorder associated with autoantibodies against desmoglein (Dsg) 3. An imbalance of type 1 regulatory T (Tr1) cells and T helper type 2 (Th2) cells specific for Dsg3 may be critical for the loss of tolerance against Dsg3 in PV. Within the population of Dsg3-responsive, interleukin (IL)-10-secreting Tr1 cell clones, two major subpopulations were identified and sorted by fluorescence-activated cell sorting (FACS) based on their size and granularity. Upon in vitro culture, the larger subpopulation differentiated back into the two former subpopulations of the Tr1 cell clones, while the smaller subpopulation died within 2 weeks. The smaller subpopulation of the Tr1 cell clones was characterized by the expression of Foxp3, the secretion of IL-10, transforming growth factor (TGF)-β and IL-5 upon stimulation with Dsg3, a proliferative response to IL-2 but not to Dsg3 or mitogenic stimuli, and an inhibitory effect on the proliferative response of Dsg3-responsive Th clones in a Dsg3-specific manner. In contrast, the larger subpopulation showed a Th-like phenotype, lacking Foxp3, cytotoxic T-lymphocyte antigen 4 (CTLA4) and glucocorticoid-induced tumour necrosis factor receptor (GITR) expression and IL-2 secretion, and did not mount a proliferative response to Dsg3 and mitogenic stimuli. The two Tr1 subpopulations showed expression of identical T-cell receptor (TCR) Vβ chains which varied among the PV patients studied. Upon inhibition of Foxp3, the smaller Tr1 subpopulation developed a proliferate response to Dsg3 and mitogenic stimuli, no longer suppressed Dsg3-specific Th cells, lost expression of GITR and CTLA4 and secreted IL-2. Thus, our observations suggest a distinct relationship between Dsg3-specific Tr1 and Th-like cells which may be critical for the continuous generation and survival of Dsg3-specific Tr1 cells. PMID:18800988

Histone modifications influence mediator interactions with chromatin

PubMed Central

Zhu, Xuefeng; Zhang, Yongqiang; Bjornsdottir, Gudrun; Liu, Zhongle; Quan, Amy; Costanzo, Michael; Dávila López, Marcela; Westholm, Jakub Orzechowski; Ronne, Hans; Boone, Charles; Gustafsson, Claes M.; Myers, Lawrence C.

2011-01-01

The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. Genome wide localization studies have demonstrated that Mediator occupancy not only correlates with high levels of transcription, but that the complex also is present at transcriptionally silenced locations. We provide evidence that Mediator localization is guided by an interaction with histone tails, and that this interaction is regulated by their post-translational modifications. A quantitative, high-density genetic interaction map revealed links between Mediator components and factors affecting chromatin structure, especially histone deacetylases. Peptide binding assays demonstrated that pure wild-type Mediator forms stable complexes with the tails of Histone H3 and H4. These binding assays also showed Mediator—histone H4 peptide interactions are specifically inhibited by acetylation of the histone H4 lysine 16, a residue critical in transcriptional silencing. Finally, these findings were validated by tiling array analysis that revealed a broad correlation between Mediator and nucleosome occupancy in vivo, but a negative correlation between Mediator and nucleosomes acetylated at histone H4 lysine 16. Our studies show that chromatin structure and the acetylation state of histones are intimately connected to Mediator localization. PMID:21742760

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis for continuous, binary, and count outcomes.

PubMed

Yip, Wai-Ki; Bonetti, Marco; Cole, Bernard F; Barcella, William; Wang, Xin Victoria; Lazar, Ann; Gelber, Richard D

2016-08-01

For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual. Medical research is now focusing more on providing personalized care for patients, which requires investigating how patient characteristics, including novel biomarkers, modify the effect of current treatment modalities. This is known as heterogeneity of treatment effects. A better understanding of the interaction between treatment and patient-specific prognostic factors will enable practitioners to expand the availability of tailored therapies, with the ultimate goal of improving patient outcomes. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement. Here, we extend the Subpopulation Treatment Effect Pattern Plot approach to continuous, binary, and count outcomes, which can be easily modeled using generalized linear models. With this extension of Subpopulation Treatment Effect Pattern Plot, these additional types of treatment effects within subpopulations defined with respect to a covariate of interest can be estimated, and the statistical significance of any observed heterogeneity of treatment effect can be assessed using permutation tests. The desirable feature that commonly used models are applied to well-defined patient subgroups to estimate treatment effects is retained in this extension. We describe a simulation study to confirm that the proper Type I error rate is maintained when there is no treatment heterogeneity, and a power study to show that the statistics have power to detect treatment heterogeneity under alternative scenarios. As an illustration, we apply the methods to data from the Aspirin/Folate Polyp Prevention Study, a clinical trial evaluating the effect of oral aspirin, folic acid, or both as a chemoprevention agent against colorectal adenomas. The pre-existing R software package stepp has been extended to handle continuous, binary, and count data using Gaussian, Bernoulli, and Poisson models, and it is available on the Comprehensive R Archive Network. The extension of the method and the availability of new software now permit STEPP to be applied to the full range of clinical trial end points. © The Author(s) 2016.

Membrane-Mediated Cooperativity of Proteins

NASA Astrophysics Data System (ADS)

Weikl, Thomas R.

2018-04-01

Besides direct protein-protein interactions, indirect interactions mediated by membranes play an important role for the assembly and cooperative function of proteins in membrane shaping and adhesion. The intricate shapes of biological membranes are generated by proteins that locally induce membrane curvature. Indirect curvature-mediated interactions between these proteins arise because the proteins jointly affect the bending energy of the membranes. These curvature-mediated interactions are attractive for crescent-shaped proteins and are a driving force in the assembly of the proteins during membrane tubulation. Membrane adhesion results from the binding of receptor and ligand proteins that are anchored in the apposing membranes. The binding of these proteins strongly depends on nanoscale shape fluctuations of the membranes, leading to a fluctuation-mediated binding cooperativity. A length mismatch between receptor-ligand complexes in membrane adhesion zones causes repulsive curvature-mediated interactions that are a driving force for the length-based segregation of proteins during membrane adhesion.

[Effective size of subpopulations in early-run sockeye salmon Oncorhynchus nerka from Azabach'e Lake (Kamchatka): the effect of relative reproductive success of different-year cohorts].

PubMed

Efremov, V V

2004-05-01

The effect of variation in reproductive success of cohorts of different year of birth (within generation) on the effective subpopulation (breeding group) size in early-run sockeye salmon Oncorhynchus nerka from Azabach'e Lake (Kamchatka). The annual variation in census size and overlapping of year classes reduced the ratio of the effective subpopulation size to the census size by 7 to 88% in different subpopulations. The total effect of the variance of reproductive success in individual years and the variance of reproductive success of different cohorts reduced the effective size/census size ratio by 68-96%.

Cluster synchronization in networks of neurons with chemical synapses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juang, Jonq, E-mail: jjuang@math.nctu.edu.tw; Liang, Yu-Hao, E-mail: moonsea.am96g@g2.nctu.edu.tw

2014-03-15

In this work, we study the cluster synchronization of chemically coupled and generally formulated networks which are allowed to be nonidentical. The sufficient condition for the existence of stably synchronous clusters is derived. Specifically, we only need to check the stability of the origins of m decoupled linear systems. Here, m is the number of subpopulations. Examples of nonidentical networks such as Hindmarsh-Rose (HR) neurons with various choices of parameters in different subpopulations, or HR neurons in one subpopulation and FitzHugh-Nagumo neurons in the other subpopulation are provided. Explicit threshold for the coupling strength that guarantees the stably cluster synchronizationmore » can be obtained.« less

Mediator binds to boundaries of chromosomal interaction domains and to proteins involved in DNA looping, RNA metabolism, chromatin remodeling, and actin assembly.

PubMed

Chereji, Razvan V; Bharatula, Vasudha; Elfving, Nils; Blomberg, Jeanette; Larsson, Miriam; Morozov, Alexandre V; Broach, James R; Björklund, Stefan

2017-09-06

Mediator is a multi-unit molecular complex that plays a key role in transferring signals from transcriptional regulators to RNA polymerase II in eukaryotes. We have combined biochemical purification of the Saccharomyces cerevisiae Mediator from chromatin with chromatin immunoprecipitation in order to reveal Mediator occupancy on DNA genome-wide, and to identify proteins interacting specifically with Mediator on the chromatin template. Tandem mass spectrometry of proteins in immunoprecipitates of mediator complexes revealed specific interactions between Mediator and the RSC, Arp2/Arp3, CPF, CF 1A and Lsm complexes in chromatin. These factors are primarily involved in chromatin remodeling, actin assembly, mRNA 3'-end processing, gene looping and mRNA decay, but they have also been shown to enter the nucleus and participate in Pol II transcription. Moreover, we have found that Mediator, in addition to binding Pol II promoters, occupies chromosomal interacting domain (CID) boundaries and that Mediator in chromatin associates with proteins that have been shown to interact with CID boundaries, such as Sth1, Ssu72 and histone H4. This suggests that Mediator plays a significant role in higher-order genome organization. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

A Dualistic Conformational Response to Substrate Binding in the Human Serotonin Transporter Reveals a High Affinity State for Serotonin*

PubMed Central

Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida; Wiborg, Ove; Sinning, Steffen

2015-01-01

Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT. PMID:25614630

Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy.

PubMed

Wu, Feng-Hua; Mu, Lei; Li, Xiao-Lan; Hu, Yi-Bing; Liu, Hui; Han, Lin-Tao; Gong, Jian-Ping

2017-10-03

The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo . Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo . Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro . Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence.

Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy

PubMed Central

Wu, Feng-Hua; Mu, Lei; Li, Xiao-Lan; Hu, Yi-Bing; Liu, Hui; Han, Lin-Tao; Gong, Jian-Ping

2017-01-01

The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo. Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo. Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro. Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence. PMID:29108242

IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis.

PubMed

Hou, Yuzhu; Zhu, Linnan; Tian, Hongling; Sun, Hai-Xi; Wang, Ruoyu; Zhang, Lianfeng; Zhao, Yong

2018-03-05

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis.

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

PubMed Central

Keitel, Ulrike; Scheel, Andreas; Thomale, Jürgen; Halpape, Rovena; Kaulfuß, Silke; Scheel, Christina; Dobbelstein, Matthias

2014-01-01

The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells. PMID:25473892

NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia

PubMed Central

LaRue, Rebecca S.; Nguyen, Hanh T.; Sachs, Karen; Noble, Klara E.; Mohd Hassan, Nurul Azyan; Diaz-Flores, Ernesto; Rathe, Susan K.; Sarver, Aaron L.; Bendall, Sean C.; Ha, Ngoc A.; Diers, Miechaleen D.; Nolan, Garry P.; Shannon, Kevin M.; Largaespada, David A.

2014-01-01

Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRASG12V). Using computational approaches to explore our gene-expression data sets, we found that NRASG12V enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9– and Myb-dependent leukemia self-renewal gene-expression program. NRASG12V was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRASG12V-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell–enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRASG12V withdrawal. NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell–specific therapies. Together, these experimental results define a RAS oncogene–driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction. PMID:25316678

CD28 T-cell costimulatory molecule expression in pemphigus vulgaris.

PubMed

Alecu, M; Ursaciuc, C; Surcel, M; Coman, G; Ciotaru, D; Dobre, M

2009-03-01

CD28 superfamily of immune costimulatory molecules could play an important role in autotolerance control. CD28 costimulation seems to be necessary for regulatory T cell (Treg) activation and successive suppressive activities involved in autoimmunity protection. This study investigates CD28 expression, especially inducible costimulator fraction, on T lymphocytes in pemphigus vulgaris (PV) patients. CD28 expression on T lymphocytes was assessed in 16 PV patients during acute attack. All patients and 10 healthy control subjects were tested for lymphocyte populations, T-cell subpopulations (T-CD4+, T-CD8+), Treg and CD28 expression on T-cell subpopulations. T, B and natural killer cells average values in PV patients were close to the control group values. Compared with control group, PV values showed lower Treg (2.2% compared with 4.7%), slightly decreased CD4+ CD28+ T cells (91% compared with 95%), higher CD4+ CD28- T cells (9% compared with 5%), decreased CD8+ CD28+ T cells (57% and 73%, respectively) and significantly enhanced CD8+ CD28- T cells (43% compared with 27%). These data suggest that Treg-mediated suppressor T-cell effects could be diminished in PV, together with an abnormal or ineffective subsequent helper T-cell suppression. CD28 high expression on helper T cells and low expression on suppressor T cells are arguments for a potential CD28 role in PV autoimmune response mechanism.

The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma.

PubMed

Ahn, Antonio; Chatterjee, Aniruddha; Eccles, Michael R

2017-06-01

Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance. First, a low microphthalmia-associated transcription factor (MITF) dedifferentiated state activates various signaling pathways. This includes WNT5A, EGFR, as well as other signaling activators, such as AXL and NF-κB. Second, the chromatin-remodeling factor Jumonji/ARID domain-containing protein 1B (JARID1B, KDM5B ) orchestrates and maintains slow cycling and treatment resistance in a small subpopulation of melanoma cells. Finally, a shift in metabolic state toward oxidative phosphorylation has been demonstrated to regulate treatment resistance in slow-cycling cells. Elucidation of the underlying processes of slow cycling and its utilization by melanoma cells may reveal new vulnerable characteristics as therapeutic targets. Moreover, combining current therapies with targeting slow-cycling subpopulations of melanoma cells may allow for more durable and greater treatment responses. Mol Cancer Ther; 16(6); 1002-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Impact of fresh or used litter on the posthatch immune system of commercial broilers.

PubMed

Lee, K W; Lillehoj, H S; Lee, S H; Jang, S I; Ritter, G Donald; Bautista, D A; Lillehoj, E P

2011-12-01

This study was carried out to investigate the effects of exposure of growing broiler chickens of commercial origin to used poultry litter on intestinal and systemic immune responses. The litter types evaluated were fresh wood shavings or used litter obtained from commercial poultry farms with or without a history of gangrenous dermatitis (GD). Immune parameters measured were serum nitric oxide (NO) levels, serum antibody titers against Eimeria or Clostridium perfringens, mitogen-induced spleen cell proliferation, and intestinal intraepithelial lymphocyte or splenic lymphocyte subpopulations. At 43 days posthatch, birds raised on used litter from a GD farm had higher serum NO levels and greater Eimeria or C. perfringens antibody levels compared with chickens raised on fresh litter or used, non-GD litter. Birds raised on non-GD and GD used litter had greater spleen cell mitogenic responses compared with chickens raised on fresh litter. Finally, spleen and intestinal lymphocyte subpopulations were increased or decreased depending on the litter type and the surface marker analyzed. Although it is likely that the presence of Eimeria oocysts and endemic viruses varies qualitatively and quantitatively between flocks and, by extension, varies between different used litter types, we believe that these data provide evidence that exposure of growing chicks to used poultry litter stimulates humoral and cell-mediated immune responses, presumably due to contact with contaminating enteric pathogens.

Starvation, Together with the SOS Response, Mediates High Biofilm-Specific Tolerance to the Fluoroquinolone Ofloxacin

PubMed Central

Bernier, Steve P.; Lebeaux, David; DeFrancesco, Alicia S.; Valomon, Amandine; Soubigou, Guillaume; Coppée, Jean-Yves; Ghigo, Jean-Marc; Beloin, Christophe

2013-01-01

High levels of antibiotic tolerance are a hallmark of bacterial biofilms. In contrast to well-characterized inherited antibiotic resistance, molecular mechanisms leading to reversible and transient antibiotic tolerance displayed by biofilm bacteria are still poorly understood. The physiological heterogeneity of biofilms influences the formation of transient specialized subpopulations that may be more tolerant to antibiotics. In this study, we used random transposon mutagenesis to identify biofilm-specific tolerant mutants normally exhibited by subpopulations located in specialized niches of heterogeneous biofilms. Using Escherichia coli as a model organism, we demonstrated, through identification of amino acid auxotroph mutants, that starved biofilms exhibited significantly greater tolerance towards fluoroquinolone ofloxacin than their planktonic counterparts. We demonstrated that the biofilm-associated tolerance to ofloxacin was fully dependent on a functional SOS response upon starvation to both amino acids and carbon source and partially dependent on the stringent response upon leucine starvation. However, the biofilm-specific ofloxacin increased tolerance did not involve any of the SOS-induced toxin–antitoxin systems previously associated with formation of highly tolerant persisters. We further demonstrated that ofloxacin tolerance was induced as a function of biofilm age, which was dependent on the SOS response. Our results therefore show that the SOS stress response induced in heterogeneous and nutrient-deprived biofilm microenvironments is a molecular mechanism leading to biofilm-specific high tolerance to the fluoroquinolone ofloxacin. PMID:23300476

Increased memory T cell populations in Pb-exposed children from an e-waste-recycling area.

PubMed

Cao, Junjun; Xu, Xijin; Zhang, Yu; Zeng, Zhijun; Hylkema, Machteld N; Huo, Xia

2018-03-01

Chronic exposure to heavy metals could affect cell-mediated immunity. The aim of this study was to explore the status of memory T cell development in preschool children from an e-waste recycling area. Blood lead (Pb) levels, peripheral T cell subpopulations, and serum levels of cytokines (IL-2/IL-7/IL-15), relevant to generation and homeostasis of memory T cells were evaluated in preschool children from Guiyu (e-waste-exposed group) and Haojiang (reference group). The correlations between blood Pb levels and percentages of memory T cell subpopulations were also evaluated. Guiyu children had higher blood Pb levels and increased percentages of CD4 + central memory T cells and CD8 + central memory T cells than in the Haojiang group. Moreover, blood Pb levels were positively associated with the percentages of CD4 + central memory T cells. In contrast, Pb exposure contributed marginally in the change of percentages of CD8 + central memory T cells in children. There was no significant difference in the serum cytokine levels between the e-waste-exposed and reference children. Taken together, preschool children from an e-waste recycling area suffer from relatively higher levels of Pb exposure, which might facilitate the development of CD4 + central memory T cells in these children. Copyright © 2017. Published by Elsevier B.V.

Bistability and Biofilm Formation in Bacillus subtilis

PubMed Central

Chai, Yunrong; Chu, Frances; Kolter, Roberto; Losick, Richard

2008-01-01

Summary Biofilms of Bacillus subtilis consist of long chains of cells that are held together in bundles by an extracellular matrix of exopolysaccharide and the protein TasA. The exopolysaccharide is produced by enzymes encoded by the epsA-O operon and the gene encoding TasA is located in the yqxM-sipW-tasA operon. Both operons are under the control of the repressor SinR. Derepression is mediated by the antirepressor SinI, which binds to SinR with a 1:1 stoichiometry. Paradoxically, in medium promoting derepression of the matrix operons, the overall concentration of SinR in the culture greatly exceeded that of SinI. We show that under biofilm-promoting conditions sinI, which is under the control of the response regulator Spo0A, was expressed only in a small subpopulation of cells, whereas sinR was expressed in almost all cells. Activation of Spo0A is known to be subject to a bistable switch, and we infer that SinI reaches levels sufficient to trigger matrix production only in the subpopulation of cells in which Spo0A is active. Additionally, evidence suggests that sinI is expressed at intermediate, but not low or high, levels of Spo0A activity, which may explain why certain nutritional conditions are more effective in promoting biofilm formation than others. PMID:18047568

Localization of multiple neurotransmitters in surgically derived specimens of human atrial ganglia.

PubMed

Hoover, D B; Isaacs, E R; Jacques, F; Hoard, J L; Pagé, P; Armour, J A

2009-12-15

Dysfunction of the intrinsic cardiac nervous system is implicated in the genesis of atrial and ventricular arrhythmias. While this system has been studied extensively in animal models, far less is known about the intrinsic cardiac nervous system of humans. This study was initiated to anatomically identify neurotransmitters associated with the right atrial ganglionated plexus (RAGP) of the human heart. Biopsies of epicardial fat containing a portion of the RAGP were collected from eight patients during cardiothoracic surgery and processed for immunofluorescent detection of specific neuronal markers. Colocalization of markers was evaluated by confocal microscopy. Most intrinsic cardiac neuronal somata displayed immunoreactivity for the cholinergic marker choline acetyltransferase and the nitrergic marker neuronal nitric oxide synthase. A subpopulation of intrinsic cardiac neurons also stained for noradrenergic markers. While most intrinsic cardiac neurons received cholinergic innervation evident as punctate immunostaining for the high affinity choline transporter, some lacked cholinergic inputs. Moreover, peptidergic, nitrergic, and noradrenergic nerves provided substantial innervation of intrinsic cardiac ganglia. These findings demonstrate that the human RAGP has a complex neurochemical anatomy, which includes the presence of a dual cholinergic/nitrergic phenotype for most of its neurons, the presence of noradrenergic markers in a subpopulation of neurons, and innervation by a host of neurochemically distinct nerves. The putative role of multiple neurotransmitters in controlling intrinsic cardiac neurons and mediating efferent signaling to the heart indicates the possibility of novel therapeutic targets for arrhythmia prevention.

Fine-scale population structure in Atlantic salmon from Maine's Penobscot River drainage

USGS Publications Warehouse

Spidle, A.P.; Bane, Schill W.; Lubinski, B.A.; King, T.L.

2001-01-01

We report a survey of micro satellite DNA variation in Atlantic salmon from the unimpounded lower reaches of Maine's Penobscot River. Our analysis indicates that Atlantic salmon in the Penobscot River are distinct from other populations that have little or no history of human-mediated repopulation, including two of its tributaries, Cove Brook and Kenduskeag Stream, another Maine river, the Ducktrap, and Canada's Miramichi and Gander rivers. Significant heterogeneity was detected in allele frequency among all three subpopulations sampled in the Penobscot drainage. The high resolution of the 12-locus suite was quantified using maximum likelihood assignment tests, which correctly identified the source of 90.4-96.1% of individuals from within the Penobscot drainage. Current populations are clearly isolated from each other, however we are unable to determine from the present data whether the populations in Cove Brook and Kenduskeag Stream are recently diverged from populations stocked into the Penobscot River over the last century, or are aboriginal in origin. The degree of population structure identified in the Penobscot drainage is noteworthy in light of its lengthy history of systematic restocking, the geographic proximity of the subpopulations, and the extent of the differentiation. Similar population structure on this extremely limited geographic scale could exist among Atlantic salmon runs elsewhere in Maine and throughout the species' range and should be taken into account for future management decisions.

Mediation Analysis with Multiple Mediators

PubMed Central

VanderWeele, T.J.; Vansteelandt, S.

2014-01-01

Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators. PMID:25580377

Mediation Analysis with Multiple Mediators.

PubMed

VanderWeele, T J; Vansteelandt, S

2014-01-01

Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators.

Redox subpopulations and the risk of cancer progression: a new method for characterizing redox heterogeneity

NASA Astrophysics Data System (ADS)

Xu, He N.; Li, Lin Z.

2016-02-01

It has been shown that a malignant tumor is akin to a complex organ comprising of various cell populations including tumor cells that are genetically, metabolically and functionally different. Our redox imaging data have demonstrated intra-tumor redox heterogeneity in all mouse xenografts derived from human melanomas, breast, prostate, and colon cancers. Based on the signals of NADH and oxidized flavoproteins (Fp, including flavin adenine dinucleotide (FAD)) and their ratio, i.e., the redox ratio, which is an indicator of mitochondrial metabolic status, we have discovered several distinct redox subpopulations in xenografts of breast tumors potentially recapitulating functional/metabolic heterogeneity within the tumor. Furthermore, xenografts of breast tumors with higher metastatic potential tend to have a redox subpopulation whose redox ratio is significantly different from that of tumors with lower metastatic potential and usually have a bi-modal distribution of the redox ratio. The redox subpopulations from human breast cancer samples can also be very complex with multiple subpopulations as determined by fitting the redox ratio histograms with multi- Gaussian functions. In this report, we present a new method for identifying the redox subpopulations within individual breast tumor xenografts and human breast tissues, which may be used to differentiate between breast cancer and normal tissue and among breast cancer with different risks of progression.

Raising an Antibody Specific to Breast Cancer Subpopulations Using Phage Display on Tissue Sections.

PubMed

Larsen, Simon Asbjørn; Meldgaard, Theresa; Fridriksdottir, Agla Jael Rubner; Lykkemark, Simon; Poulsen, Pi Camilla; Overgaard, Laura Falkensteen; Petersen, Helene Bundgaard; Petersen, Ole William; Kristensen, Peter

2016-01-01

Primary tumors display a great level of intra-tumor heterogeneity in breast cancer. The current lack of prognostic and predictive biomarkers limits accurate stratification and the ability to predict response to therapy. The aim of the present study was to select recombinant antibody fragments specific against breast cancer subpopulations, aiding the discovery of novel biomarkers. Recombinant antibody fragments were selected by phage display. A novel shadowstick technology enabled the direct selection using tissue sections of antibody fragments specific against small subpopulations of breast cancer cells. Selections were performed against a subpopulation of breast cancer cells expressing CD271+, as these previously have been indicated to be potential breast cancer stem cells. The selected antibody fragments were screened by phage ELISA on both breast cancer and myoepithelial cells. The antibody fragments were validated and evaluated by immunohistochemistry experiments. Our study revealed an antibody fragment, LH8, specific for breast cancer cells. Immunohistochemistry results indicate that this particular antibody fragment binds an antigen that exhibits differential expression in different breast cancer subpopulations. Further studies characterizing this antibody fragment, the subpopulation it binds and the cognate antigen may unearth novel biomarkers of clinical relevance. Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Population Dynamics and Life History of Euphorbia rosescens, a Perennial Herb Endemic to Florida Scrub

PubMed Central

2016-01-01

Euphorbia rosescens is a recently described plant that is narrowly endemic to the Lake Wales Ridge. Little is known of the ecology or life history of this diminutive, deeply rooted polygamodioecious perennial. We studied 13 subpopulations of this species from 2004–2012 from five habitats, sampling monthly during its growing season. Subpopulations were stable year-to-year with annual survivals > 90%, but with considerable within-year dynamics, peaking in density in April and dying back in the fall and winter. Stem densities did not vary among subpopulations, habitats, or by subpopulation gender. Annual plant dormancy was common and decreased subsequent survival. Belowground biomass averaged almost 50 times higher than aboveground biomass. Subpopulations either consisted of entirely female individuals or a mixture of male and functionally andromonoecious individuals and these subpopulation genders remained stable across years. Overall, flowering has been dominated by female plants. Plants produced modest numbers of inflorescences (cyathia), and fruit production was very low. Although most plants survived fire by resprouting, fire decreased survival and had a short-term positive effect on floral production. Lack of fecundity and recruitment are concerns for this state-endangered species, but more information is needed on its breeding system and clonality to make specific management recommendations. PMID:27454519

Genetic diversity and environmental associations of sacsaoul ( Haloxylon ammodendron)

NASA Astrophysics Data System (ADS)

Zhang, Linjing; Zhao, Guifang; Yue, Ming; Pan, Xiaoling

2003-07-01

Random amplified polymorphic DNA (RAPD) markers were used to assess levels and patterns of genetic diversity in H. ammodendron (Chenopodiaceae). A total of 117 plants from 6 subpopulations on oasis-desert ecotone was analyzed by 16 arbitrarily chosen primers resulting in highly reproducible RAPD bands. The analysis of molecular variance (AMOVA) with distances among individuals showed that most of the variation (74%) occurred among individuals within subpopulations, which is expected for a crossing organism, and 26% of variation among subpopulations. Estimates of Shannon index and Nei"s index from allele frequencies corroborated AMOVA partitioning in H. ammodendron. UPGMA cluster analyses, based on genetic distance, do not revealed grouping of some geographically proximate populations. This is the first report of the partitioning of genetic variability within and between subpopulations of H. ammodendron and provides important baseline data for optimizing sampling strategies and for conserving the genetic resources of this species. The Percentage of polymorphic loci was as high as 96%, presumably being response to oasis-desert ecotone. There were gene flows (Nm=5.38 individuals/generation), based on gene differentiation coefficient (GST was 0.1567) between subpopulations, and strong habitat selection override the gene flow to maintain the subpopulation differentiation. Correlation analyses showed that there was significant relationship between genetic diversity and soil CL ion.

An Îto stochastic differential equations model for the dynamics of the MCF-7 breast cancer cell line treated by radiotherapy.

PubMed

Oroji, Amin; Omar, Mohd; Yarahmadian, Shantia

2016-10-21

In this paper, a new mathematical model is proposed for studying the population dynamics of breast cancer cells treated by radiotherapy by using a system of stochastic differential equations. The novelty of the model is essentially in capturing the concept of the cell cycle in the modeling to be able to evaluate the tumor lifespan. According to the cell cycle, each cell belongs to one of three subpopulations G, S, or M, representing gap, synthesis and mitosis subpopulations. Cells in the M subpopulation are highly radio-sensitive, whereas cells in the S subpopulation are highly radio-resistant. Therefore, in the process of radiotherapy, cell death rates of different subpopulations are not equal. In addition, since flow cytometry is unable to detect apoptotic cells accurately, the small changes in cell death rate in each subpopulation during treatment are considered. Subsequently, the proposed model is calibrated using experimental data from previous experiments involving the MCF-7 breast cancer cell line. Consequently, the proposed model is able to predict tumor lifespan based on the number of initial carcinoma cells. The results show the effectiveness of the radiation under the condition of stability, which describes the decreasing trend of the tumor cells population. Copyright © 2016 Elsevier Ltd. All rights reserved.

Isolation and characteristics of CD133‑/A2B5+ and CD133‑/A2B5‑ cells from the SHG139s cell line.

PubMed

Han, Yong; Wang, Hangzhou; Huang, Yulun; Cheng, Zhe; Sun, Ting; Chen, Guilin; Xie, Xueshun; Zhou, Youxin; Du, Ziwei

2015-12-01

In glioma tissues, there are small cell populations with the capability of sustaining tumor formation. These cells are referred to as glioma stem cells (GSCs). However, the presence of subpopulations of GSCs, and the differences between each subpopulation remain to be fully elucidated. In the present study, CD133‑/A2B5‑ and CD133‑/A2B5+ cells from the SHG139 GSC cell line (SHG139s) were isolated using magnetic‑activated cell sorting. Following xenografting into nude mice, the two isolated subpopulations generated tumors. The characteristics of the two subpopulations were investigated extensively, and it was found that the two exhibited cancer stem cell characteristics. These cells expressed stem cell markers, exhibited a neurosphere‑like appearance, and were found to exhibit self‑renewal and multipotency capabilities. Subsequently, the self‑renewal and proliferation abilities of the two subpopulations were compared. It was found that the A2B5‑ cells had a higher proliferative index and a higher self‑renewal ability, compared with the A2B5+ cells. In addition, the A2B5‑ cells exhibited increased angiogenic ability. However, the invasion ability of the A2B5+ cells was higher than that of the A2B5‑ cells. Taken together, the results of the present study suggested that there are different cell subpopulations in GSCs, and each subpopulation has its own properties.

Correlation between extraocular muscle size and motility restriction in thyroid eye disease.

PubMed

Dagi, Lora R; Zoumalan, Christopher I; Konrad, Hindola; Trokel, Stephen L; Kazim, Michael

2011-01-01

Evaluate the relationship between extraocular muscle (EOM) size, measured by computed tomography, and ocular motility in thyroid eye disease (TED). This case series is based on a retrospective review of the records of 54 patients (108 orbits) with TED. Main outcome measures included EOM size and degree of motility restriction. The average diameter of each rectus muscle was compared with published norms. Four subpopulations based on Age (< 40 or ≥ 40 years) and State of thyroid eye disease (active or stable) were studied. Versions were measured by the corneal light reflex method. The trend of muscle diameter versus motility restriction was evaluated. The average EOM diameter was greater than the norm in the study cohort and 4 subpopulations. The average diameter was largest in the Older and Active TED subpopulations. The inferior rectus and medial rectus were most frequently restricted in the study cohort and 4 subpopulations. The medial rectus had the strongest trend between increasing diameter and motility restriction, followed by the inferior rectus and the superior muscle group (comprised of the superior rectus and levator palpebrae superioris). However, there was a general lack of strong correlation between the diameter of the rectus muscles and their respective motility, especially in the Younger subpopulation. EOM diameters are larger and have more restricted motility in the Older and Active TED subpopulations. Contrary to prior publications, the correlation between EOM diameters and motility was weak, especially in the Younger subpopulation. These findings suggest that the pathophysiology of EOM enlargement is different based upon the age of the patient and the activity of the orbitopathy.

Eight color immunophenotyping of T-, B- and NK-cell subpopulations for characterization of chronic immunodeficiencies.

PubMed

A, Boldt; S, Borte; S, Fricke; K, Kentouche; F, Emmrich; M, Borte; F, Kahlenberg; U, Sack

2014-01-16

Background: The heterogeneity of primary and secondary immunodeficiencies demands for the development of a comprehensive flow cytometric screening system, based on reference values that support a standardized immunophenotypic characterization of most lymphocyte subpopulations. Methods: Peripheral blood samples from healthy adult volunteers (n=25) were collected and split into eight panel fractions (100µl each). Subsequently, pre-mixed 8-color antibody cocktails were incubated per specific panel of whole blood to detect and differentiate cell subsets of: (i) a general lymphocyte overviews, (ii) B-cell subpopulations, (iii) CD4+ subpopulations, (iv) CD8+ subpopulations, (v) regulatory T-cells, (vi) recent thymic emigrants, (vii) NK-cell subpopulations, (viii) NK-cell activation markers. All samples were lysed, washed and measured by flow cytometry. FACS DIVA software was used for data analysis and calculation of quadrant statistics (mean values, standard error of mean, percentile ranges). Results: Whole blood staining of lymphocytes provided the analysis of: (i) CD3+, 4+, 8+, 19+, 16/56+, and activated CD4/8 cells; (ii) immature, naïve, non-switched/switched, memory, (activated) CD21 low , transitional B-cells, plasmablasts/plasmacells; (iii and iv) naïve, central memory, effector, effector memory, TH1/TH2/TH17-like and CCR5+CD8-cells; (v) CD25+, regulatory T-cells (naïve/memory, HLA-DR+); (vi) α/β- and γ/δ-T-cells, recent thymic emigrants in CD4/CD8 cells; (vii) immature/mature CD56 bright , CD94/NKG2D+ NK-cells; and (viii) Nkp30, 44, 46 and CD57+NK-cells. Clinical examples and quadrant statistics are provided. Conclusion: The present study represents a practical approach to standardize the immunophenotyping of most T-, B- and NK-cell subpopulations. That allows differentiating, whether abnormalities or developmental shifts observed in lymphocyte subpopulations originates either from primary or secondary immunological disturbance. © 2014 Clinical Cytometry Society. Copyright © 2014 Clinical Cytometry Society.

Different fibroblast subpopulations of the eye: a therapeutic target to prevent postoperative fibrosis in glaucoma therapy.

PubMed

Stahnke, Thomas; Löbler, Marian; Kastner, Christian; Stachs, Oliver; Wree, Andreas; Sternberg, Katrin; Schmitz, Klaus-Peter; Guthoff, Rudolf

2012-07-01

The aim of this study is the characterization of fibroblasts mainly responsible for fibrosis processes associated with trabeculectomy or microstent implantation for glaucoma therapy. Therefore we isolated human primary fibroblasts from choroidea, sclera, Tenon capsule, and orbital fat tissues. These fibroblast subpopulations were analysed in vitro for expression of the extracellular matrix components which are responsible for postoperative scarring in glaucoma therapy. For scarring the proteins of the collagen family are predominant and so we focused on the expression of collagen I, collagen III and collagen VI in every fibroblast subpopulation. Also, the extracellular matrix protein fibronectin which crosslinks collagen fibres or other extracellular matrix components and cell surfaces, was analyzed. Collagen I, III and VI were prominent in every fibroblast subpopulation. The highest amounts of collagen III were found in hCF and hOF, whereas the signal in hSF and hTF was negligible. Additionally, there is a link between scarring processes and proliferating potential of fibroblasts, in case of microstent implantation triggered through the infiltration of inflammatory cells. Thus we analyzed fibroblast subpopulations for the presence of TGF-β1 which is one of the most important cytokines involved in proliferation processes. TGF-β1 was prominent in all fibroblast subpopulations with lowest expression in hCF cultures. To prevent postoperative fibroblast proliferation we analyzed in vitro the proliferation-inhibitors paclitaxel and mitomycin C which are potential candidates in drug eluting drainage systems on ocular fibroblast subpopulations. These inhibitors arrest fibroblast proliferation and viability, being, however, not very specific and have a cytotoxic potential also on healthy tissues surrounding the microstent outflow area. Significant differences in protein synthesis of fibroblasts subpopulations which could be specific targets for inhibition may help to find out fibroblast specific inhibitors to prevent postoperative scarring and could prevent patients from secondary surgery after microstent implantation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Causal mediation analysis with multiple causally non-ordered mediators.

PubMed

Taguri, Masataka; Featherstone, John; Cheng, Jing

2018-01-01

In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

Role of water mediated interactions in protein-protein recognition landscapes.

PubMed

Papoian, Garegin A; Ulander, Johan; Wolynes, Peter G

2003-07-30

The energy landscape picture of protein folding and binding is employed to optimize a number of pair potentials for direct and water-mediated interactions in protein complex interfaces. We find that water-mediated interactions greatly complement direct interactions in discriminating against various types of trap interactions that model those present in the cell. We highlight the context dependent nature of knowledge-based binding potentials, as contrasted with the situation for autonomous folding. By performing a Principal Component Analysis (PCA) of the corresponding interaction matrixes, we rationalize the strength of the recognition signal for each combination of the contact type and reference trap states using the differential in the idealized "canonical" amino acid compositions of native and trap layers. The comparison of direct and water-mediated contact potential matrixes emphasizes the importance of partial solvation in stabilizing charged groups in the protein interfaces. Specific water-mediated interresidue interactions are expected to influence significantly the kinetics as well as thermodynamics of protein association.

A Cohort Study Comparing Women with Autism Spectrum Disorder with and without Generalized Joint Hypermobility

PubMed Central

Sharp, Julia L.; Edelson, Stephen M.; Kelly, Desmond P.; Casanova, Manuel F.

2018-01-01

Reports suggest comorbidity between autism spectrum disorder (ASD) and the connective tissue disorder, Ehlers-Danlos syndrome (EDS). People with EDS and the broader spectrum of Generalized Joint Hypermobility (GJH) often present with immune- and endocrine-mediated conditions. Meanwhile, immune/endocrine dysregulation is a popular theme in autism research. We surveyed a group of ASD women with/without GJH to determine differences in immune/endocrine exophenotypes. ASD women 25 years or older were invited to participate in an online survey. Respondents completed a questionnaire concerning diagnoses, immune/endocrine symptom history, experiences with pain, and seizure history. ASD women with GJH (ASD/GJH) reported more immune- and endocrine-mediated conditions than their non-GJH counterparts (p = 0.001). Autoimmune conditions were especially prominent in the ASD/GJH group (p = 0.027). Presence of immune-mediated symptoms often co-occurred with one another (p < 0.001–0.020), as did endocrine-mediated symptoms (p < 0.001–0.045), irrespective of the group. Finally, the numbers of immune- and endocrine-mediated symptoms shared a strong inter-relationship (p < 0.001), suggesting potential system crosstalk. While our results cannot estimate comorbidity, they reinforce concepts of an etiological relationship between ASD and GJH. Meanwhile, women with ASD/GJH have complex immune/endocrine exophenotypes compared to their non-GJH counterparts. Further, we discuss how connective tissue regulates the immune system and how the immune/endocrine systems in turn may modulate collagen synthesis, potentially leading to higher rates of GJH in this subpopulation. PMID:29562607

Stress and alcohol use in rural Chinese residents: A moderated mediation model examining the roles of resilience and negative emotions.

PubMed

Wang, Yan; Chen, Xinguang

2015-10-01

Little research has been done on alcohol use and dependence among rural residents in China, a sub-population that might be under increased stress due to the rapid modernization and urbanization processes. We aimed to assess rural residents' levels of stress, negative emotions, resilience, alcohol use/dependence and the complex relationships among them. Survey data from a large random sample (n=1145, mean age=35.9, SD=7.7, 50.7% male) of rural residents in Wuhan, China were collected using Audio Computer-Assisted Self-Interview. The sample had high prevalence of frequently perceived stress (47%) and high prevalence of ever (54.4%), past 30-day (40.4%), and binge drinking (13.8%). Approximately 11% met the criterion for intermediate to severe alcohol dependence. Mediation analysis indicated that the association between perceived stress (predictor) and alcohol dependence (outcome) was fully mediated by anxiety (indirect effect=.203, p<.01) and depression (indict effect=.158, p<.05); moderation analysis indicated that association between stress and two negative emotions (mediators) was significantly modified by resilience (moderator); an integrative moderated mediation analysis indicated that the indirect effect from stress to alcohol dependence through negative emotions was also moderated by resilience. Negative emotions play a key role in bridging stress and alcohol dependence, while resilience significantly buffers the impact of stress on depression, reducing the risk of alcohol dependence. Resilience training may be an effective component for alcohol intervention in rural China. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Molecular simulation of the effect of cholesterol on lipid-mediated protein-protein interactions.

PubMed

de Meyer, Frédérick J-M; Rodgers, Jocelyn M; Willems, Thomas F; Smit, Berend

2010-12-01

Experiments and molecular simulations have shown that the hydrophobic mismatch between proteins and membranes contributes significantly to lipid-mediated protein-protein interactions. In this article, we discuss the effect of cholesterol on lipid-mediated protein-protein interactions as function of hydrophobic mismatch, protein diameter and protein cluster size, lipid tail length, and temperature. To do so, we study a mesoscopic model of a hydrated bilayer containing lipids and cholesterol in which proteins are embedded, with a hybrid dissipative particle dynamics-Monte Carlo method. We propose a mechanism by which cholesterol affects protein interactions: protein-induced, cholesterol-enriched, or cholesterol-depleted lipid shells surrounding the proteins affect the lipid-mediated protein-protein interactions. Our calculations of the potential of mean force between proteins and protein clusters show that the addition of cholesterol dramatically reduces repulsive lipid-mediated interactions between proteins (protein clusters) with positive mismatch, but does not affect attractive interactions between proteins with negative mismatch. Cholesterol has only a modest effect on the repulsive interactions between proteins with different mismatch. Copyright © 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Anaemia, iron deficiency and susceptibility to infection in children in sub-Saharan Africa, guideline dilemmas.

PubMed

Jonker, Femkje A M; Te Poel, Elodie; Bates, Imelda; Boele van Hensbroek, Michael

2017-06-01

Globally, anaemia, iron deficiency and infections are responsible for a majority of the morbidity and mortality that occurs among children. As iron is essential for erythropoiesis and the human immune system, as well as a crucial element for many pathogens, these three conditions often interact. This article considers the question - have the studies conducted so far unravelled the potential complex interaction between these factors sufficiently enough to be able to develop universally applicable guidelines about iron treatment in children? It is possible, however, that the area is too complex and diverse, with many sub-populations, and that not universal, but tailor-made guidelines are needed based on some agreed principles. © 2017 John Wiley & Sons Ltd.

Parent-child mediated learning interactions as determinants of cognitive modifiability: recent research and future directions.

PubMed

Tzuriel, D

1999-05-01

The main objectives of this article are to describe the effects of mediated learning experience (MLE) strategies in mother-child interactions on the child's cognitive modifiability, the effects of distal factors (e.g., socioeconomic status, mother's intelligence, child's personality) on MLE interactions, and the effects of situational variables on MLE processes. Methodological aspects of measurement of MLE interactions and of cognitive modifiability, using a dynamic assessment approach, are discussed. Studies with infants showed that the quality of mother-infant MLE interactions predict later cognitive functioning and that MLE patterns and children's cognitive performance change as a result of intervention programs. Studies with preschool and school-aged children showed that MLE interactions predict cognitive modifiability and that distal factors predict MLE interactions but not the child's cognitive modifiability. The child's cognitive modifiability was predicted by MLE interactions in a structured but not in a free-play situation. Mediation for transcendence (e.g., teaching rules and generalizations) appeared to be the strongest predictor of children's cognitive modifiability. Discussion of future research includes the consideration of a holistic transactional approach, which refers to MLE processes, personality, and motivational-affective factors, the cultural context of mediation, perception of the whole family as a mediational unit, and the "mediational normative scripts."

Coordinated Interaction between Hippocampal Sharp-Wave Ripples and Anterior Cingulate Unit Activity

PubMed Central

2016-01-01

Hippocampal–cortical interaction during sleep promotes transformation of memory for long-term storage in the cortex. In particular, hippocampal sharp-wave ripple-associated neural activation is important for this transformation during slow-wave sleep. The anterior cingulate cortex (ACC) has been shown to be crucial for expression and likely storage of long-term memory. However, little is known about how ACC activity is influenced by hippocampal ripple activity during sleep. We report here about coordinated interactions between hippocampal ripple activity and ACC neural firings. By recording from the ACC and hippocampal CA1 simultaneously in mice, we found that almost all ACC neurons showed increased activity before hippocampal ripple activity; moreover, a subpopulation (17%) displayed a further activation immediately after ripple activity. This postripple activation of ACC neurons correlated positively with ripple amplitude, and the same neurons were excited upon electrical stimulation of the CA1. Interestingly, the preripple activation of ACC neurons was present during the sleep state, but not during the awake state. These results suggest intimate interactions between hippocampal sharp-wave ripples and ACC neurons in a state-dependent manner. Importantly, sharp-wave ripples and associated activation appear to regulate activity of a small population of ACC neurons, a process that may play a critical role in memory consolidation. SIGNIFICANCE STATEMENT The hippocampus communicates with the cortex for memory transformation. Memories of previous experiences become less dependent on the hippocampus and increasingly dependent on cortical areas, such as the anterior cingulate cortex (ACC). However, little evidence is available to directly support this hippocampus-to-cortex information transduction hypothesis of memory consolidation. Here we show that a subpopulation of ACC neurons becomes active just after hippocampal ripple activity, and that electrical stimulation of the hippocampus excites the same ACC neurons. In addition, the majority of ACC neurons are activated just before ripple activity during the sleep state, but not during the awake state. These results provide evidence supporting the hypothesis of hippocampus-to-cortex information flow for memory consolidation as well as reciprocal interaction between the hippocampus and the cortex. PMID:27733616

In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment.

PubMed

Gaibani, Paolo; Campoli, Caterina; Lewis, Russell E; Volpe, Silvia Lidia; Scaltriti, Erika; Giannella, Maddalena; Pongolini, Stefano; Berlingeri, Andrea; Cristini, Francesco; Bartoletti, Michele; Tedeschi, Sara; Ambretti, Simone

2018-06-01

KPC-producing Klebsiella pneumoniae (KPC-Kp) represent a serious problem worldwide. Herein, we describe the evolution of ceftazidime/avibactam resistance by sequencing longitudinal clinical isolates from a patient with KPC-Kp bloodstream infection undergoing ceftazidime/avibactam treatment. WGS was performed on one ceftazidime/avibactam-susceptible KPC-Kp (BOT-CA-S) and two phenotypically different ceftazidime/avibactam-resistant KPC-Kp with low (BOT-CA-R) and high (BOT-EMO) carbapenem MICs. The population diversity was assessed by the frequency of allele mutations and population analysis profiles (PAPs). Phylogenetic analysis demonstrated clonal relatedness of the KPC-Kp isolates, all belonging to the clone ST1519. The D179Y mutation in blaKPC-3 was detected in both of the ceftazidime/avibactam-resistant KPC-Kp, whereas it was absent in the ceftazidime/avibactam-susceptible isolate. The mutation emerged independently in the two ceftazidime/avibactam-resistant isolates and was associated with a significant reduction in carbapenem MICs in BOT-CA-R, but not in BOT-EMO. WGS analysis revealed that the frequency of the D179Y mutation was 96.32% and 51.05% in BOT-CA-R and BOT-EMO, respectively. PAP results demonstrated that carbapenem resistance in BOT-EMO was due to the coexistence of mixed subpopulations harbouring WT and mutated blaKPC-3. A bacterial subpopulation with high ceftazidime/avibactam resistance for BOT-EMO KPC-Kp showed low carbapenem MICs, whereas a subpopulation with high meropenem resistance had a low MIC of ceftazidime/avibactam. Our analysis indicates that mixed subpopulations of ceftazidime/avibactam-resistant KPC-Kp emerge after ceftazidime/avibactam treatment. The evolution of different subpopulations that are highly resistant to ceftazidime/avibactam likely contributes to treatment failure, thereby highlighting the need for combination treatment strategies to limit selection of ceftazidime/avibactam-resistant KPC-Kp subpopulations.

Cluster analysis reveals seasonal variation of sperm subpopulations in extended boar semen

PubMed Central

IBĂNESCU, Iulian; LEIDING, Claus; BOLLWEIN, Heinrich

2017-01-01

This study aimed to identify motile sperm subpopulations in extended boar semen and to observe the presumptive seasonal variation in their distribution. Data from 4837 boar ejaculates collected over a two-year period were analyzed in terms of kinematic parameters by Computer Assisted Sperm Analysis (CASA). Individual sperm data were used to determine subgroups of motile sperm within the ejaculates using cluster analysis. Four motile sperm subpopulations (SP) were identified, with distinct movement patterns: SP1 sperm with high velocity and high linearity; SP2 sperm with high velocity but low linearity; SP3 sperm with low velocity but high linearity; and SP4 sperm with low velocity and low linearity. SP1 constituted the least overall proportion within the ejaculates (P < 0.05). Season of semen collection significantly influenced the different proportions of sperm subpopulations. Spring was characterized by similar proportions of SP1 and SP4 (NS) and higher proportions of SP3. Summer brought a decrease in both subgroups containing fast sperm (SP1 and SP2) (P < 0.05). During autumn, increases in SP2 and SP4 were recorded. Winter substantially affected the proportions of all sperm subpopulations (P < 0.05) and SP2 became the most represented subgroup, while SP1 (fast and linear) reached its highest proportion compared to other seasons. In conclusion, extended boar semen is structured in distinct motile sperm subpopulations whose proportions vary according to the season of collection. Summer and autumn seem to have a negative impact on the fast and linear subpopulation. Cluster analysis can be useful in revealing differences in semen quality that are not normally detected by classical evaluation based on mean values. PMID:29081440

An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force.

PubMed

Whitlock, Evelyn P; Eder, Michelle; Thompson, Jamie H; Jonas, Daniel E; Evans, Corinne V; Guirguis-Blake, Janelle M; Lin, Jennifer S

2017-03-02

Guideline developers and other users of systematic reviews need information about whether a medical or preventive intervention is likely to benefit or harm some patients more (or less) than the average in order to make clinical practice recommendations tailored to these populations. However, guidance is lacking on how to include patient subpopulation considerations into the systematic reviews upon which guidelines are often based. In this article, we describe methods developed to consistently consider the evidence for relevant subpopulations in systematic reviews conducted to support primary care clinical preventive service recommendations made by the U.S. Preventive Services Task Force (USPSTF). Our approach is grounded in our experience conducting systematic reviews for the USPSTF and informed by a review of existing guidance on subgroup analysis and subpopulation issues. We developed and refined our approach based on feedback from the Subpopulation Workgroup of the USPSTF and pilot testing on reviews being conducted for the USPSTF. This paper provides processes and tools for incorporating evidence-based identification of important sources of potential heterogeneity of intervention effects into all phases of systematic reviews. Key components of our proposed approach include targeted literature searches and key informant interviews to identify the most important subpopulations a priori during topic scoping, a framework for assessing the credibility of subgroup analyses reported in studies, and structured investigation of sources of heterogeneity of intervention effects. Further testing and evaluation are necessary to refine this proposed approach and demonstrate its utility to the producers and users of systematic reviews beyond the context of the USPSTF. Gaps in the evidence on important subpopulations identified by routinely applying this process in systematic reviews will also inform future research needs.

The program structure does not reliably recover the correct population structure when sampling is uneven: subsampling and new estimators alleviate the problem.

PubMed

Puechmaille, Sebastien J

2016-05-01

Inferences of population structure and more precisely the identification of genetically homogeneous groups of individuals are essential to the fields of ecology, evolutionary biology and conservation biology. Such population structure inferences are routinely investigated via the program structure implementing a Bayesian algorithm to identify groups of individuals at Hardy-Weinberg and linkage equilibrium. While the method is performing relatively well under various population models with even sampling between subpopulations, the robustness of the method to uneven sample size between subpopulations and/or hierarchical levels of population structure has not yet been tested despite being commonly encountered in empirical data sets. In this study, I used simulated and empirical microsatellite data sets to investigate the impact of uneven sample size between subpopulations and/or hierarchical levels of population structure on the detected population structure. The results demonstrated that uneven sampling often leads to wrong inferences on hierarchical structure and downward-biased estimates of the true number of subpopulations. Distinct subpopulations with reduced sampling tended to be merged together, while at the same time, individuals from extensively sampled subpopulations were generally split, despite belonging to the same panmictic population. Four new supervised methods to detect the number of clusters were developed and tested as part of this study and were found to outperform the existing methods using both evenly and unevenly sampled data sets. Additionally, a subsampling strategy aiming to reduce sampling unevenness between subpopulations is presented and tested. These results altogether demonstrate that when sampling evenness is accounted for, the detection of the correct population structure is greatly improved. © 2016 John Wiley & Sons Ltd.

A circumpolar monitoring framework for polar bears

USGS Publications Warehouse

Vongraven, Dag; Aars, Jon; Amstrup, Steven C.; Atkinson, Stephen N.; Belikov, Stanislav; Born, Erik W.; DeBruyn, T.D.; Derocher, Andrew E.; Durner, George M.; Gill, Michael J.; Lunn, Nicholas J.; Obbard, Martyn E.; Omelak, Jack; Ovsyanikov, Nikita; Peacock, Elizabeth; Richardson, E.E.; Sahanatien, Vicki; Stirling, Ian; Wiig, Øystein

2012-01-01

Polar bears (Ursus maritimus) occupy remote regions that are characterized by harsh weather and limited access. Polar bear populations can only persist where temporal and spatial availability of sea ice provides adequate access to their marine mammal prey. Observed declines in sea ice availability will continue as long as greenhouse gas concentrations rise. At the same time, human intrusion and pollution levels in the Arctic are expected to increase. A circumpolar understanding of the cumulative impacts of current and future stressors is lacking, long-term trends are known from only a few subpopulations, and there is no globally coordinated effort to monitor effects of stressors. Here, we describe a framework for an integrated circumpolar monitoring plan to detect ongoing patterns, predict future trends, and identify the most vulnerable polar bear subpopulations. We recommend strategies for monitoring subpopulation abundance and trends, reproduction, survival, ecosystem change, human-caused mortality, human–bear conflict, prey availability, health, stature, distribution, behavioral change, and the effects that monitoring itself may have on polar bears. We assign monitoring intensity for each subpopulation through adaptive assessment of the quality of existing baseline data and research accessibility. A global perspective is achieved by recommending high intensity monitoring for at least one subpopulation in each of four major polar bear ecoregions. Collection of data on harvest, where it occurs, and remote sensing of habitat, should occur with the same intensity for all subpopulations. We outline how local traditional knowledge may most effectively be combined with the best scientific methods to provide comparable and complementary lines of evidence. We also outline how previously collected intensive monitoring data may be sub-sampled to guide future sampling frequencies and develop indirect estimates or indices of subpopulation status. Adoption of this framework will inform management and policy responses to changing worldwide polar bear status and trends.

Cell context-dependent dual effects of EFEMP1 stabilizes subpopulation equilibrium in responding to changes of in vivo growth environment.

PubMed

Hu, Yuanjie; Ke, Chao; Ru, Ning; Chen, Yumay; Yu, Liping; Siegel, Eric R; Linskey, Mark E; Wang, Ping; Zhou, Yi-Hong

2015-10-13

Conflicting functions of EFEMP1 in cancer have been reported. Using two syngeneic glioma cell lines (U251 and U251-NS) carrying two different principal cell subpopulations that express high or low EGFR, and that are able to interconvert via mis-segregation of chromosome 7 (Chr7), we studied EFEMP1's cell-context-dependent functions in regulating subpopulation equilibrium, here defined by the percentage of cells carrying different copies of Chr7. We found that EFEMP1 attenuated levels of EGFR and cellular respiration in high-EGFR-expressing cells, but increased levels of NOTCH1, MMP2, cell invasiveness, and both oxidative phosphorylation and glycolytic respiration in low-EGFR-expressing cells. Consistently, EFEMP1 suppressed intracranial xenograft formation in U251 and promoted its formation in U251-NS. Interestingly, subpopulation equilibria in xenografts of U251-NS without EFEMP1 overexpression were responsive to inoculum size (1, 10 and 100 thousand cells), which may change the tumor-onset environment. It was not observed in xenografts of U251-NS with EFEMP1 overexpression. The anti-EGFR function of EFEMP1 suppressed acceleration of growth of U251-NS, but not the subpopulation equilibrium, when serially passed under a different (serum-containing adherent) culture condition. Overall, the data suggest that the orthotopic environment of the brain tumor supports EFEMP1 in carrying out both its anti-EGFR and pro-invasive/cancer stem cell-transforming functions in the two glioma cell subpopulations during formation of a single tumor, where EFEMP1 stabilizes the subpopulation equilibrium in response to alterations of the growth environment. This finding implies that EFEMP1 may restrain cancer plasticity in coping with ever-changing tumor microenvironments and/or therapeutic-intervention stresses.

Cellular mechanisms underlying behavioral state-dependent bidirectional modulation of motor cortex output.

PubMed

Schiemann, Julia; Puggioni, Paolo; Dacre, Joshua; Pelko, Miha; Domanski, Aleksander; van Rossum, Mark C W; Duguid, Ian

2015-05-26

Neuronal activity in primary motor cortex (M1) correlates with behavioral state, but the cellular mechanisms underpinning behavioral state-dependent modulation of M1 output remain largely unresolved. Here, we performed in vivo patch-clamp recordings from layer 5B (L5B) pyramidal neurons in awake mice during quiet wakefulness and self-paced, voluntary movement. We show that L5B output neurons display bidirectional (i.e., enhanced or suppressed) firing rate changes during movement, mediated via two opposing subthreshold mechanisms: (1) a global decrease in membrane potential variability that reduced L5B firing rates (L5Bsuppressed neurons), and (2) a coincident noradrenaline-mediated increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced neurons) that elevated firing rates. Blocking noradrenergic receptors in forelimb M1 abolished the bidirectional modulation of M1 output during movement and selectively impaired contralateral forelimb motor coordination. Together, our results provide a mechanism for how noradrenergic neuromodulation and network-driven input changes bidirectionally modulate M1 output during motor behavior. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of lipoarabinomannan from Mycobacterium avium subsp avium in Freund's incomplete adjuvant on the immune response of cattle.

PubMed

Colavecchia, S B; Jolly, A; Fernández, B; Fontanals, A M; Fernández, E; Mundo, S L

2012-02-01

The aim of the present study was to determine whether lipoarabinomannan (LAM), in combination with Freund's incomplete adjuvant (FIA), was able to improve cell-mediated and antibody-mediated immune responses against ovalbumin (OVA) in cattle. Twenty-three calves were assigned to four treatment groups, which were subcutaneously immunized with either OVA plus FIA, OVA plus FIA and LAM from Mycobacterium avium subsp avium, FIA plus LAM, or FIA alone. Lymphoproliferation, IFN-γ production and cell subpopulations on peripheral blood mononuclear cells before and 15 days after treatment were evaluated. Delayed hypersensitivity was evaluated on day 57. Specific humoral immune response was measured by ELISA. Inoculation with LAM induced higher levels of lymphoproliferation and IFN-γ production in response to ConA and OVA (P < 0.05). Specific antibody titers were similar in both OVA-immunized groups. Interestingly, our results showed that the use of LAM in vaccine preparations improved specific cell immune response evaluated by lymphoproliferation and IFN-γ production by at least 50 and 25%, respectively, in cattle without interfering with tuberculosis and paratuberculosis diagnosis.

Effect of lipoarabinomannan from Mycobacterium avium subsp avium in Freund's incomplete adjuvant on the immune response of cattle

PubMed Central

Colavecchia, S.B.; Jolly, A.; Fernández, B.; Fontanals, A.M.; Fernández, E.; Mundo, S.L.

2012-01-01

The aim of the present study was to determine whether lipoarabinomannan (LAM), in combination with Freund's incomplete adjuvant (FIA), was able to improve cell-mediated and antibody-mediated immune responses against ovalbumin (OVA) in cattle. Twenty-three calves were assigned to four treatment groups, which were subcutaneously immunized with either OVA plus FIA, OVA plus FIA and LAM from Mycobacterium avium subsp avium, FIA plus LAM, or FIA alone. Lymphoproliferation, IFN-γ production and cell subpopulations on peripheral blood mononuclear cells before and 15 days after treatment were evaluated. Delayed hypersensitivity was evaluated on day 57. Specific humoral immune response was measured by ELISA. Inoculation with LAM induced higher levels of lymphoproliferation and IFN-γ production in response to ConA and OVA (P < 0.05). Specific antibody titers were similar in both OVA-immunized groups. Interestingly, our results showed that the use of LAM in vaccine preparations improved specific cell immune response evaluated by lymphoproliferation and IFN-γ production by at least 50 and 25%, respectively, in cattle without interfering with tuberculosis and paratuberculosis diagnosis. PMID:22286534

Nociception and escape behavior in planarians

NASA Astrophysics Data System (ADS)

Schoetz Collins, Eva-Maria

2015-03-01

Planarians are famous and widely studied for their regenerative capabilities. When a moving planarian is cut through the middle, the resulting head and tail pieces instantaneously retract and exhibit a characteristic escape response that differs from normal locomotion. In asexual animals, a similar reaction is observed when the planarian undergoes fission, suggesting that reproduction through self-tearing is a rather traumatic event for the animal. Using a multiscale approach, we unravel the dynamics, mechanics, and functional aspects of the planarian escape response. This musculature-driven gait was found to be a dominating response that supersedes the urge to feed or reproduce and quantitatively differs from other modes of planarian locomotion (gliding, peristalsis). We show that this escape gait constitutes the animal's pain response mediated by TRP like receptors and the neurotransmitter histamine, and that it can be induced through adverse thermal, mechanical, electrical or chemical stimuli. Ultimately, we will examine the neuronal subpopulations involved in mediating escape reflexes in planarians and how they are functionally restored during regeneration, thereby gaining mechanistic insight into the neuronal circuits required for specific behaviors. Supported by BWF CASI and Sloan Foundation.

Isolation and identification of a plasmatocyte-spreading peptide from the hemolymph of the lepidopteran insect Pseudoplusia includens.

PubMed

Clark, K D; Pech, L L; Strand, M R

1997-09-12

Insect blood cells (hemocytes) play an essential role in defense against parasites and other pathogenic organisms that infect insects. A key class of hemocytes involved in insect cellular immunity is plasmatocytes. Here we describe the isolation and identification of a peptide from the moth Pseudoplusia includens that mediates the spreading of plasmatocytes to foreign surfaces. This peptide, designated plasmatocyte-spreading peptide (PSP1), contains 23 amino acid residues in the following sequence: H-ENFNGGCLAGYMRTADGRCKPTF-OH. In vitro assays using the synthetic peptide at concentrations >/=2 nM induced plasmatocytes from P. includens to spread on the surface of culture dishes. Injection of this peptide into P. includens larvae caused a transient depletion of plasmatocytes from circulation. Labeling studies indicated that this peptide induced 75% of plasmatocytes that were double-labeled by the monoclonal antibodies 49G3A3 and 43E9A8 to spread, whereas plasma induced significantly more plasmatocytes to spread. This suggests that only a certain subpopulation of plasmatocytes responds to the peptide and that other peptidyl factors mediate plasmatocyte adhesion responses.

High-Density Lipoprotein Reduction Differentially Modulates to Classical and Nonclassical Monocyte Subpopulations in Metabolic Syndrome Patients and in LPS-Stimulated Primary Human Monocytes In Vitro

PubMed Central

Grün, Johanna L.; Manjarrez-Reyna, Aaron N.; Gómez-Arauz, Angélica Y.; Leon-Cabrera, Sonia; Bueno-Hernández, Nallely; Islas-Andrade, Sergio

2018-01-01

The effect of metabolic syndrome on human monocyte subpopulations has not yet been studied. Our main goal was to examine monocyte subpopulations in metabolic syndrome patients, while also identifying the risk factors that could directly influence these cells. Eighty-six subjects were divided into metabolic syndrome patients and controls. Monocyte subpopulations were quantified by flow cytometry, and interleukin- (IL-) 1β secretion levels were measured by ELISA. Primary human monocytes were cultured in low or elevated concentrations of high-density lipoprotein (HDL) and stimulated with lipopolysaccharide (LPS). The nonclassical monocyte (NCM) percentage was significantly increased in metabolic syndrome patients as compared to controls, whereas classical monocytes (CM) were reduced. Among all metabolic syndrome risk factors, HDL reduction exhibited the most important correlation with monocyte subpopulations and then was studied in vitro. Low HDL concentration reduced the CM percentage, whereas it increased the NCM percentage and IL-1β secretion in LPS-treated monocytes. The LPS effect was abolished when monocytes were cultured in elevated HDL concentrations. Concurring with in vitro results, IL-1β serum values significantly increased in metabolic syndrome patients with low HDL levels as compared to metabolic syndrome patients without HDL reduction. Our data demonstrate that HDL directly modulates monocyte subpopulations in metabolic syndrome. PMID:29850624

Connectivity dominates larval replenishment in a coastal reef fish metapopulation

PubMed Central

Saenz-Agudelo, Pablo; Jones, Geoffrey P.; Thorrold, Simon R.; Planes, Serge

2011-01-01

Direct estimates of larval retention and connectivity are essential to understand the structure and dynamics of marine metapopulations, and optimize the size and spacing of reserves within networks of marine-protected areas (MPAs). For coral reef fishes, while there are some empirical estimates of self-recruitment at isolated populations, exchange among sub-populations has been rarely quantified. Here, we used microsatellite DNA markers and a likelihood-based parentage analysis to assess the relative magnitude of self-recruitment and exchange among eight geographically distinct sub-populations of the panda clownfish Amphiprion polymnus along 30 km of coastline near Port Moresby, Papua New Guinea. In addition, we used an assignment/exclusion test to identify immigrants arriving from genetically distinct sources. Overall, 82 per cent of the juveniles were immigrants while 18 per cent were progeny of parents genotyped in our focal metapopulation. Of the immigrants, only 6 per cent were likely to be genetically distinct from the focal metapopulation, suggesting most of the connectivity is among sub-populations from a rather homogeneous genetic pool. Of the 18 per cent that were progeny of known adults, two-thirds dispersed among the eight sub-populations and only one-third settled back into natal sub-populations. Comparison of our data with previous studies suggested that variation in dispersal distances is likely to be influenced by the geographical setting and spacing of sub-populations. PMID:21325328

Connectivity dominates larval replenishment in a coastal reef fish metapopulation.

PubMed

Saenz-Agudelo, Pablo; Jones, Geoffrey P; Thorrold, Simon R; Planes, Serge

2011-10-07

Direct estimates of larval retention and connectivity are essential to understand the structure and dynamics of marine metapopulations, and optimize the size and spacing of reserves within networks of marine-protected areas (MPAs). For coral reef fishes, while there are some empirical estimates of self-recruitment at isolated populations, exchange among sub-populations has been rarely quantified. Here, we used microsatellite DNA markers and a likelihood-based parentage analysis to assess the relative magnitude of self-recruitment and exchange among eight geographically distinct sub-populations of the panda clownfish Amphiprion polymnus along 30 km of coastline near Port Moresby, Papua New Guinea. In addition, we used an assignment/exclusion test to identify immigrants arriving from genetically distinct sources. Overall, 82 per cent of the juveniles were immigrants while 18 per cent were progeny of parents genotyped in our focal metapopulation. Of the immigrants, only 6 per cent were likely to be genetically distinct from the focal metapopulation, suggesting most of the connectivity is among sub-populations from a rather homogeneous genetic pool. Of the 18 per cent that were progeny of known adults, two-thirds dispersed among the eight sub-populations and only one-third settled back into natal sub-populations. Comparison of our data with previous studies suggested that variation in dispersal distances is likely to be influenced by the geographical setting and spacing of sub-populations.

Lessons From the Polio Endgame: Overcoming the Failure to Vaccinate and the Role of Subpopulations in Maintaining Transmission.

PubMed

Thompson, Kimberly M; Duintjer Tebbens, Radboud J

2017-07-01

Recent detections of circulating serotype 2 vaccine-derived poliovirus in northern Nigeria (Borno and Sokoto states) and Pakistan (Balochistan Province) and serotype 1 wild poliovirus in Pakistan, Afghanistan, and Nigeria (Borno) represent public health emergencies that require aggressive response. We demonstrate the importance of undervaccinated subpopulations, using an existing dynamic poliovirus transmission and oral poliovirus vaccine evolution model. We review the lessons learned during the polio endgame about the role of subpopulations in sustaining transmission, and we explore the implications of subpopulations for other vaccine-preventable disease eradication efforts. Relatively isolated subpopulations benefit little from high surrounding population immunity to transmission and will sustain transmission as long as they do not attain high vaccination coverage. Failing to reach such subpopulations with high coverage represents the root cause of polio eradication delays. Achieving and maintaining eradication requires addressing the weakest links, which includes immunizing populations in insecure areas and/or with disrupted or poor-performing health systems and managing the risks of individuals with primary immunodeficiencies who can excrete vaccine-derived poliovirus long-term. Eradication efforts for vaccine-preventable diseases need to create performance expectations for countries to immunize all people living within their borders and maintain high coverage with appropriate interventions.Keywords. Polio; eradication; transmission; heterogeneity. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

A Review of Peer-Mediated Social Interaction Interventions for Students with Autism in Inclusive Settings

ERIC Educational Resources Information Center

Watkins, Laci; O'Reilly, Mark; Kuhn, Michelle; Gevarter, Cindy; Lancioni, Giulio E.; Sigafoos, Jeff; Lang, Russell

2015-01-01

This review addresses the use of peer-mediated interventions (PMI) to improve the social interaction skills of students with autism spectrum disorder (ASD) in inclusive settings. The purpose of this review is to (a) identify the characteristics and components of peer-mediated social interaction interventions, (b) evaluate the effectiveness of PMI…

Mediation of the Relationship between Maternal Phthalate Exposure and Preterm Birth by Oxidative Stress with Repeated Measurements across Pregnancy.

PubMed

Ferguson, Kelly K; Chen, Yin-Hsiu; VanderWeele, Tyler J; McElrath, Thomas F; Meeker, John D; Mukherjee, Bhramar

2017-03-01

Mediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease. We examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress. This nested case-control study of preterm birth ( n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure-mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure-mediator interaction. We observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure-mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure-mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively. This demonstrates mediation of the phthalate-preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure-mediator interaction may exist. Citation: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488-494; http://dx.doi.org/10.1289/EHP282.

Quantifying landscape linkages among giant panda subpopulations in regional scale conservation.

PubMed

Qi, Dunwu; Hu, Yibo; Gu, Xiaodong; Yang, Xuyi; Yang, Guang; Wei, Fuwen

2012-06-01

Understanding habitat requirements and identifying landscape linkages are essential for the survival of isolated populations of endangered species. Currently, some of the giant panda populations are isolated, which threatens their long-term survival, particularly in the Xiaoxiangling mountains. In the present study, we quantified niche requirements and then identified potential linkages of giant panda subpopulations in the most isolated region, using ecological niche factor analysis and a least-cost path model. Giant pandas preferred habitat with conifer forest and gentle slopes (>20 to ≤30°). Based on spatial distribution of suitable habitat, linkages were identified for the Yele subpopulation to 4 other subpopulations (Liziping, Matou, Xinmin and Wanba). Their lengths ranged from 15 to 54 km. The accumulated cost ranged from 693 to 3166 and conifer forest covered over 31%. However, a variety of features (e.g. major roads, human settlements and large unforested areas) might act as barriers along the linkages for giant panda dispersal. Our analysis quantified giant panda subpopulation connectivity to ensure long-term survival. © 2012 ISZS, Blackwell Publishing and IOZ/CAS.

Distinct projection targets define subpopulations of mouse brainstem vagal neurons that express the autism-associated MET receptor tyrosine kinase.

PubMed

Kamitakahara, Anna; Wu, Hsiao-Huei; Levitt, Pat

2017-12-15

Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a MET EGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: (a) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, (b) EGFP+ neurons in the medial DMV projecting to the stomach, and (b) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggests that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. © 2017 Wiley Periodicals, Inc.

The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause.

PubMed

Chirgwin, Jacquie; Sun, Zhuoxin; Smith, Ian; Price, Karen N; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M; Goldhirsch, Aron; Coates, Alan S

2012-01-01

Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤ 55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause

PubMed Central

Sun, Zhuoxin; Smith, Ian; Price, Karen N.; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M.; Goldhirsch, Aron; Coates, Alan S.

2016-01-01

Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients. PMID:21892704

When push comes to shove: Exclusion processes with nonlocal consequences

NASA Astrophysics Data System (ADS)

Almet, Axel A.; Pan, Michael; Hughes, Barry D.; Landman, Kerry A.

2015-11-01

Stochastic agent-based models are useful for modelling collective movement of biological cells. Lattice-based random walk models of interacting agents where each site can be occupied by at most one agent are called simple exclusion processes. An alternative motility mechanism to simple exclusion is formulated, in which agents are granted more freedom to move under the compromise that interactions are no longer necessarily local. This mechanism is termed shoving. A nonlinear diffusion equation is derived for a single population of shoving agents using mean-field continuum approximations. A continuum model is also derived for a multispecies problem with interacting subpopulations, which either obey the shoving rules or the simple exclusion rules. Numerical solutions of the derived partial differential equations compare well with averaged simulation results for both the single species and multispecies processes in two dimensions, while some issues arise in one dimension for the multispecies case.

Differential Interaction of Platelet-Derived Extracellular Vesicles with Leukocyte Subsets in Human Whole Blood.

PubMed

Weiss, René; Gröger, Marion; Rauscher, Sabine; Fendl, Birgit; Eichhorn, Tanja; Fischer, Michael B; Spittler, Andreas; Weber, Viktoria

2018-04-26

Secretion and exchange of biomolecules via extracellular vesicles (EVs) are crucial mechanisms in intercellular communication, and the roles of EVs in infection, inflammation, or thrombosis have been increasingly recognized. EVs have emerged as central players in immune regulation and can enhance or suppress the immune response, depending on the state of donor and recipient cells. We investigated the interaction of blood cell-derived EVs with leukocyte subpopulations (monocytes and their subsets, granulocytes, B cells, T cells, and NK cells) directly in whole blood using a combination of flow cytometry, imaging flow cytometry, cell sorting, and high resolution confocal microscopy. Platelet-derived EVs constituted the majority of circulating EVs and were preferentially associated with granulocytes and monocytes, while they scarcely interacted with lymphocytes. Further flow cytometric differentiation of monocyte subsets provided clear indications for a preferential association of platelet-derived EVs with intermediate (CD14 ++ CD16 + ) monocytes in whole blood.

DOMMINO 2.0: integrating structurally resolved protein-, RNA-, and DNA-mediated macromolecular interactions

PubMed Central

Kuang, Xingyan; Dhroso, Andi; Han, Jing Ginger; Shyu, Chi-Ren; Korkin, Dmitry

2016-01-01

Macromolecular interactions are formed between proteins, DNA and RNA molecules. Being a principle building block in macromolecular assemblies and pathways, the interactions underlie most of cellular functions. Malfunctioning of macromolecular interactions is also linked to a number of diseases. Structural knowledge of the macromolecular interaction allows one to understand the interaction’s mechanism, determine its functional implications and characterize the effects of genetic variations, such as single nucleotide polymorphisms, on the interaction. Unfortunately, until now the interactions mediated by different types of macromolecules, e.g. protein–protein interactions or protein–DNA interactions, are collected into individual and unrelated structural databases. This presents a significant obstacle in the analysis of macromolecular interactions. For instance, the homogeneous structural interaction databases prevent scientists from studying structural interactions of different types but occurring in the same macromolecular complex. Here, we introduce DOMMINO 2.0, a structural Database Of Macro-Molecular INteractiOns. Compared to DOMMINO 1.0, a comprehensive database on protein-protein interactions, DOMMINO 2.0 includes the interactions between all three basic types of macromolecules extracted from PDB files. DOMMINO 2.0 is automatically updated on a weekly basis. It currently includes ∼1 040 000 interactions between two polypeptide subunits (e.g. domains, peptides, termini and interdomain linkers), ∼43 000 RNA-mediated interactions, and ∼12 000 DNA-mediated interactions. All protein structures in the database are annotated using SCOP and SUPERFAMILY family annotation. As a result, protein-mediated interactions involving protein domains, interdomain linkers, C- and N- termini, and peptides are identified. Our database provides an intuitive web interface, allowing one to investigate interactions at three different resolution levels: whole subunit network, binary interaction and interaction interface. Database URL: http://dommino.org PMID:26827237

Comparative Genomics in Homo sapiens.

PubMed

Oti, Martin; Sammeth, Michael

2018-01-01

Genomes can be compared at different levels of divergence, either between species or within species. Within species genomes can be compared between different subpopulations, such as human subpopulations from different continents. Investigating the genomic differences between different human subpopulations is important when studying complex diseases that are affected by many genetic variants, as the variants involved can differ between populations. The 1000 Genomes Project collected genome-scale variation data for 2504 human individuals from 26 different populations, enabling a systematic comparison of variation between human subpopulations. In this chapter, we present step-by-step a basic protocol for the identification of population-specific variants employing the 1000 Genomes data. These variants are subsequently further investigated for those that affect the proteome or RNA splice sites, to investigate potentially biologically relevant differences between the populations.

Proteomic Analysis of the Mediator Complex Interactome in Saccharomyces cerevisiae.

PubMed

Uthe, Henriette; Vanselow, Jens T; Schlosser, Andreas

2017-02-27

Here we present the most comprehensive analysis of the yeast Mediator complex interactome to date. Particularly gentle cell lysis and co-immunopurification conditions allowed us to preserve even transient protein-protein interactions and to comprehensively probe the molecular environment of the Mediator complex in the cell. Metabolic 15 N-labeling thereby enabled stringent discrimination between bona fide interaction partners and nonspecifically captured proteins. Our data indicates a functional role for Mediator beyond transcription initiation. We identified a large number of Mediator-interacting proteins and protein complexes, such as RNA polymerase II, general transcription factors, a large number of transcriptional activators, the SAGA complex, chromatin remodeling complexes, histone chaperones, highly acetylated histones, as well as proteins playing a role in co-transcriptional processes, such as splicing, mRNA decapping and mRNA decay. Moreover, our data provides clear evidence, that the Mediator complex interacts not only with RNA polymerase II, but also with RNA polymerases I and III, and indicates a functional role of the Mediator complex in rRNA processing and ribosome biogenesis.

Comparison of methods for the analysis of relatively simple mediation models.

PubMed

Rijnhart, Judith J M; Twisk, Jos W R; Chinapaw, Mai J M; de Boer, Michiel R; Heymans, Martijn W

2017-09-01

Statistical mediation analysis is an often used method in trials, to unravel the pathways underlying the effect of an intervention on a particular outcome variable. Throughout the years, several methods have been proposed, such as ordinary least square (OLS) regression, structural equation modeling (SEM), and the potential outcomes framework. Most applied researchers do not know that these methods are mathematically equivalent when applied to mediation models with a continuous mediator and outcome variable. Therefore, the aim of this paper was to demonstrate the similarities between OLS regression, SEM, and the potential outcomes framework in three mediation models: 1) a crude model, 2) a confounder-adjusted model, and 3) a model with an interaction term for exposure-mediator interaction. Secondary data analysis of a randomized controlled trial that included 546 schoolchildren. In our data example, the mediator and outcome variable were both continuous. We compared the estimates of the total, direct and indirect effects, proportion mediated, and 95% confidence intervals (CIs) for the indirect effect across OLS regression, SEM, and the potential outcomes framework. OLS regression, SEM, and the potential outcomes framework yielded the same effect estimates in the crude mediation model, the confounder-adjusted mediation model, and the mediation model with an interaction term for exposure-mediator interaction. Since OLS regression, SEM, and the potential outcomes framework yield the same results in three mediation models with a continuous mediator and outcome variable, researchers can continue using the method that is most convenient to them.

[Effects decomposition in mediation analysis: a numerical example].

PubMed

Zugna, Daniela; Richiardi, Lorenzo

2018-01-01

Mediation analysis aims to decompose the total effect of the exposure on the outcome into a direct effect (unmediated) and an indirect effect (mediated by a mediator). When the interest also lies on understanding whether the exposure effect differs in different sub-groups of study population or under different scenarios, the mediation analysis needs to be integrated with interaction analysis. In this setting it is necessary to decompose the total effect not only into two components, the direct and indirect effects, but other two components linked to interaction. The interaction between the exposure and the mediator in their effect on the outcome could indeed act through the effect of the exposure on the mediator or through the mediator when the mediator is not totally explained by the exposure. We describe options for decomposition, proposed in literature, of the total effect and we illustrate them through a hypothetical example of the effect of age at diagnosis of cancer on survival, mediated and unmediated by the therapeutical approach, and a numerical example.

Cellular Specificity of the Blood–CSF Barrier for Albumin Transfer across the Choroid Plexus Epithelium

PubMed Central

Liddelow, Shane A.; Dzięgielewska, Katarzyna M.; Møllgård, Kjeld; Whish, Sophie C.; Noor, Natassya M.; Wheaton, Benjamin J.; Gehwolf, Renate; Wagner, Andrea; Traweger, Andreas; Bauer, Hannelore; Bauer, Hans-Christian; Saunders, Norman R.

2014-01-01

To maintain the precise internal milieu of the mammalian central nervous system, well-controlled transfer of molecules from periphery into brain is required. Recently the soluble and cell-surface albumin-binding glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been implicated in albumin transport into developing brain, however the exact mechanism remains unknown. We postulate that SPARC is a docking site for albumin, mediating its uptake and transfer by choroid plexus epithelial cells from blood into cerebrospinal fluid (CSF). We used in vivo physiological measurements of transfer of endogenous (mouse) and exogenous (human) albumins, in situ Proximity Ligation Assay (in situ PLA), and qRT-PCR experiments to examine the cellular mechanism mediating protein transfer across the blood–CSF interface. We report that at all developmental stages mouse albumin and SPARC gave positive signals with in situ PLAs in plasma, CSF and within individual plexus cells suggesting a possible molecular interaction. In contrast, in situ PLA experiments in brain sections from mice injected with human albumin showed positive signals for human albumin in the vascular compartment that were only rarely identifiable within choroid plexus cells and only at older ages. Concentrations of both endogenous mouse albumin and exogenous (intraperitoneally injected) human albumin were estimated in plasma and CSF and expressed as CSF/plasma concentration ratios. Human albumin was not transferred through the mouse blood–CSF barrier to the same extent as endogenous mouse albumin, confirming results from in situ PLA. During postnatal development Sparc gene expression was higher in early postnatal ages than in the adult and changed in response to altered levels of albumin in blood plasma in a differential and developmentally regulated manner. Here we propose a possible cellular route and mechanism by which albumin is transferred from blood into CSF across a sub-population of specialised choroid plexus epithelial cells. PMID:25211495

Adipocyte-Macrophage Cross-Talk in Obesity.

PubMed

Engin, Ayse Basak

2017-01-01

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction has a primary importance in obesity. Large amounts of macrophages are accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway also promotes more macrophage accumulation into the obese adipose tissue. However, increased local extracellular lipid concentrations is a final mechanism for adipose tissue macrophage accumulation. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-alpha) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1beta) by macrophages; both adipocyte and macrophage induction by toll like receptor-4 (TLR4) through nuclear factor-kappaB (NF-kappaB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in macrophage accumulation and in the development of adipose tissue inflammation. Old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. The obesity-induced changes in adipose tissue macrophage numbers are mainly due to increases in the triple-positive CD11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. The ratio of M1-to-M2 macrophages is increased in obesity. Furthermore, hypoxia along with higher concentrations of free fatty acids exacerbates macrophage-mediated inflammation in obesity. The metabolic status of adipocytes is a major determinant of macrophage inflammatory output. Macrophage/adipocyte fatty-acid-binding proteins act at the interface of metabolic and inflammatory pathways. Both macrophages and adipocytes are the sites for active lipid metabolism and signaling.

Cellular players that shape evolving pathology and neurodegeneration following traumatic brain injury.

PubMed

Puntambekar, Shweta S; Saber, Maha; Lamb, Bruce T; Kokiko-Cochran, Olga N

2018-03-27

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and has emerged as a critical risk factor for multiple neurodegenerative diseases, particularly Alzheimer's disease (AD). How the inflammatory cascade resulting from mechanical stress, axonal shearing and the loss of neurons and glia following initial impact in TBI, contributes to the development of AD-like disease is unclear. Neuroinflammation, characterized by blood-brain barrier (BBB) dysfunction and activation of brain-resident microglia and astrocytes, resulting in secretion of inflammatory mediators and subsequent recruitment of peripheral immune cells has been the focus of extensive research in attempts to identify drug-targets towards improving functional outcomes post TBI. While knowledge of intricate cellular interactions that shape lesion pathophysiology is incomplete, a major limitation in the field is the lack of understanding of how distinct cell types differentially alter TBI pathology. The aim of this review is to highlight functional differences between populations of bone marrow derived, infiltrating monocytes/macrophages and brain-resident microglia based on differential expression of the chemokine receptors CCR2 and CX 3 CR1. This review will focus on how unique subsets of mononuclear phagocytes shape TBI pathophysiology, neurotoxicity and BBB function, in a disease-stage dependent manner. Additionally, this review summarizes the role of multiple microglia and macrophage receptors, namely CCR2, CX 3 CR1 and Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) in pathological neuroinflammation and neurodegeneration vs. recovery following TBI. TREM2 has been implicated in mediating AD-related pathology, and variants in TREM2 are particularly important due to their correlation with exacerbated neurodegeneration. Finally, this review highlights behavioral outcomes associated with microglial vs. macrophage variances, the need for novel treatment strategies that target unique subpopulations of peripheral macrophages, and the importance of development of therapeutics to modulate inflammatory functions of brain-resident microglia at specific stages of TBI. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of female bovine plasma collected at different days of the estrous cycle on epididymal spermatozoa motility.

PubMed

Nait Mouloud, M; Ouennoughi, F; Yaiche, L; Kaidi, R; Iguer-Ouada, M

2017-03-15

The aim of this study was to assess the effects of female bovine plasma collected at different days of the reproductive cycle on epididymal spermatozoa motility and to test hypothesis that the subpopulations pattern of motile spermatozoa is affected by this treatment. Blood plasma samples were collected from five Holstein Friesian cows at different stages of the estrous cycle (days 0, 5, 10, 12 and 18), one pregnant cow and one adult bull and were diluted 1:9 (V/V) with normal saline. Female charcoal-treated plasma, Bull plasma and saline were used as controls. Semen samples were obtained from cauda epididymidis through retrograde flushing and diluted in saline to approximately 60 × 106 sperm/ml. The extended semen was diluted 1:2 (V/V) with tested media and motility was evaluated at 15 min and then every hour for 6 h using a computer-assisted semen analysis. Multivariate clustering procedure was applied to identify and quantify specific subpopulations within the semen samples. The statistical analysis clustered all the motile spermatozoa into three separate subpopulations with defined patterns of movement: Subpopulation 1 poorly motile and non-progressive spermatozoa (39.3%), subpopulation 2 including the fastest and the most vigorous spermatozoa (46.4%) and subpopulation 3 represented by slow, non-vigorous but linear spermatozoa (14.3%). Initially, sperm samples supplemented with female, male or female charcoal-treated plasma stimulated equally total motility and spermatozoa belonging to subpopulation 2 regardless of the estrous cycle stage. After 1-h incubation, the motility of these both categories of spermatozoa (total motile and those assigned to subpopulation 2) is enhanced and maintained more in day 12, 18 and pregnant cow plasma than in female plasma from earlier stage of the estrous cycle (day 0, 5 and 10), male plasma and female-charcoal treated plasma. In conclusion, the overall results showed that female plasma stimulated significantly sperm motility, especially at the late stage of the estrous cycle. Additionally, to the diverse compounds contained in blood plasma, progesterone may play a key role in such motility activation. Copyright © 2016 Elsevier Inc. All rights reserved.

Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation.

PubMed

Choi, Dongsic; Lee, Tae Hoon; Spinelli, Cristiana; Chennakrishnaiah, Shilpa; D'Asti, Esterina; Rak, Janusz

2017-07-01

Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to-cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV-mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker and companion diagnostics. Indeed, studies are underway to further explore the multiple links between molecular causality in cancer and various aspects of cellular vesiculation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Developing an eco-routing application.

DOT National Transportation Integrated Search

2014-01-01

The study develops eco-routing algorithms and investigates and quantifies the system-wide impacts of implementing an eco-routing system. Two eco-routing algorithms are developed: one based on vehicle sub-populations (ECO-Subpopulation Feedback Assign...

Improving removal-based estimates of abundance by sampling a population of spatially distinct subpopulations

USGS Publications Warehouse

Dorazio, R.M.; Jelks, H.L.; Jordan, F.

2005-01-01

 A statistical modeling framework is described for estimating the abundances of spatially distinct subpopulations of animals surveyed using removal sampling. To illustrate this framework, hierarchical models are developed using the Poisson and negative-binomial distributions to model variation in abundance among subpopulations and using the beta distribution to model variation in capture probabilities. These models are fitted to the removal counts observed in a survey of a federally endangered fish species. The resulting estimates of abundance have similar or better precision than those computed using the conventional approach of analyzing the removal counts of each subpopulation separately. Extension of the hierarchical models to include spatial covariates of abundance is straightforward and may be used to identify important features of an animal's habitat or to predict the abundance of animals at unsampled locations.

Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies

PubMed Central

Thapa, Dharendra; Shepherd, Danielle L.

2014-01-01

Cardiac tissue contains discrete pools of mitochondria that are characterized by their subcellular spatial arrangement. Subsarcolemmal mitochondria (SSM) exist below the cell membrane, interfibrillar mitochondria (IFM) reside in rows between the myofibrils, and perinuclear mitochondria are situated at the nuclear poles. Microstructural imaging of heart tissue coupled with the development of differential isolation techniques designed to sequentially separate spatially distinct mitochondrial subpopulations have revealed differences in morphological features including shape, absolute size, and internal cristae arrangement. These findings have been complemented by functional studies indicating differences in biochemical parameters and, potentially, functional roles for the ATP generated, based upon subcellular location. Consequently, mitochondrial subpopulations appear to be influenced differently during cardiac pathologies including ischemia/reperfusion, heart failure, aging, exercise, and diabetes mellitus. These influences may be the result of specific structural and functional disparities between mitochondrial subpopulations such that the stress elicited by a given cardiac insult differentially impacts subcellular locales and the mitochondria contained within. The goal of this review is to highlight some of the inherent structural and functional differences that exist between spatially distinct cardiac mitochondrial subpopulations as well as provide an overview of the differential impact of various cardiac pathologies on spatially distinct mitochondrial subpopulations. As an outcome, we will instill a basis for incorporating subcellular spatial location when evaluating the impact of cardiac pathologies on the mitochondrion. Incorporation of subcellular spatial location may offer the greatest potential for delineating the influence of cardiac pathology on this critical organelle. PMID:24778166

Testing spatial heterogeneity with stock assessment models

PubMed Central

Eero, Margit; Silva, Alexandra; Ulrich, Clara; Pawlowski, Lionel; Holmes, Steven J.; Ibaibarriaga, Leire; De Oliveira, José A. A.; Riveiro, Isabel; Alzorriz, Nekane; Citores, Leire; Scott, Finlay; Uriarte, Andres; Carrera, Pablo; Duhamel, Erwan; Mosqueira, Iago

2018-01-01

This paper describes a methodology that combines meta-population theory and stock assessment models to gain insights about spatial heterogeneity of the meta-population in an operational time frame. The methodology was tested with stochastic simulations for different degrees of connectivity between sub-populations and applied to two case studies, North Sea cod (Gadus morua) and Northeast Atlantic sardine (Sardina pilchardus). Considering that the biological components of a population can be partitioned into discrete spatial units, we extended this idea into a property of additivity of sub-population abundances. If the additivity results hold true for putative sub-populations, then assessment results based on sub-populations will provide information to develop and monitor the implementation of finer scale/local management. The simulation study confirmed that when sub-populations are independent and not too heterogeneous with regards to productivity, the sum of stock assessment model estimates of sub-populations’ SSB is similar to the SSB estimates of the meta-population. It also showed that a strong diffusion process can be detected and that the stronger the connection between SSB and recruitment, the better the diffusion process will be detected. On the other hand it showed that weak to moderate diffusion processes are not easy to identify and large differences between sub-populations productivities may be confounded with weak diffusion processes. The application to North Sea cod and Atlantic sardine exemplified how much insight can be gained. In both cases the results obtained were sufficiently robust to support the regional analysis. PMID:29364901

Not so simple, not so subtle: the interspecies competition between Bacillus simplex and Bacillus subtilis and its impact on the evolution of biofilms

PubMed Central

Rosenberg, Gili; Steinberg, Nitai; Oppenheimer-Shaanan, Yaara; Olender, Tsvia; Doron, Shany; Ben-Ari, Julius; Sirota-Madi, Alexandra; Bloom-Ackermann, Zohar; Kolodkin-Gal, Ilana

2016-01-01

Bacillus subtilis biofilms have a fundamental role in shaping the soil ecosystem. During this process, they unavoidably interact with neighbour bacterial species. We studied the interspecies interactions between biofilms of the soil-residing bacteria B. subtilis and related Bacillus species. We found that proximity between the biofilms triggered recruitment of motile B. subtilis cells, which engulfed the competing Bacillus simplex colony. Upon interaction, B. subtilis secreted surfactin and cannibalism toxins, at concentrations that were inert to B. subtilis itself, which eliminated the B. simplex colony, as well as colonies of Bacillus toyonensis. Surfactin toxicity was correlated with the presence of short carbon-tail length isomers, and synergistic with the cannibalism toxins. Importantly, during biofilm development and interspecies interactions a subpopulation in B. subtilis biofilm lost its native plasmid, leading to increased virulence against the competing Bacillus species. Overall, these findings indicate that genetic programs and traits that have little effect on biofilm development when each species is grown in isolation have a dramatic impact when different bacterial species interact. PMID:28721238

Influence of landscape and social interactions on transmission of disease in a social cervid.

PubMed

Vander Wal, Eric; Paquet, Paul C; Andrés, José A

2012-03-01

The mechanisms of pathogen transmission are often social behaviours. These occur at local scales and are affected by landscape-scale population structure. Host populations frequently exist in patchy and isolated environments that create a continuum of genetic and social familiarity. Such variability has an important multispatial effect on pathogen spread. We assessed elk dispersal (i.e. likelihood of interdeme pathogen transmission) through spatially explicit genetic analyses. At a landscape scale, the elk population was composed of one cluster within a southeast-to-northwest cline spanning three spatially discrete subpopulations of elk across two protected areas in Manitoba (Canada). Genetic data are consistent with spatial variability in apparent prevalence of bovine tuberculosis (TB) in elk. Given the existing population structure, between-subpopulation spread of disease because of elk dispersal is unlikely. Furthermore, to better understand the risk of spread and distribution of the TB, we used a combination of close-contact logging biotelemetry and genetic data, which highlights how social intercourse may affect pathogen transmission. Our results indicate that close-contact interaction rate and duration did not covary with genetic relatedness. Thus, direct elk-to-elk transmission of disease is unlikely to be constrained to related individuals. That social intercourse in elk is not limited to familial groups provides some evidence pathogen transmission may be density-dependent. We show that the combination of landscape-scale genetics, relatedness and local-scale social behaviours is a promising approach to understand and predict landscape-level pathogen transmission within our system and within all social ungulate systems affected by transmissible diseases. © 2012 Blackwell Publishing Ltd.

Sperm kinematics and subpopulational responses during the cryopreservation process in caprine ejaculates.

PubMed

Barbas, J P; Leahy, T; Horta, A E; García-Herreros, M

2018-03-20

Sperm cryopreservation in goats has been a challenge for many years due to the detrimental effects of seminal plasma enzymes produced by the bulbo-urethral glands which catalyse the hydrolysis of lecithins in egg yolk to fatty acids and lysolecithins which are deleterious to spermatozoa. This fact implies to carry out additional processing steps during sperm cryopreservation for seminal plasma removal triggering different sperm responses which may affect sperm functionality. The objective of the present study was to determine specific sperm subpopulation responses in different handling steps during the cryopreservation process by using functional sperm kinematic descriptors in caprine ejaculates. Buck ejaculates (n = 40) were analysed for sperm concentration, viability, morphology and acrosome integrity. Moreover, sperm motility was assessed using a computer-assisted sperm analysis (CASA) system after five different handling steps (fresh sperm, 1st washing, 2nd washing, cooling and frozen-thawed sperm) during a standard cryopreservation protocol for goat semen. The results were analysed using Principal Component Analysis (PCA) and multivariate clustering procedures to establish the relationship between the distribution of the subpopulations found and the functional sperm motility in each step. Except for the 1st and 4th steps, four sperm kinematic subpopulations were observed explaining more than 75% of the variance. Based on velocity and linearity parameters and the subpopulations disclosed, the kinematic response varies among processing steps modifying sperm movement trajectories in a subpopulation-specific and handling step-dependent manner (p < 0.001). The predominant motile subpopulation in freshly ejaculated buck sperm had very fast velocity characteristics and a non-linear trajectory (41.1%). Washing buck sperm twice altered the subpopulation structure as well as cooling which resulted in a dramatic reduction in sperm velocities (p < 0.01). Frozen-thawed spermatozoa showed similar characteristics to cooled sperm except there was a further increase in linearity with a large proportion of sperm attributed to new slow, linear cluster (32.5%). In conclusion, this study confirms the variability and heterogeneity of goat sperm kinematic patterns throughout the cryopreservation process and suggests that the predominant motility pattern (assayed in vitro via CASA) of high quality spermatozoa might be typified by high speed and a non-linear trajectory. The relationships among the number and distribution of sperm subpopulations and the different handling steps were particularlly relevant, specially after the cooling and the post-thawing steps, when effects derived from these critical handling steps were evident and altered drastically the sperm motion patterns. Copyright © 2018 Elsevier Inc. All rights reserved.

Mod5 protein binds to tRNA gene complexes and affects local transcriptional silencing

PubMed Central

Pratt-Hyatt, Matthew; Pai, Dave A.; Haeusler, Rebecca A.; Wozniak, Glenn G.; Good, Paul D.; Miller, Erin L.; McLeod, Ian X.; Yates, John R.; Hopper, Anita K.; Engelke, David R.

2013-01-01

The tRNA gene-mediated (tgm) silencing of RNA polymerase II promoters is dependent on subnuclear clustering of the tRNA genes, but genetic analysis shows that the silencing requires additional mechanisms. We have identified proteins that bind tRNA gene transcription complexes and are required for tgm silencing but not required for gene clustering. One of the proteins, Mod5, is a tRNA modifying enzyme that adds an N6-isopentenyl adenosine modification at position 37 on a small number of tRNAs in the cytoplasm, although a subpopulation of Mod5 is also found in the nucleus. Recent publications have also shown that Mod5 has tumor suppressor characteristics in humans as well as confers drug resistance through prion-like misfolding in yeast. Here, we show that a subpopulation of Mod5 associates with tRNA gene complexes in the nucleolus. This association occurs and is required for tgm silencing regardless of whether the pre-tRNA transcripts are substrates for Mod5 modification. In addition, Mod5 is bound to nuclear pre-tRNA transcripts, although they are not substrates for the A37 modification. Lastly, we show that truncation of the tRNA transcript to remove the normal tRNA structure also alleviates silencing, suggesting that synthesis of intact pre-tRNAs is required for the silencing mechanism. These results are discussed in light of recent results showing that silencing near tRNA genes also requires chromatin modification. PMID:23898186

CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer

PubMed Central

Gu-Trantien, Chunyan; Migliori, Edoardo; de Wind, Alexandre; Brohée, Sylvain; Garaud, Soizic; Noël, Grégory; Dang Chi, Vu Luan; Lodewyckx, Jean-Nicolas; Naveaux, Céline; Duvillier, Hugues; Larsimont, Denis

2017-01-01

T follicular helper cells (TFH cells) are important regulators of antigen-specific B cell responses. The B cell chemoattractant CXCL13 has recently been linked with TFH cell infiltration and improved survival in human cancer. Although human TFH cells can produce CXCL13, their immune functions are currently unknown. This study presents data from human breast cancer, advocating a role for tumor-infiltrating CXCL13-producing (CXCR5–) TFH cells, here named TFHX13 cells, in promoting local memory B cell differentiation. TFHX13 cells potentially trigger tertiary lymphoid structure formation and thereby generate germinal center B cell responses at the tumor site. Follicular DCs are not potent CXCL13 producers in breast tumor tissues. We used the TFH cell markers PD-1 and ICOS to identify distinct effector and regulatory CD4+ T cell subpopulations in breast tumors. TFHX13 cells are an important component of the PD-1hiICOSint effector subpopulation and coexpanded with PD-1intICOShiFOXP3hi Tregs. IL2 deprivation induces CXCL13 expression in vitro with a synergistic effect from TGFβ1, providing insight into TFHX13 cell differentiation in response to Treg accumulation, similar to conventional TFH cell responses. Our data suggest that human TFHX13 cell differentiation may be a key factor in converting Treg-mediated immune suppression to de novo activation of adaptive antitumor humoral responses in the chronic inflammatory breast cancer microenvironment. PMID:28570278

Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses

PubMed Central

Azzam, Diana J; Zhao, Dekuang; Sun, Jun; Minn, Andy J; Ranganathan, Prathibha; Drews-Elger, Katherine; Han, Xiaoqing; Picon-Ruiz, Manuel; Gilbert, Candace A; Wander, Seth A; Capobianco, Anthony J; El-Ashry, Dorraya; Slingerland, Joyce M

2013-01-01

Increasing evidence suggests that stem-like cells mediate cancer therapy resistance and metastasis. Breast tumour-initiating stem cells (T-ISC) are known to be enriched in CD44+CD24neg/low cells. Here, we identify two T-ISC subsets within this population in triple negative breast cancer (TNBC) lines and dissociated primary breast cancer cultures: CD44+CD24low+ subpopulation generates CD44+CD24neg progeny with reduced sphere formation and tumourigenicity. CD44+CD24low+ populations contain subsets of ALDH1+ and ESA+ cells, yield more frequent spheres and/or T-ISC in limiting dilution assays, preferentially express metastatic gene signatures and show greater motility, invasion and, in the MDA-MB-231 model, metastatic potential. CD44+CD24low+ but not CD44+CD24neg express activated Notch1 intracellular domain (N1-ICD) and Notch target genes. We show N1-ICD transactivates SOX2 to increase sphere formation, ALDH1+ and CD44+CD24low+cells. Gamma secretase inhibitors (GSI) reduced sphere formation and xenograft growth from CD44+CD24low+ cells, but CD44+CD24neg were resistant. While GSI hold promise for targeting T-ISC, stem cell heterogeneity as observed herein, could limit GSI efficacy. These data suggest a breast T-ISC hierarchy in which distinct pathways drive developmentally related subpopulations with different anti-cancer drug responsiveness. PMID:23982961

Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth

PubMed Central

Zorro Manrique, Soraya; Duque Correa, Maria Adelaida; Hoelzinger, Dominique B.; Dominguez, Ana Lucia; Mirza, Noweeda; Lin, Hsi-Hsien; Stein-Streilein, Joan; Gordon, Siamon

2011-01-01

Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b+F4/80+CD68+, indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b+F4/80+Foxp3+ macrophages using Foxp3-GFP mice. Analysis of CD11b+F4/80+Foxp3+ macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3− macrophages did not. Suppression of T cell proliferation was mediated through soluble factors. Foxp3− macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3+ macrophages. The cytokine and transcriptional profiles of Foxp3+ macrophages were distinct from those of Foxp3− macrophages, indicating that these cells have different biological functions. Functional in vivo analyses indicated that CD11b+F4/80+Foxp3+ macrophages are important in tumor promotion and the induction of T reg cell conversion. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells in which expression of Foxp3 correlates with suppressive function. PMID:21670203

Retinal Astrocytes and GABAergic Wide-Field Amacrine Cells Express PDGFRα: Connection to Retinal Ganglion Cell Neuroprotection by PDGF-AA.

PubMed

Takahama, Shokichi; Adetunji, Modupe O; Zhao, Tantai; Chen, Shan; Li, Wei; Tomarev, Stanislav I

2017-09-01

Our previous experiments demonstrated that intravitreal injection of platelet-derived growth factor-AA (PDGF-AA) provides retinal ganglion cell (RGC) neuroprotection in a rodent model of glaucoma. Here we used PDGFRα-enhanced green fluorescent protein (EGFP) mice to identify retinal cells that may be essential for RGC protection by PDGF-AA. PDGFRα-EGFP mice expressing nuclear-targeted EGFP under the control of the PDGFRα promoter were used. Localization of PDGFRα in the neural retina was investigated by confocal imaging of EGFP fluorescence and immunofluorescent labeling with a panel of antibodies recognizing different retinal cell types. Primary cultures of mouse RGCs were produced by immunopanning. Neurobiotin injection of amacrine cells in a flat-mounted retina was used for the identification of EGFP-positive amacrine cells in the inner nuclear layer. In the mouse neural retina, PDGFRα was preferentially localized in the ganglion cell and inner nuclear layers. Immunostaining of the retina demonstrated that astrocytes in the ganglion cell layer and a subpopulation of amacrine cells in the inner nuclear layer express PDGFRα, whereas RGCs (in vivo or in vitro) did not. PDGFRα-positive amacrine cells are likely to be Type 45 gamma-aminobutyric acidergic (GABAergic) wide-field amacrine cells. These data indicate that the neuroprotective effect of PDGF-AA in a rodent model of glaucoma could be mediated by astrocytes and/or a subpopulation of amacrine cells. We suggest that after intravitreal injection of PDGF-AA, these cells secrete factors protecting RGCs.

Role of Immunologic Disturbance in Human Oncogenesis: Some Facts and Fancies*

PubMed Central

Kaplan, Henry S.

1971-01-01

A brief review is presented of the evidence linking the development of certain types of neoplasms, and of the malignant lymphomas in particular, to chronic immunosuppression in animals and man and to the naturally occurring human immunologic deficiency states. The discussion then focuses on Hodgkin's disease and considers recent evidence concerning the relation between the clinical stage of the disease and its associated defect in cell-mediated immunity. Finally, the prior occurrence of infectious mononucleosis in some cases of Hodgkin's disease is considered in the context of the hypothesis that the neoplastic cells of Hodgkin's disease may evolve from a chronic immunologic reaction, analogous to that of graft-versus-host, stemming from the induction of antigenic alteration in a subpopulation of lymphocytes by certain types of non-neoplastic viral infections. PMID:4401360

Modeling US Adult Obesity Trends: A System Dynamics Model for Estimating Energy Imbalance Gap

PubMed Central

Rahmandad, Hazhir; Huang, Terry T.-K.; Bures, Regina M.; Glass, Thomas A.

2014-01-01

Objectives. We present a system dynamics model that quantifies the energy imbalance gap responsible for the US adult obesity epidemic among gender and racial subpopulations. Methods. We divided the adult population into gender–race/ethnicity subpopulations and body mass index (BMI) classes. We defined transition rates between classes as a function of metabolic dynamics of individuals within each class. We estimated energy intake in each BMI class within the past 4 decades as a multiplication of the equilibrium energy intake of individuals in that class. Through calibration, we estimated the energy gap multiplier for each gender–race–BMI group by matching simulated BMI distributions for each subpopulation against national data with maximum likelihood estimation. Results. No subpopulation showed a negative or zero energy gap, suggesting that the obesity epidemic continues to worsen, albeit at a slower rate. In the past decade the epidemic has slowed for non-Hispanic Whites, is starting to slow for non-Hispanic Blacks, but continues to accelerate among Mexican Americans. Conclusions. The differential energy balance gap across subpopulations and over time suggests that interventions should be tailored to subpopulations’ needs. PMID:24832405

Increased level of linkage disequilibrium in rural compared with urban communities: a factor to consider in association-study design.

PubMed

Vitart, Veronique; Carothers, Andrew D; Hayward, Caroline; Teague, Peter; Hastie, Nicholas D; Campbell, Harry; Wright, Alan F

2005-05-01

Few studies have investigated genetic differentiation within nonisolate European populations, despite the initiation of large national sample collections such as U.K. Biobank. Here, we used short tandem repeat markers to explore fine-scale genetic structure and to examine the extent of linkage disequilibrium (LD) within national subpopulations. We studied 955 unrelated individuals of local ancestry from nine Scottish rural regions and the urban center of Edinburgh, as well as 96 unrelated individuals from the general U.K. population. Despite little overall differentiation on the basis of allele frequencies, there were clear differences among subpopulations in the extent of pairwise LD, measured between a subset of X-linked markers, that reflected presumed differences in the depths of the underlying genealogies within these subpopulations. Therefore, there are strategic advantages in studying rural subpopulations, in terms of increased power and reduced cost, that are lost by sampling across regions or within urban populations. Similar rural-urban contrasts are likely to exist in many other populations with stable rural subpopulations, which could influence the design of genetic association studies and national biobank data collections.

Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water.

PubMed

Frawley, Rachel P; Smith, Matthew J; White, Kimber L; Elmore, Susan A; Herbert, Ron; Moore, Rebecca; Staska, Lauren M; Behl, Mamta; Hooth, Michelle J; Kissling, Grace E; Germolec, Dori R

2016-09-01

Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0-2000 mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3(+) T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity.

Immunotoxic Effects of Sodium Tungstate Dihydrate on Female B6C3F1/N Mice When Administered in Drinking Water

PubMed Central

Frawley, Rachel P.; Smith, Matthew J.; White, Kimber L; Elmore, Susan; Herbert, Ron; Moore, Rebecca; Staska, Lauren M.; Behl, Mamta; Hooth, Michelle J.; Kissling, Grace E.; Germolec, Dori R.

2018-01-01

Tungsten is a naturally occurring, high tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0–2000 mg STD/L in their drinking water for 28 days, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3+ T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely effect cell-mediated immunity. PMID:27223060

Habitat quality mediates personality through differences in social context.

PubMed

Belgrad, Benjamin A; Griffen, Blaine D

2017-06-01

Assessing the stability of animal personalities has become a major goal of behavioral ecologists. Most personality studies have utilized solitary individuals, but little is known on the extent that individuals retain their personality across ecologically relevant group settings. We conducted a field survey which determined that mud crabs, Panopeus herbstii, remain scattered as isolated individuals on degraded oyster reefs while high quality reefs can sustain high crab densities (>10 m -2 ). We examined the impact of these differences in social context on personality by quantifying the boldness of the same individual crabs when in isolation and in natural cohorts. Crabs were also exposed to either a treatment of predator cues or a control of no cue throughout the experiment to assess the strength of this behavioral reaction norm. Crabs were significantly bolder when in groups than as solitary individuals with predator cue treatments exhibiting severally reduced crab activity levels in comparison to corresponding treatments with no predator cues. Behavioral plasticity depended on the individual and was strongest in the presence of predator cues. While bold crabs largely maintained their personality in isolation and group settings, shy crabs would become substantially bolder when among conspecifics. These results imply that the shifts in crab boldness were a response to changes in perceived predation risk, and provide a mechanism for explaining variation in behavioral plasticity. Such findings suggest that habitat degradation may produce subpopulations with different behavioral patterns because of differing social interactions between individual animals.

Methionine enkephalin (MENK) inhibits tumor growth through regulating CD4+Foxp3+ regulatory T cells (Tregs) in mice.

PubMed

Li, Xuan; Meng, Yiming; Plotnikoff, Nicolas P; Youkilis, Gene; Griffin, Noreen; Wang, Enhua; Lu, Changlong; Shan, Fengping

2015-01-01

Methionine enkephalin (MENK), an endogenous neuropeptide, plays an crucial role in both neuroendocrine and immune systems. CD4+Foxp3+ regulatory T cells (Tregs) are identified as a major subpopulation of T lymphocytes in suppressing immune system to keep balanced immunity. The aim of this research work was to elucidate the mechanisms via which MENK interacts with Tregs in cancer situation. The influence of MENK on transforming growth factor-β (TGF-β) mediated conversion from naïve CD4+CD25- T cells to CD4+CD25+ Tregs was determined and the data from flow cytometry (FCM) analysis indicated that MENK effectively inhibited the expression of Foxp3 during the process of TGF-βinduction. Furthermore, this inhibiting process was accompanied by diminishing phosphorylation and nuclear translocation of Smad2/3, confirmed by western blot (WB) analysis and immunofluorescence (IF) at molecular level. We established sarcoma mice model with S180 to investigate whether MENK could modulate Tregs in tumor circumstance. Our findings showed that MENK delayed the development of tumor in S180 tumor bearing mice and down-regulated level of Tregs. Together, these novel findings reached a conclusion that MENK could inhibit Tregs activity directly and retard tumor development through down-regulating Tregs in mice. This work advances the deepening understanding of the influence of MENK on Tregs in cancer situation, and relation of MENK with immune system, supporting the implication of MENK as a new strategy for cancer immunotherapy.

Pollinator-mediated gene flow fosters genetic variability in a narrow alpine endemic, Abronia alpina (Nyctaginaceae).

PubMed

Jabis, Meredith D; Ayers, Tina J; Allan, Gerard J

2011-10-01

For rare and endemic plants that exist in small, isolated habitats, natural selection is expected to favor self-compatibility, which can result in low genetic diversity due to inbreeding and genetic drift. Using Abronia alpina, a rare alpine endemic of the California Floristic Province, we demonstrate that there are exceptions to these predictions. We present the results of both a pollination experiment and a genetic study using AFLPs (amplified fragment length polymorphisms). Using controlled hand-pollination and pollinator observations, we examined the breeding system, pollination ecology, and mechanism for self-incompatibility in A. alpina. Abronia alpina exhibits an allogamous mating system with probable self-incompatibility resulting from limited growth of pollen tubes originating from self-pollination. Only xenogamous crosses and open-pollinated controls produced seed, and only xenogamous crosses produced pollen tubes that reached the ovary. The molecular study shows that A. alpina has substantial genetic diversity for a rare, endemic species, evidenced by the high percentage of polymorphic loci and average expected heterozygosity. Gene flow among subpopulations, as inferred from AFLP markers, appears to be substantial, although the Kern River is an important physical barrier. Our results indicate that A. alpina is dependent on insects for both seed production and the maintenance of genetic diversity. This finding suggests that pollinators may be crucial to the long-term adaptive potential of rare, endemic plants and that conservation of rare endemics is, in part, dependent on community-level interactions such as plant-pollinator mutualisms.

Conservation Status of Killer Whales, Orcinus orca, in the Strait of Gibraltar.

PubMed

Esteban, R; Verborgh, P; Gauffier, P; Alarcón, D; Salazar-Sierra, J M; Giménez, J; Foote, A D; de Stephanis, R

Killer whales (Orcinus orca) in the Mediterranean Sea are currently restricted to the Strait of Gibraltar and surrounding waters. Thirty-nine individuals were present in 2011, with a well-differentiated social structure, organized into five pods. Killer whale occurrence in the Strait is apparently related to the migration of their main prey, Atlantic bluefin tuna (Thunnus thynnus). In spring, whale distribution was restricted to shallow waters off the western coast of the Strait where all pods were observed actively hunting tuna. In summer, the whales were observed in the shallow central waters of the Strait. A relatively new feeding strategy has been observed among two of the five pods. These two pods interact with an artisanal drop-line fishery. Pods depredating the fishery had access to larger tuna in comparison with pods that were actively hunting. The Strait of Gibraltar killer whales are socially and ecologically different from individuals in the Canary Islands. Molecular genetic research has indicated that there is little or no female-mediated gene migration between these areas. Conservation threats include small population size, prey depletion, vessel traffic, and contaminants. We propose the declaration of the Strait of Gibraltar killer whales as an endangered subpopulation. A conservation plan to protect the Strait of Gibraltar killer whales is urgently needed, and we recommend implementation of a seasonal management area where activities producing underwater noise are restricted, and the promotion of bluefin tuna conservation. © 2016 Elsevier Ltd. All rights reserved.

Granule cell excitability regulates gamma and beta oscillations in a model of the olfactory bulb dendrodendritic microcircuit

PubMed Central

Osinski, Bolesław L.

2016-01-01

Odors evoke gamma (40–100 Hz) and beta (20–30 Hz) oscillations in the local field potential (LFP) of the mammalian olfactory bulb (OB). Gamma (and possibly beta) oscillations arise from interactions in the dendrodendritic microcircuit between excitatory mitral cells (MCs) and inhibitory granule cells (GCs). When cortical descending inputs to the OB are blocked, beta oscillations are extinguished whereas gamma oscillations become larger. Much of this centrifugal input targets inhibitory interneurons in the GC layer and regulates the excitability of GCs, which suggests a causal link between the emergence of beta oscillations and GC excitability. We investigate the effect that GC excitability has on network oscillations in a computational model of the MC-GC dendrodendritic network with Ca2+-dependent graded inhibition. Results from our model suggest that when GC excitability is low, the graded inhibitory current mediated by NMDA channels and voltage-dependent Ca2+ channels (VDCCs) is also low, allowing MC populations to fire in the gamma frequency range. When GC excitability is increased, the activation of NMDA receptors and other VDCCs is also increased, allowing the slow decay time constants of these channels to sustain beta-frequency oscillations. Our model argues that Ca2+ flow through VDCCs alone could sustain beta oscillations and that the switch between gamma and beta oscillations can be triggered by an increase in the excitability state of a subpopulation of GCs. PMID:27121582

Heterogeneity of Focal Adhesions and Focal Contacts in Motile Fibroblasts.

PubMed

Gladkikh, Aleena; Kovaleva, Anastasia; Tvorogova, Anna; Vorobjev, Ivan A

2018-01-01

Cell-extracellular matrix (ECM) adhesion is an important property of virtually all cells in multicellular organisms. Cell-ECM adhesion studies, therefore, are very significant both for biology and medicine. Over the last three decades, biomedical studies resulted in a tremendous advance in our understanding of the molecular basis and functions of cell-ECM adhesion. Based on morphological and molecular criteria, several different types of model cell-ECM adhesion structures including focal adhesions, focal complexes, fibrillar adhesions, podosomes, and three-dimensional matrix adhesions have been described. All the subcellular structures that mediate cell-ECM adhesion are quite heterogeneous, often varying in size, shape, distribution, dynamics, and, to a certain extent, molecular constituents. The morphological "plasticity" of cell-ECM adhesion perhaps reflects the needs of cells to sense, adapt, and respond to a variety of extracellular environments. In addition, cell type (e.g., differentiation status, oncogenic transformation, etc.) often exerts marked influence on the structure of cell-ECM adhesions. Although molecular, genetic, biochemical, and structural studies provide important maps or "snapshots" of cell-ECM adhesions, the area of research that is equally valuable is to study the heterogeneity of FA subpopulations within cells. Recently time-lapse observations on the FA dynamics become feasible, and behavior of individual FA gives additional information on cell-ECM interactions. Here we describe a robust method of labeling of FA using plasmids with fluorescent markers for paxillin and vinculin and quantifying the morphological and dynamical parameters of FA.

The Quality of Mediational Teaching Practiced by Teachers in Special Education: An Observational Study in Norwegian Primary Schools

ERIC Educational Resources Information Center

Nyborg, Geir

2011-01-01

In this case study the quality of mediational teaching was evaluated for interactions between teachers and pupils in special education in regular Norwegian primary schools. Mediational teaching is interpreted as a process by which a teacher mediates a given curriculum using certain categories in interactions with a pupil. The categories are…

Proteomic Analysis of the Mediator Complex Interactome in Saccharomyces cerevisiae

PubMed Central

Uthe, Henriette; Vanselow, Jens T.; Schlosser, Andreas

2017-01-01

Here we present the most comprehensive analysis of the yeast Mediator complex interactome to date. Particularly gentle cell lysis and co-immunopurification conditions allowed us to preserve even transient protein-protein interactions and to comprehensively probe the molecular environment of the Mediator complex in the cell. Metabolic 15N-labeling thereby enabled stringent discrimination between bona fide interaction partners and nonspecifically captured proteins. Our data indicates a functional role for Mediator beyond transcription initiation. We identified a large number of Mediator-interacting proteins and protein complexes, such as RNA polymerase II, general transcription factors, a large number of transcriptional activators, the SAGA complex, chromatin remodeling complexes, histone chaperones, highly acetylated histones, as well as proteins playing a role in co-transcriptional processes, such as splicing, mRNA decapping and mRNA decay. Moreover, our data provides clear evidence, that the Mediator complex interacts not only with RNA polymerase II, but also with RNA polymerases I and III, and indicates a functional role of the Mediator complex in rRNA processing and ribosome biogenesis. PMID:28240253

Effect of 90-day space flight (MDS-ISS) on immunological parameters in mice: lymphocyte distribution and function

NASA Astrophysics Data System (ADS)

Roberts, Arthur; Lhuillier, Andrew; Liu, Yi; Ruggiu, Alessandra; Shi, Yufang

Elucidation of the effects of space flight on the immune system of astronauts and other animal species is important for the survival and success of manned space flight, especially long-term missions. Space flight exposes astronauts to microgravity, galactic cosmic radiation (GCR), and various psycho-social stressors. Blood samples from astronauts returning from space flight have shown changes in the numbers and types of circulating leukocytes. Similarly, normal lym-phocyte homeostasis has been shown to be severely affected in mice using ground-based models of microgravity and GCR exposure, as demonstrated by profound effects on several immuno-logical parameters examined by other investigators and ourselves. In particular, lymphocyte numbers are significantly reduced and subpopulation distribution is altered in the spleen, thy-mus, and peripheral blood following hindlimb unloading (HU) in mice. Lymphocyte depletion was found to be mediated through corticosteroid-induced apoptosis, although the molecular mechanism of apoptosis induction is still under investigation. The proliferative capacity of TCR-stimulated lymphocytes was also inhibited after HU. We have similarly shown that mice exposed to high-energy 56Fe ion radiation have decreased lymphocyte numbers and perturba-tions in proportions of various subpopulations, including CD4+ and CD8+ T cells, and B cells in the spleen, and maturation stages of immature T cells in the thymus. To compare these ground-based results to the effects of actual space-flight, fresh spleen and thymus samples were recently obtained from normal and transgenic mice immediately after 90 d. space-flight in the MDS, and identically-housed ground control mice. Total leukocyte numbers in each organ were enumerated, and subpopulation distribution was examined by flow cytometric analysis of CD3, CD4, CD8, CD19, CD25, DX-5, and CD11b. Splenic T cells were stimulated with anti-CD3 and assessed for proliferation after 2-4 d., and production of several cytokines was examined using Luminex technology and quantitative PCR. These data are currently being collected and analyzed.

Hedonic Benefits of Close and Distant Interaction Partners: The Mediating Roles of Social Approval and Authenticity.

PubMed

Venaglia, Rachel B; Lemay, Edward P

2017-09-01

The current research utilized ecological momentary assessment methodology to examine affective responses to interacting with close versus distant interaction partners during naturally occurring social interactions, and to test predictions regarding the mediating roles of perceived social approval and authenticity. Analysis of 4,602 social interactions reported by 176 participants suggested that, relative to interactions with distant partners, interactions with close partners were characterized by more positive affect. This effect was mediated by perceived social approval and authenticity. These findings suggest that social interactions with close others confer greater hedonic benefits relative to interactions with distant partners due to greater confidence in social approval and feelings of authenticity. Exploratory analyses suggested that interactions with close partners featured warmer and less shy behavior, and that participants who placed more importance on close relationships (as measured by high relational-interdependent self-construal) experienced more approval and authenticity in their interactions, particularly with distant partners.

The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation.

PubMed

Malik, Sohail; Roeder, Robert G

2010-11-01

The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.

Hypoxia tolerance is conserved across genetically distinct sub-populations of an iconic, tropical Australian teleost (Lates calcarifer)

PubMed Central

Collins, Geoffrey M.; Clark, Timothy D.; Rummer, Jodie L.; Carton, Alexander G.

2013-01-01

Tropical coastal systems are particularly prone to periods of environmental hypoxia, which can result from organismal respiration as well as thermal stratification, and may be further exacerbated by anthropogenic disturbances. In this study, we used five genetically distinct sub-populations of Australian barramundi (Lates calcarifer) to examine the extent of intraspecific variability in hypoxia tolerance. Fish were maintained at two temperatures (26 or 36°C), representing the seasonal thermal range for this species across its tropical distribution in Australia. All fish maintained a constant oxygen consumption rate as air saturation of the water decreased from 100% down to a critical oxygen saturation ([O2]crit) of 15.44 ± 3.20 and 21.07 ± 3.92% (means ± SD) at 26 and 36°C, respectively. Mean [O2]crit, used as a performance measure of hypoxia tolerance, did not differ between sub-populations. No differences were found for resting between sub-populations at 26°C, but modest differences were detected between two sub-populations at 36°C (3.36 ± 0.62 and 2.83 ± 0.27 mg O2 kg−1 min−1 for Gladstone and Broome sub-populations, respectively). Resting was lower for sub-populations at 26°C (1.46 ± 0.26 mg O2 kg−1 min−1) than at 36°C (3.10 ± 0.43 mg O2 kg−1 min−1), with a temperature coefficient (Q10) of 2.12 ± 0.30. We conclude that both hypoxia tolerance and resting are conserved across the distribution of barramundi in Australia, which reflects the capacity of this species to cope in environments with large fluctuations in both temperature and dissolved oxygen. PMID:27293613

Winter Habitat Preferences for Florida Manatees and Vulnerability to Cold

PubMed Central

Laist, David W.; Taylor, Cynthia; Reynolds, John E.

2013-01-01

To survive cold winter periods most, if not all, Florida manatees rely on warm-water refuges in the southern two-thirds of the Florida peninsula. Most refuges are either warm-water discharges from power plant and natural springs, or passive thermal basins that temporarily trap relatively warm water for a week or more. Strong fidelity to one or more refuges has created four relatively discrete Florida manatee subpopulations. Using statewide winter counts of manatees from 1999 to 2011, we provide the first attempt to quantify the proportion of animals using the three principal refuge types (power plants, springs, and passive thermal basins) statewide and for each subpopulation. Statewide across all years, 48.5% of all manatees were counted at power plant outfalls, 17.5% at natural springs, and 34.9 % at passive thermal basins or sites with no known warm-water features. Atlantic Coast and Southwest Florida subpopulations comprised 82.2% of all manatees counted (45.6% and 36.6%, respectively) with each subpopulation relying principally on power plants (66.6% and 47.4%, respectively). The upper St. Johns River and Northwest Florida subpopulations comprised 17.8% of all manatees counted with almost all animals relying entirely on springs (99.2% and 88.6% of those subpopulations, respectively). A record high count of 5,076 manatees in January 2010 revealed minimum sizes for the four subpopulations of: 230 manatees in the upper St. Johns River; 2,548 on the Atlantic Coast; 645 in Northwest Florida; and 1,774 in Southwest Florida. Based on a comparison of carcass recovery locations for 713 manatees killed by cold stress between 1999 and 2011 and the distribution of known refuges, it appears that springs offer manatees the best protection against cold stress. Long-term survival of Florida manatees will require improved efforts to enhance and protect manatee access to and use of warm-water springs as power plant outfalls are shut down. PMID:23527063

Multimodal Optimization by Covariance Matrix Self-Adaptation Evolution Strategy with Repelling Subpopulations.

PubMed

Ahrari, Ali; Deb, Kalyanmoy; Preuss, Mike

2017-01-01

During the recent decades, many niching methods have been proposed and empirically verified on some available test problems. They often rely on some particular assumptions associated with the distribution, shape, and size of the basins, which can seldom be made in practical optimization problems. This study utilizes several existing concepts and techniques, such as taboo points, normalized Mahalanobis distance, and the Ursem's hill-valley function in order to develop a new tool for multimodal optimization, which does not make any of these assumptions. In the proposed method, several subpopulations explore the search space in parallel. Offspring of a subpopulation are forced to maintain a sufficient distance to the center of fitter subpopulations and the previously identified basins, which are marked as taboo points. The taboo points repel the subpopulation to prevent convergence to the same basin. A strategy to update the repelling power of the taboo points is proposed to address the challenge of basins of dissimilar size. The local shape of a basin is also approximated by the distribution of the subpopulation members converging to that basin. The proposed niching strategy is incorporated into the covariance matrix self-adaptation evolution strategy (CMSA-ES), a potent global optimization method. The resultant method, called the covariance matrix self-adaptation with repelling subpopulations (RS-CMSA), is assessed and compared to several state-of-the-art niching methods on a standard test suite for multimodal optimization. An organized procedure for parameter setting is followed which assumes a rough estimation of the desired/expected number of minima available. Performance sensitivity to the accuracy of this estimation is also studied by introducing the concept of robust mean peak ratio. Based on the numerical results using the available and the introduced performance measures, RS-CMSA emerges as the most successful method when robustness and efficiency are considered at the same time.

Relationship between mediation analysis and the structured life course approach

PubMed Central

Howe, Laura D; Smith, Andrew D; Macdonald-Wallis, Corrie; Anderson, Emma L; Galobardes, Bruna; Lawlor, Debbie A; Ben-Shlomo, Yoav; Hardy, Rebecca; Cooper, Rachel; Tilling, Kate; Fraser, Abigail

2016-01-01

Abstract Many questions in life course epidemiology involve mediation and/or interaction because of the long latency period between exposures and outcomes. In this paper, we explore how mediation analysis (based on counterfactual theory and implemented using conventional regression approaches) links with a structured approach to selecting life course hypotheses. Using theory and simulated data, we show how the alternative life course hypotheses assessed in the structured life course approach correspond to different combinations of mediation and interaction parameters. For example, an early life critical period model corresponds to a direct effect of the early life exposure, but no indirect effect via the mediator and no interaction between the early life exposure and the mediator. We also compare these methods using an illustrative real-data example using data on parental occupational social class (early life exposure), own adult occupational social class (mediator) and physical capability (outcome). PMID:27681097

Could Killing Bacterial Subpopulations Hit Tuberculosis out of the Park?

PubMed

Baranowski, Catherine; Rubin, Eric J

2016-07-14

One hurdle to treating tuberculosis could be that it is so difficult to kill nonreplicating subpopulations of the causative pathogens. This work describes two new cephalosporin derivatives that specifically target this population of Mycobacterium tuberculosis.

Nonequilibrium Population Dynamics of Phenotype Conversion of Cancer Cells

PubMed Central

Zhou, Joseph Xu; Pisco, Angela Oliveira; Qian, Hong; Huang, Sui

2014-01-01

Tumorigenesis is a dynamic biological process that involves distinct cancer cell subpopulations proliferating at different rates and interconverting between them. In this paper we proposed a mathematical framework of population dynamics that considers both distinctive growth rates and intercellular transitions between cancer cell populations. Our mathematical framework showed that both growth and transition influence the ratio of cancer cell subpopulations but the latter is more significant. We derived the condition that different cancer cell types can maintain distinctive subpopulations and we also explain why there always exists a stable fixed ratio after cell sorting based on putative surface markers. The cell fraction ratio can be shifted by changing either the growth rates of the subpopulations (Darwinism selection) or by environment-instructed transitions (Lamarckism induction). This insight can help us to understand the dynamics of the heterogeneity of cancer cells and lead us to new strategies to overcome cancer drug resistance. PMID:25438251

Discretization and control of an SEIR epidemic model under equilibrium Wiener noise disturbances

NASA Astrophysics Data System (ADS)

Alonso, Santiago; De la Sen, Manuel; Nistal, Raul; Ibeas, Asier

2017-11-01

A discretized SEIR epidemic model, subject to Wiener noise disturbances of the equilibrium points, is studied. The discrete-time model is got from a general discretization technique applied to its continuous-time counterpart so that its behaviour be close to its continuous-time counterpart irrespective of the size of the discretization period. The positivity and stability of a normalized version of such a discrete-time model are emphasized. The paper also proposes the design of a periodic impulsive vaccination which is periodically injected to the susceptible subpopulation in order to eradicate the propagation of the disease or, at least, to reduce its unsuitable infective effects within the potentially susceptible subpopulation. The existence and asymptotic stability of a disease-free periodic solution are proved. In particular, both the exposed and infectious subpopulations converge asymptotically to zero as time tends to infinity while the normalized subpopulations of susceptible and recovered by immunization oscillate.

ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity

PubMed Central

Landreville, Solange; Agapova, Olga A.; Kneass, Zachary T.; Salesse, Christian; Harbour, J. William

2011-01-01

SUMMARY Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1− bulk tumor cells. ABCB1+ cells also exhibited enhanced clonogenicity, anchorage independent growth, tumorigenicity and mitochondrial activity compared to ABCB1− cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1+ cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others, and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma. PMID:21575142

Estimation of treatment effect in a subpopulation: An empirical Bayes approach.

PubMed

Shen, Changyu; Li, Xiaochun; Jeong, Jaesik

2016-01-01

It is well recognized that the benefit of a medical intervention may not be distributed evenly in the target population due to patient heterogeneity, and conclusions based on conventional randomized clinical trials may not apply to every person. Given the increasing cost of randomized trials and difficulties in recruiting patients, there is a strong need to develop analytical approaches to estimate treatment effect in subpopulations. In particular, due to limited sample size for subpopulations and the need for multiple comparisons, standard analysis tends to yield wide confidence intervals of the treatment effect that are often noninformative. We propose an empirical Bayes approach to combine both information embedded in a target subpopulation and information from other subjects to construct confidence intervals of the treatment effect. The method is appealing in its simplicity and tangibility in characterizing the uncertainty about the true treatment effect. Simulation studies and a real data analysis are presented.

Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors

PubMed Central

Kardava, Lela; Moir, Susan; Wang, Wei; Ho, Jason; Buckner, Clarisa M.; Posada, Jacqueline G.; O’Shea, Marie A.; Roby, Gregg; Chen, Jenny; Sohn, Hae Won; Chun, Tae-Wook; Pierce, Susan K.; Fauci, Anthony S.

2011-01-01

Chronic immune activation in HIV-infected individuals leads to accumulation of exhausted tissue-like memory B cells. Exhausted lymphocytes display increased expression of multiple inhibitory receptors, which may contribute to the inefficiency of HIV-specific antibody responses. Here, we show that downregulation of B cell inhibitory receptors in primary human B cells led to increased tissue-like memory B cell proliferation and responsiveness against HIV. In human B cells, siRNA knockdown of 9 known and putative B cell inhibitory receptors led to enhanced B cell receptor–mediated (BCR-mediated) proliferation of tissue-like memory but not other B cell subpopulations. The strongest effects were observed with the putative inhibitory receptors Fc receptor–like–4 (FCRL4) and sialic acid–binding Ig-like lectin 6 (Siglec-6). Inhibitory receptor downregulation also led to increased levels of HIV-specific antibody-secreting cells and B cell–associated chemokines and cytokines. The absence of known ligands for FCRL4 and Siglec-6 suggests these receptors may regulate BCR signaling through their own constitutive or tonic signaling. Furthermore, the extent of FCLR4 knockdown effects on BCR-mediated proliferation varied depending on the costimulatory ligand, suggesting that inhibitory receptors may engage specific pathways in inhibiting B cell proliferation. These findings on HIV-associated B cell exhaustion define potential targets for reversing the deleterious effect of inhibitory receptors on immune responses against persistent viral infections. PMID:21633172

IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity.

PubMed

Kocur, Magdalena; Schneider, Reiner; Pulm, Ann-Kathrin; Bauer, Jens; Kropp, Sonja; Gliem, Michael; Ingwersen, Jens; Goebels, Norbert; Alferink, Judith; Prozorovski, Timour; Aktas, Orhan; Scheu, Stefanie

2015-04-03

Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological disability. Interferon β (IFNβ) represents a standard treatment for relapsing-remitting MS and exogenous administration of IFNβ exhibits protective effects in experimentally induced CNS autoimmunity. Also, genetic deletion of IFNβ in mice leads to an aggravation of disease symptoms in the MS model of experimental autoimmune encephalomyelitis (EAE). However, neither the underlying mechanisms mediating the beneficial effects nor the cellular source of IFNβ have been fully elucidated. In this report, a subpopulation of activated microglia was identified as the major producers of IFNβ in the CNS at the peak of EAE using an IFNβ-fluorescence reporter mouse model. These IFNβ expressing microglia specifically localized to active CNS lesions and were associated with myelin debris in demyelinated cerebellar organotypic slice cultures (OSCs). In response to IFNβ microglia showed an enhanced capacity to phagocytose myelin in vitro and up-regulated the expression of phagocytosis-associated genes. IFNβ treatment was further sufficient to stimulate association of microglia with myelin debris in OSCs. Moreover, IFNβ-producing microglia mediated an enhanced removal of myelin debris when co-transplanted onto demyelinated OSCs as compared to IFNβ non-producing microglia. These data identify activated microglia as the major producers of protective IFNβ at the peak of EAE and as orchestrators of IFNβ-induced clearance of myelin debris.

A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens.

PubMed

Wright, William J; Schlüter, Oliver M; Dong, Yan

2017-04-01

The nucleus accumbens (NAc) gates motivated behaviors through the functional output of principle medium spiny neurons (MSNs), whereas dysfunctional output of NAc MSNs contributes to a variety of psychiatric disorders. Fast-spiking interneurons (FSIs) are sparsely distributed throughout the NAc, forming local feedforward inhibitory circuits. It remains elusive how FSI-based feedforward circuits regulate the output of NAc MSNs. Here, we investigated a distinct subpopulation of NAc FSIs that express the cannabinoid receptor type-1 (CB1). Using a combination of paired electrophysiological recordings and pharmacological approaches, we characterized and compared feedforward inhibition of NAc MSNs from CB1 + FSIs and lateral inhibition from recurrent MSN collaterals. We observed that CB1 + FSIs exerted robust inhibitory control over a large percentage of nearby MSNs in contrast to local MSN collaterals that provided only sparse and weak inhibitory input to their neighboring MSNs. Furthermore, CB1 + FSI-mediated feedforward inhibition was preferentially suppressed by endocannabinoid (eCB) signaling, whereas MSN-mediated lateral inhibition was unaffected. Finally, we demonstrated that CB1 + FSI synapses onto MSNs are capable of undergoing experience-dependent long-term depression in a voltage- and eCB-dependent manner. These findings demonstrated that CB1 + FSIs are a major source of local inhibitory control of MSNs and a critical component of the feedforward inhibitory circuits regulating the output of the NAc.

A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens

PubMed Central

Wright, William J; Schlüter, Oliver M; Dong, Yan

2017-01-01

The nucleus accumbens (NAc) gates motivated behaviors through the functional output of principle medium spiny neurons (MSNs), whereas dysfunctional output of NAc MSNs contributes to a variety of psychiatric disorders. Fast-spiking interneurons (FSIs) are sparsely distributed throughout the NAc, forming local feedforward inhibitory circuits. It remains elusive how FSI-based feedforward circuits regulate the output of NAc MSNs. Here, we investigated a distinct subpopulation of NAc FSIs that express the cannabinoid receptor type-1 (CB1). Using a combination of paired electrophysiological recordings and pharmacological approaches, we characterized and compared feedforward inhibition of NAc MSNs from CB1+ FSIs and lateral inhibition from recurrent MSN collaterals. We observed that CB1+ FSIs exerted robust inhibitory control over a large percentage of nearby MSNs in contrast to local MSN collaterals that provided only sparse and weak inhibitory input to their neighboring MSNs. Furthermore, CB1+ FSI-mediated feedforward inhibition was preferentially suppressed by endocannabinoid (eCB) signaling, whereas MSN-mediated lateral inhibition was unaffected. Finally, we demonstrated that CB1+ FSI synapses onto MSNs are capable of undergoing experience-dependent long-term depression in a voltage- and eCB-dependent manner. These findings demonstrated that CB1+ FSIs are a major source of local inhibitory control of MSNs and a critical component of the feedforward inhibitory circuits regulating the output of the NAc. PMID:27929113

Pollinator-mediated interactions in experimental arrays vary with neighbor identity.

PubMed

Ha, Melissa K; Ivey, Christopher T

2017-02-01

Local ecological conditions influence the impact of species interactions on evolution and community structure. We investigated whether pollinator-mediated interactions between coflowering plants vary with plant density, coflowering neighbor identity, and flowering season. We conducted a field experiment in which flowering time and floral neighborhood were manipulated in a factorial design. Early- and late-flowering Clarkia unguiculata plants were placed into arrays with C. biloba neighbors, noncongeneric neighbors, additional conspecific plants, or no additional plants as a density control. We compared whole-plant pollen limitation of seed set, pollinator behavior, and pollen deposition among treatments. Interactions mediated by shared pollinators depended on the identity of the neighbor and possibly changed through time, although flowering-season comparisons were compromised by low early-season plant survival. Interactions with conspecific neighbors were likely competitive late in the season. Interactions with C. biloba appeared to involve facilitation or neutral interactions. Interactions with noncongeners were more consistently competitive. The community composition of pollinators varied among treatment combinations. Pollinator-mediated interactions involved competition and likely facilitation, depending on coflowering neighbor. Experimental manipulation helped to reveal context-dependent variation in indirect biotic interactions. © 2017 Botanical Society of America.

Anticipated Ongoing Interaction versus Channel Effects of Relational Communication in Computer-Mediated Interaction.

ERIC Educational Resources Information Center

Walther, Joseph B.

1994-01-01

Assesses the related effects of anticipated future interaction and different communication media (computer-mediated versus face-to-face communication) on the communication of relational intimacy and composure. Shows that the assignment of long-term versus short-term partnerships has a larger impact on anticipated future interaction reported by…

ESL Students' Interaction in Second Life: Task-Based Synchronous Computer-Mediated Communication

ERIC Educational Resources Information Center

Jee, Min Jung

2010-01-01

The purpose of the present study was to explore ESL students' interactions in task-based synchronous computer-mediated communication (SCMC) in Second Life, a virtual environment by which users can interact through representational figures. I investigated Low-Intermediate and High-Intermediate ESL students' interaction patterns before, during, and…

Cultural Psychology of Differences and EMS; a New Theoretical Framework for Understanding and Reconstructing Culture.

PubMed

Yamamoto, Toshiya

2017-09-01

In this paper I introduce the outlines of our new type of theoretical framework named 'Cultural psychology of Differences' for understanding cultural others and dialogically reconstructing interactions among cultural others. In order to understand cultural others, it is necessary for us to reconstruct a new concept which enables us to analyze dynamic generation processes of culture. We propose the concept of Expanded Mediational Structure, EMS, as an elementary unit for understanding human social interactions. EMS is composed of subjects who interacts each other using objects of some kind as mediators, and a normative mediator, NM, which mediates their interactions. It is necessary to generate, share and adjust a NM to keep social interactions stable, and culture will appear when interaction malfunction is attributed to a gaps of NMs. The concept of EMS helps us to understand how culture is functionally substantialized in the plane of collective (or communal) intersubjectivity and how cultural conflicts develop and intensify. Focusing on the generation process of culture through interactions provides us with another option to understand cultural others through dialogical interactions with them.

CAREGIVER-CHILD INTERACTION, CAREGIVER TRANSITIONS, AND GROUP SIZE AS MEDIATORS BETWEEN INTERVENTION CONDITION AND ATTACHMENT AND PHYSICAL GROWTH OUTCOMES IN INSTITUTIONALIZED CHILDREN.

PubMed

Warner, Hilary A; McCall, Robert B; Groark, Christina J; Kim, Kevin H; Muhamedrahimov, Rifkat J; Palmov, Oleg I; Nikiforova, Natalia V

2017-09-01

This report describes a secondary analysis of data from a comprehensive intervention project which included training and structural changes in three Baby Homes in St. Petersburg, Russian Federation. Multiple mediator models were tested according to the R.M. Baron and D.A. Kenny () causal-steps approach to examine whether caregiver-child interaction quality, number of caregiver transitions, and group size mediated the effects of the intervention on children's attachment behaviors and physical growth. The study utilized a subsample of 163 children from the original Russian Baby Home project, who were between 11 and 19 months at the time of assessment. Results from comparisons of the training and structural changes versus no intervention conditions are presented. Caregiver-child interaction quality and number of caregiver transitions fully mediated the association between intervention condition and attachment behavior. No other mediation was found. Results suggest that the quality of interaction between caregivers and children in institutional care is of primary importance to children's development, but relationship context may play a less direct mediational role, supporting caregiver-child interactions. © 2017 Michigan Association for Infant Mental Health.

Dark matter self-interactions from a general spin-0 mediator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kahlhoefer, Felix; Schmidt-Hoberg, Kai; Wild, Sebastian, E-mail: felix.kahlhoefer@desy.de, E-mail: kai.schmidt-hoberg@desy.de, E-mail: sebastian.wild@desy.de

2017-08-01

Dark matter particles interacting via the exchange of very light spin-0 mediators can have large self-interaction rates and obtain their relic abundance from thermal freeze-out. At the same time, these models face strong bounds from direct and indirect probes of dark matter as well as a number of constraints on the properties of the mediator. We investigate whether these constraints can be consistent with having observable effects from dark matter self-interactions in astrophysical systems. For the case of a mediator with purely scalar couplings we point out the highly relevant impact of low-threshold direct detection experiments like CRESST-II, which essentiallymore » rule out the simplest realization of this model. These constraints can be significantly relaxed if the mediator has CP-violating couplings, but then the model faces strong constraints from CMB measurements, which can only be avoided in special regions of parameter space.« less

Sperm subpopulations in avian species: a comparative study between the rooster (Gallus domesticus) and Guinea fowl (Numida meleagris).

PubMed

García-Herreros, Manuel

2016-01-01

The main aims of this research were to study possible differences in objective morphometric sperm characteristics, establish normative sperm morphometry standards, and evaluate the presumed different subpopulation distribution of avian spermatozoa from the rooster (Gallus domesticus ) and Guinea fowl (Numida meleagris ) as model avian species. Seventy-two ejaculates (36 per species studied) were obtained manually, following a training period involving gently combined dorso-abdominal and lumbo-sacral massage of the birds. Ejaculates were processed for volume, sperm concentration, viability, motility, and morphology. Moreover, samples were submitted for sperm morphometric assessment using objective Computer-Assisted Semen Analysis for Morphometry (CASA-Morph) methods, with sperm morphometric descriptors evaluated by Principal Component Analysis (PCA) and multivariate clustering analyses. There were several differences observed between the avian species in values obtained for ejaculate volume and sperm concentration (P < 0.001). Irrespective of species, PCA revealed two Principal Components (PCs) explaining more than 80% of the variance. In addition, the number of subpopulations differed with species (three and five subpopulations for rooster and Guinea fowl, respectively). Moreover, the distribution of the sperm subpopulations was found to be structurally different between species. In conclusion, our findings from using CASA-Morph methods indicate pronounced sperm morphometric variation between these two avian species. Because of the strong differences observed in morphometric parameter values and their subpopulation distribution, these results suggest that application of objective analytical methods such as CASA-Morph could substantially improve the reliability of comparative studies and help establish valid normative sperm morphological values for avian species.

Habitat degradation affects the summer activity of polar bears.

PubMed

Ware, Jasmine V; Rode, Karyn D; Bromaghin, Jeffrey F; Douglas, David C; Wilson, Ryan R; Regehr, Eric V; Amstrup, Steven C; Durner, George M; Pagano, Anthony M; Olson, Jay; Robbins, Charles T; Jansen, Heiko T

2017-05-01

Understanding behavioral responses of species to environmental change is critical to forecasting population-level effects. Although climate change is significantly impacting species' distributions, few studies have examined associated changes in behavior. Polar bear (Ursus maritimus) subpopulations have varied in their near-term responses to sea ice decline. We examined behavioral responses of two adjacent subpopulations to changes in habitat availability during the annual sea ice minimum using activity data. Location and activity sensor data collected from 1989 to 2014 for 202 adult female polar bears in the Southern Beaufort Sea (SB) and Chukchi Sea (CS) subpopulations were used to compare activity in three habitat types varying in prey availability: (1) land; (2) ice over shallow, biologically productive waters; and (3) ice over deeper, less productive waters. Bears varied activity across and within habitats with the highest activity at 50-75% sea ice concentration over shallow waters. On land, SB bears exhibited variable but relatively high activity associated with the use of subsistence-harvested bowhead whale carcasses, whereas CS bears exhibited low activity consistent with minimal feeding. Both subpopulations had fewer observations in their preferred shallow-water sea ice habitats in recent years, corresponding with declines in availability of this substrate. The substantially higher use of marginal habitats by SB bears is an additional mechanism potentially explaining why this subpopulation has experienced negative effects of sea ice loss compared to the still-productive CS subpopulation. Variability in activity among, and within, habitats suggests that bears alter their behavior in response to habitat conditions, presumably in an attempt to balance prey availability with energy costs.

Habitat degradation affects the summer activity of polar bears

USGS Publications Warehouse

Ware, Jasmine V.; Rode, Karyn D.; Bromaghin, Jeffrey F.; Douglas, David C.; Wilson, Ryan R.; Regehr, Eric V.; Amstrup, Steven C.; Durner, George M.; Pagano, Anthony M.; Olson, Jay; Robbins, Charles T.; Jansen, Heiko T

2017-01-01

Understanding behavioral responses of species to environmental change is critical to forecasting population-level effects. Although climate change is significantly impacting species’ distributions, few studies have examined associated changes in behavior. Polar bear (Ursus maritimus) subpopulations have varied in their near-term responses to sea ice decline. We examined behavioral responses of two adjacent subpopulations to changes in habitat availability during the annual sea ice minimum using activity data. Location and activity sensor data collected from 1989 to 2014 for 202 adult female polar bears in the Southern Beaufort Sea (SB) and Chukchi Sea (CS) subpopulations were used to compare activity in three habitat types varying in prey availability: (1) land; (2) ice over shallow, biologically productive waters; and (3) ice over deeper, less productive waters. Bears varied activity across and within habitats with the highest activity at 50–75% sea ice concentration over shallow waters. On land, SB bears exhibited variable but relatively high activity associated with the use of subsistence-harvested bowhead whale carcasses, whereas CS bears exhibited low activity consistent with minimal feeding. Both subpopulations had fewer observations in their preferred shallow-water sea ice habitats in recent years, corresponding with declines in availability of this substrate. The substantially higher use of marginal habitats by SB bears is an additional mechanism potentially explaining why this subpopulation has experienced negative effects of sea ice loss compared to the still-productive CS subpopulation. Variability in activity among, and within, habitats suggests that bears alter their behavior in response to habitat conditions, presumably in an attempt to balance prey availability with energy costs.

Sperm subpopulations in avian species: a comparative study between the rooster (Gallus domesticus) and Guinea fowl (Numida meleagris)

PubMed Central

García-Herreros, Manuel

2016-01-01

The main aims of this research were to study possible differences in objective morphometric sperm characteristics, establish normative sperm morphometry standards, and evaluate the presumed different subpopulation distribution of avian spermatozoa from the rooster (Gallus domesticus) and Guinea fowl (Numida meleagris) as model avian species. Seventy-two ejaculates (36 per species studied) were obtained manually, following a training period involving gently combined dorso-abdominal and lumbo-sacral massage of the birds. Ejaculates were processed for volume, sperm concentration, viability, motility, and morphology. Moreover, samples were submitted for sperm morphometric assessment using objective Computer-Assisted Semen Analysis for Morphometry (CASA-Morph) methods, with sperm morphometric descriptors evaluated by Principal Component Analysis (PCA) and multivariate clustering analyses. There were several differences observed between the avian species in values obtained for ejaculate volume and sperm concentration (P < 0.001). Irrespective of species, PCA revealed two Principal Components (PCs) explaining more than 80% of the variance. In addition, the number of subpopulations differed with species (three and five subpopulations for rooster and Guinea fowl, respectively). Moreover, the distribution of the sperm subpopulations was found to be structurally different between species. In conclusion, our findings from using CASA-Morph methods indicate pronounced sperm morphometric variation between these two avian species. Because of the strong differences observed in morphometric parameter values and their subpopulation distribution, these results suggest that application of objective analytical methods such as CASA-Morph could substantially improve the reliability of comparative studies and help establish valid normative sperm morphological values for avian species. PMID:27751988

Density-mediated, context-dependent consumer-resource interactions between ants and extrafloral nectar plants.

PubMed

Chamberlain, Scott A; Holland, J Nathaniel

2008-05-01

Interspecific interactions are often mediated by the interplay between resource supply and consumer density. The supply of a resource and a consumer's density response to it may in turn yield context-dependent use of other resources. Such consumer-resource interactions occur not only for predator-prey and competitive interactions, but for mutualistic ones as well. For example, consumer-resource interactions between ants and extrafloral nectar (EFN) plants are often mutualistic, as EFN resources attract and reward ants which protect plants from herbivory. Yet, ants also commonly exploit floral resources, leading to antagonistic consumer-resource interactions by disrupting pollination and plant reproduction. EFN resources associated with mutualistic ant-plant interactions may also mediate antagonistic ant-flower interactions through the aggregative density response of ants on plants, which could either exacerbate ant-flower interactions or alternatively satiate and distract ants from floral resources. In this study, we examined how EFN resources mediate the density response of ants on senita cacti in the Sonoran Desert and their context-dependent use of floral resources. Removal of EFN resources reduced the aggregative density of ants on plants, both on hourly and daily time scales. Yet, the increased aggregative ant density on plants with EFN resources decreased rather than increased ant use of floral resources, including contacts with and time spent in flowers. Behavioral assays showed no confounding effect of floral deterrents on ant-flower interactions. Thus, ant use of floral resources depends on the supply of EFN resources, which mediates the potential for both mutualistic and antagonistic interactions by increasing the aggregative density of ants protecting plants, while concurrently distracting ants from floral resources. Nevertheless, only certain years and populations of study showed an increase in plant reproduction through herbivore protection or ant distraction from floral resources. Despite pronounced effects of EFN resources mediating the aggregative density of ants on plants and their context-dependent use of floral resources, consumer-resource interactions remained largely commensalistic.

Macrophage Sub-Populations and the Lipoxin A4 Receptor Implicate Active Inflammation during Equine Tendon Repair

PubMed Central

Dakin, Stephanie Georgina; Werling, Dirk; Hibbert, Andrew; Abayasekara, Dilkush Robert Ephrem; Young, Natalie Jayne; Smith, Roger Kenneth Whealands; Dudhia, Jayesh

2012-01-01

Macrophages (Mϕ) orchestrate inflammatory and reparatory processes in injured connective tissues but their role during different phases of tendon healing is not known. We investigated the contribution of different Mϕ subsets in an equine model of naturally occurring tendon injury. Post mortem tissues were harvested from normal (uninjured), sub-acute (3–6 weeks post injury) and chronically injured (>3 months post injury) superficial digital flexor tendons. To determine if inflammation was present in injured tendons, Mϕ sub-populations were quantified based on surface antigen expression of CD172a (pan Mϕ), CD14highCD206low (pro-inflammatory M1Mϕ), and CD206high (anti-inflammatory M2Mϕ) to assess potential polarised phenotypes. In addition, the Lipoxin A4 receptor (FPR2/ALX) was used as marker for resolving inflammation. Normal tendons were negative for both Mϕ and FPR2/ALX. In contrast, M1Mϕ predominated in sub-acute injury, whereas a potential phenotype-switch to M2Mϕ polarity was seen in chronic injury. Furthermore, FPR2/ALX expression by tenocytes was significantly upregulated in sub-acute but not chronic injury. Expression of the FPR2/ALX ligand Annexin A1 was also significantly increased in sub-acute and chronic injuries in contrast to low level expression in normal tendons. The combination of reduced FPR2/ALX expression and persistence of the M2Mϕ phenotype in chronic injury suggests a potential mechanism for incomplete resolution of inflammation after tendon injury. To investigate the effect of pro-inflammatory mediators on lipoxin A4 (LXA4) production and FPR2/ALX expression in vitro, normal tendon explants were stimulated with interleukin-1 beta and prostaglandin E2. Stimulation with either mediator induced LXA4 release and maximal upregulation of FPR2/ALX expression after 72 hours. Taken together, our data suggests that although tenocytes are capable of mounting a protective mechanism to counteract inflammatory stimuli, this appears to be of insufficient duration and magnitude in natural tendon injury, which may potentiate chronic inflammation and fibrotic repair, as indicated by the presence of M2Mϕ. PMID:22384219

Macrophage sub-populations and the lipoxin A4 receptor implicate active inflammation during equine tendon repair.

PubMed

Dakin, Stephanie Georgina; Werling, Dirk; Hibbert, Andrew; Abayasekara, Dilkush Robert Ephrem; Young, Natalie Jayne; Smith, Roger Kenneth Whealands; Dudhia, Jayesh

2012-01-01

Macrophages (Mφ) orchestrate inflammatory and reparatory processes in injured connective tissues but their role during different phases of tendon healing is not known. We investigated the contribution of different Mφ subsets in an equine model of naturally occurring tendon injury. Post mortem tissues were harvested from normal (uninjured), sub-acute (3-6 weeks post injury) and chronically injured (>3 months post injury) superficial digital flexor tendons. To determine if inflammation was present in injured tendons, Mφ sub-populations were quantified based on surface antigen expression of CD172a (pan Mφ), CD14(high)CD206(low) (pro-inflammatory M1Mφ), and CD206(high) (anti-inflammatory M2Mφ) to assess potential polarised phenotypes. In addition, the Lipoxin A(4) receptor (FPR2/ALX) was used as marker for resolving inflammation. Normal tendons were negative for both Mφ and FPR2/ALX. In contrast, M1Mφ predominated in sub-acute injury, whereas a potential phenotype-switch to M2Mφ polarity was seen in chronic injury. Furthermore, FPR2/ALX expression by tenocytes was significantly upregulated in sub-acute but not chronic injury. Expression of the FPR2/ALX ligand Annexin A1 was also significantly increased in sub-acute and chronic injuries in contrast to low level expression in normal tendons. The combination of reduced FPR2/ALX expression and persistence of the M2Mφ phenotype in chronic injury suggests a potential mechanism for incomplete resolution of inflammation after tendon injury. To investigate the effect of pro-inflammatory mediators on lipoxin A(4) (LXA(4)) production and FPR2/ALX expression in vitro, normal tendon explants were stimulated with interleukin-1 beta and prostaglandin E(2). Stimulation with either mediator induced LXA(4) release and maximal upregulation of FPR2/ALX expression after 72 hours. Taken together, our data suggests that although tenocytes are capable of mounting a protective mechanism to counteract inflammatory stimuli, this appears to be of insufficient duration and magnitude in natural tendon injury, which may potentiate chronic inflammation and fibrotic repair, as indicated by the presence of M2Mφ.

PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma

PubMed Central

Beldi-Ferchiou, Asma; Lambert, Marion; Dogniaux, Stéphanie; Vély, Frédéric; Vivier, Eric; Olive, Daniel; Dupuy, Stéphanie; Levasseur, Frank; Zucman, David; Lebbé, Céleste; Sène, Damien; Hivroz, Claire; Caillat-Zucman, Sophie

2016-01-01

Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors. PD-1pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro, PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance. PMID:27662664

Statistical models for detecting differential chromatin interactions mediated by a protein.

PubMed

Niu, Liang; Li, Guoliang; Lin, Shili

2014-01-01

Chromatin interactions mediated by a protein of interest are of great scientific interest. Recent studies show that protein-mediated chromatin interactions can have different intensities in different types of cells or in different developmental stages of a cell. Such differences can be associated with a disease or with the development of a cell. Thus, it is of great importance to detect protein-mediated chromatin interactions with different intensities in different cells. A recent molecular technique, Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET), which uses formaldehyde cross-linking and paired-end sequencing, is able to detect genome-wide chromatin interactions mediated by a protein of interest. Here we proposed two models (One-Step Model and Two-Step Model) for two sample ChIA-PET count data (one biological replicate in each sample) to identify differential chromatin interactions mediated by a protein of interest. Both models incorporate the data dependency and the extent to which a fragment pair is related to a pair of DNA loci of interest to make accurate identifications. The One-Step Model makes use of the data more efficiently but is more computationally intensive. An extensive simulation study showed that the models can detect those differentially interacted chromatins and there is a good agreement between each classification result and the truth. Application of the method to a two-sample ChIA-PET data set illustrates its utility. The two models are implemented as an R package MDM (available at http://www.stat.osu.edu/~statgen/SOFTWARE/MDM).

Statistical Models for Detecting Differential Chromatin Interactions Mediated by a Protein

PubMed Central

Niu, Liang; Li, Guoliang; Lin, Shili

2014-01-01

Chromatin interactions mediated by a protein of interest are of great scientific interest. Recent studies show that protein-mediated chromatin interactions can have different intensities in different types of cells or in different developmental stages of a cell. Such differences can be associated with a disease or with the development of a cell. Thus, it is of great importance to detect protein-mediated chromatin interactions with different intensities in different cells. A recent molecular technique, Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET), which uses formaldehyde cross-linking and paired-end sequencing, is able to detect genome-wide chromatin interactions mediated by a protein of interest. Here we proposed two models (One-Step Model and Two-Step Model) for two sample ChIA-PET count data (one biological replicate in each sample) to identify differential chromatin interactions mediated by a protein of interest. Both models incorporate the data dependency and the extent to which a fragment pair is related to a pair of DNA loci of interest to make accurate identifications. The One-Step Model makes use of the data more efficiently but is more computationally intensive. An extensive simulation study showed that the models can detect those differentially interacted chromatins and there is a good agreement between each classification result and the truth. Application of the method to a two-sample ChIA-PET data set illustrates its utility. The two models are implemented as an R package MDM (available at http://www.stat.osu.edu/~statgen/SOFTWARE/MDM). PMID:24835279

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions.

PubMed

Purushothaman, Anurag; Bandari, Shyam Kumar; Liu, Jian; Mobley, James A; Brown, Elizabeth E; Sanderson, Ralph D

2016-01-22

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions*

PubMed Central

Purushothaman, Anurag; Bandari, Shyam Kumar; Liu, Jian; Mobley, James A.; Brown, Elizabeth E.; Sanderson, Ralph D.

2016-01-01

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression. PMID:26601950

Negotiating technology-mediated interaction in health care

PubMed Central

Håland, Erna; Melby, Line

2015-01-01

The health-care sector is increasingly faced with different forms of technology that are introduced to mediate interaction, thus fully or partially replacing face-to-face meetings. In this article we address health personnel's experiences with three such technologies, namely: electronic messages, video conferences and net-based discussion forums. Drawing on Goffman's perspectives on interaction and frame, we argue that when technologies are introduced to mediate interaction, new frames for understanding and making sense of situations are created. These new frames imply new ways of organising and making sense of experience, and require work by the participants in the interaction. In this article, based on interviews from two Norwegian research projects, we investigate health personnel's work to make sense of technology-mediated interaction in health care. We discuss this work represented in four categories: how to perform in a competent manner, how to negotiate immediacy, how to enable social cues and how to establish and maintain commitment. Concluding, we argue that the introduction of mediating technologies redefines what is considered up-to-date, ‘good' health-care work and challenges health personnel to change (some of) their work practices and moves, as a result, far beyond simple interventions aimed at making work more efficient. PMID:25685073

Diel Vertical Migration Thresholds of Karenia brevis (Dinophyceae).

EPA Science Inventory

Light and nutrient availability change throughout dinoflagellate diel vertical migration (DVM) and/or with subpopulation location in the water column along the west Florida shelf. Typically, the vertical depth of the shelf is greater than the distance a subpopulation can vertical...

Phase II Trials for Heterogeneous Patient Populations with a Time-to-Event Endpoint.

PubMed

Jung, Sin-Ho

2017-07-01

In this paper, we consider a single-arm phase II trial with a time-to-event end-point. We assume that the study population has multiple subpopulations with different prognosis, but the study treatment is expected to be similarly efficacious across the subpopulations. We review a stratified one-sample log-rank test and present its sample size calculation method under some practical design settings. Our sample size method requires specification of the prevalence of subpopulations. We observe that the power of the resulting sample size is not very sensitive to misspecification of the prevalence.

Point estimation following two-stage adaptive threshold enrichment clinical trials.

PubMed

Kimani, Peter K; Todd, Susan; Renfro, Lindsay A; Stallard, Nigel

2018-05-31

Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial. © 2018 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Comparison of sperm motility subpopulation structure among wild anadromous and farmed male Atlantic salmon (Salmo salar) parr using a CASA system.

PubMed

Caldeira, Carina; García-Molina, Almudena; Valverde, Anthony; Bompart, Daznia; Hassane, Megan; Martin, Patrick; Soler, Carles

2018-04-13

Atlantic salmon (Salmo salar) is an endangered freshwater species that needs help to recover its wild stocks. However, the priority in aquaculture is to obtain successful fertilisation and genetic variability to secure the revival of the species. The aims of the present work were to study sperm subpopulation structure and motility patterns in wild anadromous males and farmed male Atlantic salmon parr. Salmon sperm samples were collected from wild anadromous salmon (WS) and two generations of farmed parr males. Sperm samples were collected from sexually mature males and sperm motility was analysed at different times after activation (5 and 35s). Differences among the three groups were analysed using statistical techniques based on Cluster analysis the Bayesian method. Atlantic salmon were found to have three sperm subpopulations, and the spermatozoa in ejaculates of mature farmed parr males had a higher velocity and larger size than those of WS males. This could be an adaptation to high sperm competition because salmonid species are naturally adapted to this process. Motility analysis enables us to identify sperm subpopulations, and it may be useful to correlate these sperm subpopulations with fertilisation ability to test whether faster-swimming spermatozoa have a higher probability of success.

Chimeralike states in a network of oscillators under attractive and repulsive global coupling.

PubMed

Mishra, Arindam; Hens, Chittaranjan; Bose, Mridul; Roy, Prodyot K; Dana, Syamal K

2015-12-01

We report chimeralike states in an ensemble of oscillators using a type of global coupling consisting of two components: attractive and repulsive mean-field feedback. We identify the existence of two types of chimeralike states in a bistable Liénard system; in one type, both the coherent and the incoherent populations are in chaotic states (which we refer to as chaos-chaos chimeralike states) and, in another type, the incoherent population is in periodic state while the coherent population has irregular small oscillation. We find a metastable state in a parameter regime of the Liénard system where the coherent and noncoherent states migrate in time from one to another subpopulation. The relative size of the incoherent subpopulation, in the chimeralike states, remains almost stable with increasing size of the network. The generality of the coupling configuration in the origin of the chimeralike states is tested, using a second example of bistable system, the van der Pol-Duffing oscillator where the chimeralike states emerge as weakly chaotic in the coherent subpopulation and chaotic in the incoherent subpopulation. Furthermore, we apply the coupling, in a simplified form, to form a network of the chaotic Rössler system where both the noncoherent and the coherent subpopulations show chaotic dynamics.

Coexistence of the social types: genetic population structure in the ant Formica exsecta.

PubMed

Seppä, Perttu; Gyllenstrand, Niclas; Corander, Jukka; Pamilo, Pekka

2004-11-01

The ant Formica exsecta has two types of colonies that exist in sympatry but usually as separate subpopulations: colonies with simple social organization and single queens (M type) or colonial networks with multiple queens (P type). We used both nuclear (DNA microsatellites) and mitochondrial markers to study the transition between the social types, and the contribution of males and females in gene flow within and between the types. Our results showed that the social types had different spatial genetic structures. The M subpopulations formed a fairly uniform population, whereas the P subpopulations were, on average, more differentiated from each other than from the nearby M subpopulations and could have been locally established from the M-type colonies, followed by philopatric behavior and restricted emigration of females. Thus, the relationship between the two social types resembles that of source (M type) and sink (P type) populations. The comparison of mitochondrial (phiST) and nuclear (FST) differentiation indicates that the dispersal rate of males is four to five times larger than that of females both among the P-type subpopulations and between the social types. Our results suggest that evolution toward complex social organization can have an important effect on genetic population structure through changes in dispersal behavior associated with different sociogenetic organizations.

Organizational justice, psychological distress, and work engagement in Japanese workers.

PubMed

Inoue, Akiomi; Kawakami, Norito; Ishizaki, Masao; Shimazu, Akihito; Tsuchiya, Masao; Tabata, Masaji; Akiyama, Miki; Kitazume, Akiko; Kuroda, Mitsuyo

2010-01-01

To investigate the cross-sectional association between organizational justice (i.e., procedural justice and interactional justice) and psychological distress or work engagement, as well as the mediating roles of other job stressors (i.e., job demands and job control, or their combination, effort-reward imbalance [ERI], and worksite support). A total of 243 workers (185 males and 58 females) from a manufacturing factory in Japan were surveyed using a self-administered questionnaire including the Organizational Justice Questionnaire, Job Content Questionnaire, Effort-Reward Imbalance Questionnaire, K6 scale, Utrecht Work Engagement Scale, and other covariates. Multiple mediation analyses with the bootstrap technique were conducted. In the bivariate analysis, procedural justice and interactional justice were significantly and negatively associated with psychological distress; they were significantly and positively associated with work engagement. In the mediation analysis, reward at work (or ERI) significantly mediated between procedural justice or interactional justice and psychological distress; worksite support significantly mediated between procedural justice or interactional justice and work engagement. The effects of organizational justice on psychological distress seem to be mediated by reward at work (or ERI) while those regarding work engagement may be mediated by worksite support to a large extent, at least in Japanese workers.

Therapeutic potential of Mediator complex subunits in metabolic diseases.

PubMed

Ranjan, Amol; Ansari, Suraiya A

2018-01-01

The multisubunit Mediator is an evolutionary conserved transcriptional coregulatory complex in eukaryotes. It is needed for the transcriptional regulation of gene expression in general as well as in a gene specific manner. Mediator complex subunits interact with different transcription factors as well as components of RNA Pol II transcription initiation complex and in doing so act as a bridge between gene specific transcription factors and general Pol II transcription machinery. Specific interaction of various Mediator subunits with nuclear receptors (NRs) and other transcription factors involved in metabolism has been reported in different studies. Evidences indicate that ligand-activated NRs recruit Mediator complex for RNA Pol II-dependent gene transcription. These NRs have been explored as therapeutic targets in different metabolic diseases; however, they show side-effects as targets due to their overlapping involvement in different signaling pathways. Here we discuss the interaction of various Mediator subunits with transcription factors involved in metabolism and whether specific interaction of these transcription factors with Mediator subunits could be potentially utilized as therapeutic strategy in a variety of metabolic diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Individual versus Interactive Task-Based Performance through Voice-Based Computer-Mediated Communication

ERIC Educational Resources Information Center

Granena, Gisela

2016-01-01

Interaction is a necessary condition for second language (L2) learning (Long, 1980, 1996). Research in computer-mediated communication has shown that interaction opportunities make learners pay attention to form in a variety of ways that promote L2 learning. This research has mostly investigated text-based rather than voice-based interaction. The…

Calcium accelerates SNARE-mediated lipid mixing through modulating α-synuclein membrane interaction.

PubMed

Zhang, Zeting; Jiang, Xin; Xu, Danrui; Zheng, Wenwen; Liu, Maili; Li, Conggang

2018-04-04

α-Synuclein is involved in Parkinson's disease, and its interaction with cell membrane is vital to its pathological and physiological functions. We have shown that Ca 2+ can regulate α-synuclein membrane interaction, but the physiological role of Ca 2+ in modulating α-synuclein membrane interaction is still unexplored. Based on the previous findings that α-synuclein inhibits membrane fusion and its inhibitory effect is highly related to its membrane binding, here we employed solution state Nuclear Magnetic Resonance (NMR) spectroscopy and the ensemble fluorescence fusion assay to show that Ca 2+ can modulate the inhibitory effect of α-synuclein on SNARE-mediated membrane fusion through disrupting α-synuclein membrane interaction, resulting in acceleration of SNARE-mediated membrane fusion. These results suggest a modulatory effect of Ca 2+ on membrane mediated normal function of α-synuclein, which of importance for the study of the Parkinson's disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Lotka-Volterra pairwise modeling fails to capture diverse pairwise microbial interactions

PubMed Central

Momeni, Babak; Xie, Li; Shou, Wenying

2017-01-01

Pairwise models are commonly used to describe many-species communities. In these models, an individual receives additive fitness effects from pairwise interactions with each species in the community ('additivity assumption'). All pairwise interactions are typically represented by a single equation where parameters reflect signs and strengths of fitness effects ('universality assumption'). Here, we show that a single equation fails to qualitatively capture diverse pairwise microbial interactions. We build mechanistic reference models for two microbial species engaging in commonly-found chemical-mediated interactions, and attempt to derive pairwise models. Different equations are appropriate depending on whether a mediator is consumable or reusable, whether an interaction is mediated by one or more mediators, and sometimes even on quantitative details of the community (e.g. relative fitness of the two species, initial conditions). Our results, combined with potential violation of the additivity assumption in many-species communities, suggest that pairwise modeling will often fail to predict microbial dynamics. DOI: http://dx.doi.org/10.7554/eLife.25051.001 PMID:28350295

Molecular Mechanistic Insights into the Endothelial Receptor Mediated Cytoadherence of Plasmodium falciparum-Infected Erythrocytes

PubMed Central

Li, Ang; Lim, Tong Seng; Shi, Hui; Yin, Jing; Tan, Swee Jin; Li, Zhengjun; Low, Boon Chuan; Tan, Kevin Shyong Wei; Lim, Chwee Teck

2011-01-01

Cytoadherence or sequestration is essential for the pathogenesis of the most virulent human malaria species, Plasmodium falciparum (P. falciparum). Similar to leukocyte-endothelium interaction in response to inflammation, cytoadherence of P. falciparum infected red blood cells (IRBCs) to endothelium occurs under physiological shear stresses in blood vessels and involves an array of molecule complexes which cooperate to form stable binding. Here, we applied single-molecule force spectroscopy technique to quantify the dynamic force spectra and characterize the intrinsic kinetic parameters for specific ligand-receptor interactions involving two endothelial receptor proteins: thrombospondin (TSP) and CD36. It was shown that CD36 mediated interaction was much more stable than that mediated by TSP at single molecule level, although TSP-IRBC interaction appeared stronger than CD36-IRBC interaction in the high pulling rate regime. This suggests that TSP-mediated interaction may initiate cell adhesion by capturing the fast flowing IRBCs whereas CD36 functions as the ‘holder’ for providing stable binding. PMID:21437286

Hierarchical organization of eglin c native state dynamics is shaped by competing direct and water-mediated interactions.

PubMed

Materese, Christopher Kroboth; Goldmon, Christa Charisse; Papoian, Garegin A

2008-08-05

The native state dynamics of the small globular serine protease inhibitor eglin c has been studied in a long 336 ns computer simulation in explicit solvent. We have elucidated the energy landscape explored during the course of the simulation by using Principal Component Analysis. We observe several basins in the energy landscape in which the system lingers for extended periods. Through an iterative process we have generated a tree-like hierarchy of states describing the observed dynamics. We observe a range of divergent contact types including salt bridges, hydrogen bonds, hydrophilic interactions, and hydrophobic interactions, pointing to the frustration between competing interactions. Additionally, we find evidence of competing water-mediated interactions. Divergence in water-mediated interactions may be found to supplement existing direct contacts, but they are also found to be independent of such changes. Water-mediated contacts facilitate interactions between residues of like charge as observed in the simulation. Our results provide insight into the complexity of the dynamic native state of a globular protein and directly probe the residual frustration in the native state.

AGE-DEPENDENT HETEROGENEITY OF GENE EXPRESSIONS IN FISHER 344 RAT RETINAL.

EPA Science Inventory

Recent evidence suggests the elderly may be a sensitive subpopulation with regard to environmental exposure to toxic compounds. One source of this sensitivity within the aged subpopulation could be an enhanced variability in response to exposures. This variability, if sufficien...

Collider study on the loop-induced dark matter mediation

NASA Astrophysics Data System (ADS)

Tsai, Yuhsin

2016-06-01

Collider experiments are one of the most promising ways to constrain Dark Matter (DM) interactions. For DM couplings involving light mediators, especially for the loop-mediated interactions, a meaningful interpretation of the results requires to go beyond effective field theory. In this note we discuss the study of the magnetic dipole interacting DM, focusing on a model with anarchic dark flavor structure. By including the momentum-dependent form factors that mediate the coupling - given by the Dark Penguin - in collider processes, we study bounds from monophoton, diphoton, and non-pointing photon searches at the LHC. We also compare our results to constraints from the direct detection experiments.

Chemical Structure and Morphology of Dorsal Root Ganglion Neurons from Naive and Inflamed Mice*

PubMed Central

Barabas, Marie E.; Mattson, Eric C.; Aboualizadeh, Ebrahim; Hirschmugl, Carol J.; Stucky, Cheryl L.

2014-01-01

Fourier transform infrared spectromicroscopy provides label-free imaging to detect the spatial distribution of the characteristic functional groups in proteins, lipids, phosphates, and carbohydrates simultaneously in individual DRG neurons. We have identified ring-shaped distributions of lipid and/or carbohydrate enrichment in subpopulations of neurons which has never before been reported. These distributions are ring-shaped within the cytoplasm and are likely representative of the endoplasmic reticulum. The prevalence of chemical ring subtypes differs between large- and small-diameter neurons. Peripheral inflammation increased the relative lipid content specifically in small-diameter neurons, many of which are nociceptive. Because many small-diameter neurons express an ion channel involved in inflammatory pain, transient receptor potential ankyrin 1 (TRPA1), we asked whether this increase in lipid content occurs in TRPA1-deficient (knock-out) neurons. No statistically significant change in lipid content occurred in TRPA1-deficient neurons, indicating that the inflammation-mediated increase in lipid content is largely dependent on TRPA1. Because TRPA1 is known to mediate mechanical and cold sensitization that accompanies peripheral inflammation, our findings may have important implications for a potential role of lipids in inflammatory pain. PMID:25271163

G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions.

PubMed

Bouchard, Caroline; Pagé, Julie; Bédard, Andréanne; Tremblay, Pierrot; Vallières, Luc

2007-06-01

G protein-coupled receptor 84 (GPR84) is a recently discovered member of the seven transmembrane receptor superfamily whose function and regulation are unknown. Here, we report that in mice suffering from endotoxemia, microglia express GPR84 in a strong and sustained manner. This property is shared by subpopulations of peripheral macrophages and, to a much lesser extent, monocytes. The induction of GPR84 expression by endotoxin is mediated, at least in part, by proinflammatory cytokines, notably tumor necrosis factor (TNF) and interleukin-1 (IL-1), because mice lacking either one or both of these molecules have fewer GPR84-expressing cells in their cerebral cortex than wild-type mice during the early phase of endotoxemia. Moreover, when injected intracerebrally or added to microglial cultures, recombinant TNF stimulates GPR84 expression through a dexamethasone-insensitive mechanism. Finally, we show that microglia produce GPR84 not only during endotoxemia, but also during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In conclusion, this study reports the identification of a new sensitive marker of microglial activation, which may play an important regulatory role in neuroimmunological processes, acting downstream to the effects of proinflammatory mediators.

The type of ATG matters -- natural killer cells are influenced differentially by Thymoglobulin, Lymphoglobulin and ATG-Fresenius.

PubMed

Penack, Olaf; Fischer, Lars; Gentilini, Chiara; Nogai, Axel; Muessig, Arne; Rieger, Kathrin; Ganepola, Susanne; Thiel, Eckhard; Uharek, Lutz

2007-11-01

Although ATG is frequently used in hematopoietic stem cell transplantation and solid organ transplantation, little is known on its effects on NK cells, which mediate important functions in post-transplantation immunology. We incubated peripheral blood lymphocytes of healthy donors with Thymoglobulin, Lymphoglobulin or ATG-Fresenius. Cell death and apoptosis of NK cells and T cells were determined by flow cytometry using propidium iodide and Annexin V. As expected, there were no significant differences between the different ATGs regarding their T cell toxicity. Surprisingly, we found profound differences between the different ATGs regarding their impact on NK cells: In clinically relevant concentrations Lymphoglobulin had less toxic effects on NK cells as compared to Thymoglobulin or ATG-Fresenius: the median percentages of apoptotic or necrotic NK cells in response to 1 mug/ml Lymphoglobulin, ATG-Fresenius and Thymoglobulin were 2%, 35% and 38%, respectively (p<0.001). This is the first report of differential effects of different ATGs on NK cells. Lymphoglobulin appears to be superior to Thymoglobulin or ATG Fresenius regarding the preservation of NK cell mediated immunity. Randomized trials addressing the impact of different ATGs on lymphocyte subpopulations in the clinical setting are urgently warranted.

Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation.

PubMed

Pavan Grandhi, Taraka Sai; Potta, Thrimoorthy; Nitiyanandan, Rajeshwar; Deshpande, Indrani; Rege, Kaushal

2017-10-01

Tumors undergo periods of dormancy followed by reactivation leading to metastatic disease. Arrest in the G0/G1 phase of the cell cycle and resistance to chemotherapeutic drugs are key hallmarks of dormant tumor cells. Here, we describe a 3D platform of bladder cancer cell dormancy and reactivation facilitated by a novel aminoglycoside-derived hydrogel, Amikagel. These 3D dormant tumor microenvironments (3D-DTMs) were arrested in the G0/G1 phase and were highly resistant to anti-proliferative drugs. Inhibition of targets in the cellular protein production machinery led to induction of endoplasmic reticulum (ER) stress and complete ablation of 3D-DTMs. Nanoparticle-mediated calcium delivery significantly accelerated ER stress-mediated 3D-DTM death. Transfer of 3D-DTMs onto weaker and adhesive Amikagels resulted in selective reactivation of a sub-population of N-cadherin deficient cells from dormancy. Whole-transcriptome analyses further indicated key biochemical differences between dormant and proliferative cancer cells. Taken together, our results indicate that 3D bladder cancer microenvironments of dormancy and reactivation can facilitate fundamental advances and novel drug discovery in cancer. Copyright © 2017. Published by Elsevier Ltd.

A Generalized Weizsacker-Williams Method Applied to Pion Production in Proton-Proton Collisions

NASA Technical Reports Server (NTRS)

Ahern, Sean C.; Poyser, William J.; Norbury, John W.; Tripathi, R. K.

2002-01-01

A new "Generalized" Weizsacker-Williams method (GWWM) is used to calculate approximate cross sections for relativistic peripheral proton-proton collisions. Instead of a mass less photon mediator, the method allows for the mediator to have mass for short range interactions. This method generalizes the Weizsacker-Williams method (WWM) from Coulomb interactions to GWWM for strong interactions. An elastic proton-proton cross section is calculated using GWWM with experimental data for the elastic p+p interaction, where the mass p+ is now the mediator. The resulting calculated cross sections is compared to existing data for the elastic proton-proton interaction. A good approximate fit is found between the data and the calculation.

Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas

PubMed Central

Montone, Kathleen T; Wang, Li-Ping; Gimotty, Phyllis A; Hammond, Rachel; Diehl, J Alan; Rustgi, Anil K; Lee, John T; Rasanen, Kati; Weinstein, Gregory S

2011-01-01

Curative eradication of all cells within carcinomas is seldom achievable with chemotherapy alone. This limitation may be partially attributable to tumor cell subpopulations with intrinsic resistance to current drugs. Within squamous cell carcinoma (SCC) cell lines, we previously characterized a subpopulation of mesenchymal-like cells displaying phenotypic plasticity and increased resistance to both cytotoxic and targeted agents. These mesenchymal-like (Ecad-lo) cells are separable from epithelial-like (Ecad-hi) cells based on loss of surface E-cadherin and expression of vimentin. Despite their long-term plasticity, both Ecad-lo and Ecad-hi subsets in short-term culture maintained nearly uniform phenotypes after purification. This stability allowed testing of segregated subpopulations for relative sensitivity to the cytotoxic agent cisplatin in comparison to salinomycin, a compound with reported activity against CD44+CD24− stem-like cells in breast carcinomas. Salinomycin showed comparable efficacy against both Ecad-hi and Ecad-lo cells in contrast to cisplatin, which selectively depleted Ecad-hi cells. An in vivo correlate of these mesenchymal-like Ecad-lo cells was identified by immunohistochemical detection of vimentin-positive malignant subsets across a part of direct tumor xenografts (DTXs) of advanced stage SCC patient samples. Cisplatin treatment of mice with established DTXs caused enrichment of vimentin-positive malignant cells in residual tumors, but salinomycin depleted the same subpopulation. These results demonstrate that mesenchymal-like SCC cells, which resist current chemotherapies, respond to a treatment strategy developed against a stem-like subset in breast carcinoma. Further, they provide evidence of mesenchymal-like subsets being well-represented across advanced stage SCCs, suggesting that intrinsic drug resistance in this subpopulation has high clinical relevance. PMID:21558812

Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas.

PubMed

Basu, Devraj; Montone, Kathleen T; Wang, Li-Ping; Gimotty, Phyllis A; Hammond, Rachel; Diehl, J Alan; Rustgi, Anil K; Lee, John T; Rasanen, Kati; Weinstein, Gregory S; Herlyn, Meenhard

2011-06-15

Curative eradication of all cells within carcinomas is seldom achievable with chemotherapy alone. This limitation may be partially attributable to tumor cell subpopulations with intrinsic resistance to current drugs. Within squamous cell carcinoma (SCC) cell lines, we previously characterized a subpopulation of mesenchymal-like cells displaying phenotypic plasticity and increased resistance to both cytotoxic and targeted agents. These mesenchymal-like (Ecad-lo) cells are separable from epithelial-like (Ecad-hi) cells based on loss of surface E-cadherin and expression of vimentin. Despite their long-term plasticity, both Ecad-lo and Ecad-hi subsets in short-term culture maintained nearly uniform phenotypes after purification. This stability allowed testing of segregated subpopulations for relative sensitivity to the cytotoxic agent cisplatin in comparison to salinomycin, a compound with reported activity against CD44(+)CD24(-) stem-like cells in breast carcinomas. Salinomycin showed comparable efficacy against both Ecad-hi and Ecad-lo cells in contrast to cisplatin, which selectively depleted Ecad-hi cells. An in vivo correlate of these mesenchymal-like Ecad-lo cells was identified by immunohistochemical detection of vimentin-positive malignant subsets across a part of direct tumor xenografts (DTXs) of advanced stage SCC patient samples. Cisplatin treatment of mice with established DTXs caused enrichment of vimentin-positive malignant cells in residual tumors, but salinomycin depleted the same subpopulation. These results demonstrate that mesenchymal-like SCC cells, which resist current chemotherapies, respond to a treatment strategy developed against a stem-like subset in breast carcinoma. Further, they provide evidence of mesenchymal-like subsets being well-represented across advanced stage SCCs, suggesting that intrinsic drug resistance in this subpopulation has high clinical relevance.

Intraspecific bloom succession in the harmful dinoflagellate Cochlodinium polykrikoides (Dinophyceae) extended the blooming period in Korean coastal waters in 2009.

PubMed

Park, Bum Soo; Kim, Jin Ho; Kim, Joo-Hwan; Baek, Seung Ho; Han, Myung-Soo

2018-01-01

Although there have been extensive studies on dinoflagellate blooms in recent decades, the mechanism that allows the maintenance of blooms over long periods remains uncertain, and studies on genetically differentiated subpopulations may provide insights into this mechanism. In this study, the influence of two genetically distinct subpopulations of the dinoflagellate Cochlodinium polykrikoides, referred to as Group I and IV, on bloom duration in Korean coastal waters (KCW) was examined using a quantitative PCR (qPCR) assay. In this study, a C. polykrikoides bloom occurred over a longer period in 2009 (49 days), whereas the bloom period was shorter in 2010 (35 days). The qPCR results indicate that intraspecific bloom succession between Groups I and IV occurred in 2009, whereas only a single subpopulation (Group I) was responsible for the bloom in 2010. Based on the statistical analysis, the Group I and Group IV blooms occurred under significantly different environmental conditions (p ≤ 0.05) in terms of water temperature, pH, and phosphate concentration, and these subpopulations exhibited significantly different relationships with environmental factors, particularly water temperature (p < 0.01). This variability may allow blooms to continue through intraspecific bloom succession even after environmental conditions change. Southern KCW are affected by outer regions via the Tsushima Warm Current (TWC) every summer. Group IV (≤1108 ± 69 cells L -1 ) was primarily observed along the route of the TWC in summer 2009, when the bloom of this subpopulation occurred in southern KCW. These results suggest that Group IV transported via the TWC may have influenced the bloom dynamics of this subpopulation in summer 2009. Copyright © 2017 Elsevier B.V. All rights reserved.

CD133+CD54+CD44+ circulating tumor cells as a biomarker of treatment selection and liver metastasis in patients with colorectal cancer

PubMed Central

Wang, Cun; Huang, Qiaorong; Meng, Wentong; Yu, Yongyang; Yang, Lie; Peng, Zhihai; Hu, Jiankun; Li, Yuan; Mo, Xianming; Zhou, Zongguang

2016-01-01

Introduction Liver is the most common site of distant metastasis in colorectal cancer (CRC). Early diagnosis and appropriate treatment selection decides overall prognosis of patients. However, current diagnostic measures were basically imaging but not functional. Circulating tumor cells (CTCs) known as hold the key to understand the biology of metastatic mechanism provide a novel and auxiliary diagnostic strategy for CRC with liver metastasis (CRC-LM). Results The expression of CD133+ and CD133+CD54+CD44+ cellular subpopulations were higher in the peripheral blood of CRC-LM patients when compared with those without metastasis (P<0.001). Multivariate analysis proved the association between the expression of CD133+CD44+CD54+ cellular subpopulation and the existence of CRC-LM (P<0.001). The combination of abdominal CT/MRI, CEA and the CD133+CD44+CD54+ cellular subpopulation showed increased detection and discrimination rate for liver metastasis, with a sensitivity of 88.2% and a specificity of 92.4%. Meanwhile, it also show accurate predictive value for liver metastasis (OR=2.898, 95% C.I.1.374–6.110). Materials and Method Flow cytometry and multivariate analysis was performed to detect the expression of cancer initiating cells the correlation between cellular subpopulations and liver metastasis in patients with CRC. The receiver operating characteristic curves combined with the area under the curve were generated to compare the predictive ability of the cellular subpopulation for liver metastasis with current CT and MRI images. Conclusions The identification, expression and application of CTC subpopulations will provide an ideal cellular predictive marker for CRC liver metastasis and a potential marker for further investigation. PMID:27764803

New support for an old hypothesis: density affects extra-pair paternity

PubMed Central

Mayer, Christian; Pasinelli, Gilberto

2013-01-01

Density has been suggested to affect variation in extra-pair paternity (EPP) in avian mating systems, because increasing density promotes encounter rates and thus mating opportunities. However, the significance of density affecting EPP variation in intra- and interspecific comparisons has remained controversial, with more support from intraspecific comparisons. Neither experimental nor empirical studies have consistently provided support for the density hypothesis. Testing the density hypothesis is challenging because density measures may not necessarily reflect extra-pair mating opportunities, mate guarding efforts may covary with density, populations studied may differ in migratory behavior and/or climatic conditions, and variation in density may be insufficient. Accounting for these potentially confounding factors, we tested whether EPP rates within and among subpopulations of the reed bunting (Emberiza schoeniclus) were related to density. Our analyses were based on data from 13 subpopulations studied over 4 years. Overall, 56.4% of totally 181 broods contained at least one extra-pair young (EPY) and 37.1% of totally 669 young were of extra-pair origin. Roughly 90% of the extra-pair fathers were from the adjacent territory or from the territory after the next one. Within subpopulations, the proportion of EPY in broods was positively related to local breeding density. Similarly, among subpopulations, proportion of EPY was positively associated with population density. EPP was absent in subpopulations consisting of single breeding pairs, that is, without extra-pair mating opportunities. Our study confirms that density is an important biological factor, which significantly influences the amount of EPP within and among subpopulations, but also suggests that other mechanisms influence EPP beyond the variation explained by density. PMID:23533071

Differential distribution of sperm subpopulations and incidence of pleiomorphisms in ejaculates of captive howling monkeys ( Alouatta caraya)

NASA Astrophysics Data System (ADS)

Valle, R. R.; Carvalho, F. M.; Muniz, J. A. P. C.; Leal, C. L. V.; García-Herreros, M.

2013-10-01

The aim of this study was to develop an objective method to determine the incidence of pleiomorphisms and its influence on the distribution of sperm morphometric subpopulations in ejaculates of howling monkeys ( Alouatta caraya) by using a combination of computerized analysis system (ASMA) and principal component analysis (PCA) methods. Ejaculates were collected by electroejaculation methods on a regular basis from five individuals maintained under identical captive environmental, nutritional, and management conditions. Each sperm head was measured for dimensional parameters (Area [ A, (square micrometers)], Perimeter [ P, (micrometers)], Length [ L, (micrometers)], and Width [ W, (micrometers)]) and shape-derived parameters (Ellipticity [( L/ W)], Elongation [( L - W)/( L + W)], and Rugosity [(4л A/ P 2)]). PCA revealed two principal components explaining more than the 96 % of the variance. Clustering methods and discriminant analyzes were performed and seven separate subpopulations were identified. There were differences ( P < 0.001) in the distribution of the seven subpopulations as well as in the incidence of abnormal pleiomorphisms (58.6 %, 49.8 %, 35.1 %, 66.4 %, and 55.1 %, P < 0.05) among the five donors tested. Our results indicated that differences among individuals related to the incidence of pleiomorphisms, and sperm subpopulational structure was not related to the captivity conditions or the sperm collection method, since all individuals were studied under identical conditions. In conclusion, the combination of ASMA and PCA is a useful clinical diagnostic resource for detecting deficiencies in sperm morphology and sperm subpopulations in A. caraya ejaculates that could be used in ex situ conservation programs of threatened species in Alouatta genus or even other endangered neotropical primate species.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karpinets, Tatiana V; Pelletier, Dale A; Pan, Chongle

Understanding of cellular processes involved in the anaerobic degradation of complex organic compounds by microorganisms is crucial for development of innovative biotechnologies for bioethanol production and for efficient degradation of toxic organic compounds. In natural environment the degradation is usually accomplished by syntrophic consortia comprised of different bacterial species. Here we show that the metabolically versatile phototrophic bacterium Rhodopseudomonas palustris may form its own syntrophic consortia, when it grows anaerobically on p-coumarate or benzoate as a sole carbon source. In the study we reveal the consortia from a comparison of large-scale measurements of mRNA and protein expressions under p-coumarate andmore » benzoate degrading conditions using a novel computational approach referred as phenotype fingerprinting. In this approach marker genes for known R. palustris phenotypes are employed to calculate their expression from the gene and protein expressions in each studied condition. Subpopulations of the consortia are inferred from the expression of phenotypes and known metabolic modes of the R. palustris growth. We find that p-coumarate degrading condition leads to at least three R. palustris subpopulations utilizing p-coumarate, benzoate, and CO2 and H2. Benzoate degrading condition also produces at least three subpopulations utilizing benzoate, CO2 and H2, and N2 and formate. Communication among syntrophs and inter-syntrophic dynamics in each consortium are indicated by up-regulation of transporters and genes involved in the curli formation and chemotaxis. The photoautotrphic subpopulation found in both consortia is characterized by activation of two cbb operons and the uptake hydrogenase system. A specificity of N2-fixing subpopulation in the benzoate degrading consortium is the preferential activation of the vanadium nitrogenase over the molybdenum nitrogenase. The N2-fixing subpopulation in the consortium is confirmed by consumption of dissolved nitrogen gas under the benzoate degrading conditions.« less

Metapopulation effective size and conservation genetic goals for the Fennoscandian wolf (Canis lupus) population

PubMed Central

Laikre, L; Olsson, F; Jansson, E; Hössjer, O; Ryman, N

2016-01-01

The Scandinavian wolf population descends from only five individuals, is isolated, highly inbred and exhibits inbreeding depression. To meet international conservation goals, suggestions include managing subdivided wolf populations over Fennoscandia as a metapopulation; a genetically effective population size of Ne⩾500, in line with the widely accepted long-term genetic viability target, might be attainable with gene flow among subpopulations of Scandinavia, Finland and Russian parts of Fennoscandia. Analytical means for modeling Ne of subdivided populations under such non-idealized situations have been missing, but we recently developed new mathematical methods for exploring inbreeding dynamics and effective population size of complex metapopulations. We apply this theory to the Fennoscandian wolves using empirical estimates of demographic parameters. We suggest that the long-term conservation genetic target for metapopulations should imply that inbreeding rates in the total system and in the separate subpopulations should not exceed Δf=0.001. This implies a meta-Ne of NeMeta⩾500 and a realized effective size of each subpopulation of NeRx⩾500. With current local effective population sizes and one migrant per generation, as recommended by management guidelines, the meta-Ne that can be reached is ~250. Unidirectional gene flow from Finland to Scandinavia reduces meta-Ne to ~130. Our results indicate that both local subpopulation effective sizes and migration among subpopulations must increase substantially from current levels to meet the conservation target. Alternatively, immigration from a large (Ne⩾500) population in northwestern Russia could support the Fennoscandian metapopulation, but immigration must be substantial (5–10 effective immigrants per generation) and migration among Fennoscandian subpopulations must nevertheless increase. PMID:27328654

Mediator-dependent Nuclear Receptor Functions

PubMed Central

Chen, Wei; Roeder, Robert

2011-01-01

As gene-specific transcription factors, nuclear hormone receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss (i) our current understanding of pathways that nuclear receptors and other interacting cofactors employ to recruit Mediator to target gene enhancers and promoters, including conditional requirements for the strong NR-Mediator interactions mediated by the NR AF2 domain and the MED1 LXXLLL motifs and (ii) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. PMID:21854863

Relationship between mediation analysis and the structured life course approach.

PubMed

Howe, Laura D; Smith, Andrew D; Macdonald-Wallis, Corrie; Anderson, Emma L; Galobardes, Bruna; Lawlor, Debbie A; Ben-Shlomo, Yoav; Hardy, Rebecca; Cooper, Rachel; Tilling, Kate; Fraser, Abigail

2016-08-01

Many questions in life course epidemiology involve mediation and/or interaction because of the long latency period between exposures and outcomes. In this paper, we explore how mediation analysis (based on counterfactual theory and implemented using conventional regression approaches) links with a structured approach to selecting life course hypotheses. Using theory and simulated data, we show how the alternative life course hypotheses assessed in the structured life course approach correspond to different combinations of mediation and interaction parameters. For example, an early life critical period model corresponds to a direct effect of the early life exposure, but no indirect effect via the mediator and no interaction between the early life exposure and the mediator. We also compare these methods using an illustrative real-data example using data on parental occupational social class (early life exposure), own adult occupational social class (mediator) and physical capability (outcome). © The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.

Bacterial predator–prey dynamics in microscale patchy landscapes

PubMed Central

Rotem, Or; Jurkevitch, Edouard; Dekker, Cees

2016-01-01

Soil is a microenvironment with a fragmented (patchy) spatial structure in which many bacterial species interact. Here, we explore the interaction between the predatory bacterium Bdellovibrio bacteriovorus and its prey Escherichia coli in microfabricated landscapes. We ask how fragmentation influences the prey dynamics at the microscale and compare two landscape geometries: a patchy landscape and a continuous landscape. By following the dynamics of prey populations with high spatial and temporal resolution for many generations, we found that the variation in predation rates was twice as large in the patchy landscape and the dynamics was correlated over shorter length scales. We also found that while the prey population in the continuous landscape was almost entirely driven to extinction, a significant part of the prey population in the fragmented landscape persisted over time. We observed significant surface-associated growth, especially in the fragmented landscape and we surmise that this sub-population is more resistant to predation. Our results thus show that microscale fragmentation can significantly influence bacterial interactions. PMID:26865299

Experimental Tests of Normative Group Influence and Representation Effects in Computer-Mediated Communication: When Interacting Via Computers Differs from Interacting With Computers.

ERIC Educational Resources Information Center

Lee, Eun-Ju; Nass, Clifford

2002-01-01

Presents two experiments to address the questions of if and how normative social influence operates in anonymous computer-mediated communication and human-computer interaction. Finds that the perception of interaction partner (human vs. computer) moderated the group conformity effect such that the undergraduate student subjects expressed greater…

Granulocytes of the red claw crayfish Cherax quadricarinatus can endocytose beads, E. coli and WSSV, but in different ways.

PubMed

Duan, Hu; Jin, Songjun; Zhang, Yan; Li, Fuhua; Xiang, Jianhai

2014-10-01

The hemocytes of the red claw crayfish Cherax quadricarinatus are classified by morphologic observation into the following types: hyalinocytes (H), semi-granulocytes (SG) and granulocytes (G). Density gradient centrifugation with Percoll was developed to separate these three subpopulations of hemocytes. Beads, Escherichia coli, and FITC labeling WSSV were used to investigate the characteristics of granulocytes by using scanning electron microscope, transmission electron microscope, and laser scan confocal microscope. Results showed that granulocytes could phagocytose beads and E. coli by endocytic pathways. WSSV could rely on caveolae-mediated endocytosis to mainly enter into granulocytes. These results could elucidate the mechanism of the innate immunity function of granulocytes, and it also showed the mechanism by which WSSV invaded granulocytes in the red claw crayfish. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors.

PubMed

Starostina, Natalia G; Kipreos, Edward T

2012-01-01

The mammalian CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors (CKIs) comprises three proteins--p21(Cip1/WAF1), p27(Kip1), and p57(Kip2)--that bind and inhibit cyclin-CDK complexes, which are key regulators of the cell cycle. CIP/KIP CKIs have additional independent functions in regulating transcription, apoptosis and actin cytoskeletal dynamics. These divergent functions are performed in distinct cellular compartments and contribute to the seemingly contradictory observation that the CKIs can both suppress and promote cancer. Multiple ubiquitin ligases (E3s) direct the proteasome-mediated degradation of p21, p27 and p57. This review analyzes recent data highlighting our current understanding of how distinct E3 pathways regulate subpopulations of the CKIs to control their diverse functions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Modulation of Respiratory Frequency by Peptidergic Input to Rhythmogenic Neurons in the PreBötzinger Complex

PubMed Central

Gray, Paul A.; Rekling, Jens C.; Bocchiaro, Christopher M.; Feldman, Jack L.

2010-01-01

Neurokinin-1 receptor (NK1R) and μ-opioid receptor (μOR) agonists affected respiratory rhythm when injected directly into the preBötzinger Complex (preBötC), the hypothesized site for respiratory rhythmogenesis in mammals. These effects were mediated by actions on preBötC rhythmogenic neurons. The distribution of NK1R+ neurons anatomically defined the preBötC. Type 1 neurons in the preBötC, which have rhythmogenic properties, expressed both NK1Rs and μORs, whereas type 2 neurons expressed only NK1Rs. These findings suggest that the preBötC is a definable anatomic structure with unique physiological function and that a subpopulation of neurons expressing both NK1Rs and μORs generate respiratory rhythm and modulate respiratory frequency. PMID:10567264

Variable responses of small and large human hepatocytes to hypoxia and hypoxia/reoxygenation (H–R)

PubMed Central

Bhogal, Ricky H.; Weston, Christopher J.; Curbishley, Stuart M.; Bhatt, Anand N.; Adams, David H.; Afford, Simon C.

2011-01-01

Hypoxia and hypoxia–reoxygenation (H–R) regulate human hepatocyte cell death by mediating the accumulation of reactive oxygen species (ROS). Hepatocytes within the liver are organised into peri-portal (PP) and peri-venous (PV) subpopulations. PP and PV hepatocytes differ in size and function. We investigated whether PP and PV human hepatocytes exhibit differential susceptibility to hypoxic stress. Isolated hepatocytes were used in an in vitro model of hypoxia and H–R. ROS production and cell death were assessed using flow cytometry. PV, and not PP hepatocytes, accumulate intracellular ROS in a mitochondrial dependent manner during hypoxia and H–R. This increased ROS regulates hepatocyte apoptosis and necrosis via a mitochondrial pathway. These findings have implications on the understanding of liver injury and application of potential therapeutic strategies. PMID:21356211

CHARACTERIZING AND PROVIDING ADEQUATE PROTECTION FOR SUSCEPTIBLE SUBPOPULATIONS: SUSCEPTIBLE POPULATIONS: SUSCEPTIBILITY ASSOCIATED WITH THE AGED

EPA Science Inventory

SUMMARY: An important Agency mandate is to identify subpopulations particularly susceptible to adverse effects associated with exposure to environmental contaminants. For example, a critical public health question is the extent to which exposure to environmental contaminants cont...

Are the Liberal Arts an Endangered Species?

ERIC Educational Resources Information Center

Zammuto, Raymond F.

1984-01-01

Changes in the composition of colleges and universities during the 1970s and the changes in the subpopulation of institutions with a high commitment to liberal arts education were studied. The effect these changes had on the diversity of the population and subpopulation is described. (MLW)

Synchronous Computer-Mediated Communication and Interaction

ERIC Educational Resources Information Center

Ziegler, Nicole

2016-01-01

The current study reports on a meta-analysis of the relative effectiveness of interaction in synchronous computer-mediated communication (SCMC) and face-to-face (FTF) contexts. The primary studies included in the analysis were journal articles and dissertations completed between 1990 and 2012 (k = 14). Results demonstrate that interaction in SCMC…

Gendered Interactions in Computer-Mediated Computer Conferencing

ERIC Educational Resources Information Center

Lawlor, Carmen

2006-01-01

Computer mediated conferencing (CMC) has been widely viewed as a valuable forum for providing opportunities for interaction among learners in a distance education setting. Interaction in distance contexts; however, is not well understood, and it has been argued that social markers are cued in online communications and that gender influences…

Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil.

PubMed

Ishida, Kaoru; Ito, Chie; Ohmori, Yukimi; Kume, Kohei; Sato, Kei A; Koizumi, Yuka; Konta, Akari; Iwaya, Takeshi; Nukatsuka, Mamoru; Kobunai, Takashi; Takechi, Teiji; Nishizuka, Satoshi S

2017-05-23

Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.

Ethical Dilemmas in Protecting Susceptible Subpopulations From Environmental Health Risks: Liberty, Utility, Fairness, and Accountability for Reasonableness

PubMed Central

Resnik, David B.; MacDougall, D. Robert; Smith, Elise M.

2018-01-01

Various U.S. laws, such as the Clean Air Act and the Food Quality Protection Act, require additional protections for susceptible subpopulations who face greater environmental health risks. The main ethical rationale for providing these protections is to ensure that environmental health risks are distributed fairly. In this article, we (1) consider how several influential theories of justice deal with issues related to the distribution of environmental health risks; (2) show that these theories often fail to provide specific guidance concerning policy choices; and (3) argue that an approach to public decision making known as accountability for reasonableness can complement theories of justice in establishing acceptable environmental health risks for the general population and susceptible subpopulations. Since accountability for reasonableness focuses on the fairness of the decision-making process, not the outcome, it does not guarantee that susceptible subpopulations will receive a maximum level of protection, regardless of costs or other morally relevant considerations. PMID:29466133

Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.

PubMed

Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C

2016-02-01

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

Kidney cell electrophoresis in space flight: Rationale, methods, results and flow cytometry applications

NASA Technical Reports Server (NTRS)

Todd, P.; Morrison, Dennis R.; Barlow, Grant H.; Lewis, Marian L.; Lanham, J. W.; Cleveland, C.; Williams, K.; Kunze, M. E.; Goolsby, C. L.

1988-01-01

Cultures of human embryonic kidney cells consistently contain an electrophoretically separable subpopulation of cells that produce high levels of urokinase and have an electrophoretic mobility about 85 percent as high as that of the most mobile human embryonic kidney cells. This subpopulation is rich in large epithelioid cells that have relatively little internal structure. When resolution and throughput are adequate, free fluid electrophoresis can be used to isolate a broad band of low mobility cells which also produces high levels of plasminogen activators (PAs). In the course of performing this, it was discovered that all electrophoretic subpopulations of cultured human embryonic kidney cells produce some PAs and that separate subpopulations produce high quantities of different types of PA's. This information and the development of sensitive assays for this project have provided new insights into cell secretion mechanisms related to fibrinolysis. These advances would probably not have been made without the NASA program to explore fundamental questions of free fluid electrophoresis in space.

Puma (Puma concolor) epididymal sperm morphometry

PubMed Central

Cucho, Hernán; Alarcón, Virgilio; Ordóñez, César; Ampuero, Enrique; Meza, Aydee; Soler, Carles

2016-01-01

The Andean puma (Puma concolor) has not been widely studied, particularly in reference to its semen characteristics. The aim of the present study was to define the morphometry of puma sperm heads and classify their subpopulations by cluster analysis. Samples were recovered postmortem from two epididymides from one animal and prepared for morphological observation after staining with the Hemacolor kit. Morphometric data were obtained from 581 spermatozoa using a CASA-Morph system, rendering 13 morphometric parameters. The principal component (PC) analysis was performed followed by cluster analysis for the establishment of subpopulations. Two PC components were obtained, the first related to size and the second to shape. Three subpopulations were observed, corresponding to elongated and intermediate-size sperm heads and acrosomes, to large heads with large acrosomes, and to small heads with short acrosomes. In conclusion, puma spermatozoa showed no uniform sperm morphology but three clear subpopulations. These results should be used for future work in the establishment of an adequate germplasm bank of this species. PMID:27678466

Puma (Puma concolor) epididymal sperm morphometry.

PubMed

Cucho, Hernán; Alarcón, Virgilio; Ordóñez, César; Ampuero, Enrique; Meza, Aydee; Soler, Carles

2016-01-01

The Andean puma (Puma concolor) has not been widely studied, particularly in reference to its semen characteristics. The aim of the present study was to define the morphometry of puma sperm heads and classify their subpopulations by cluster analysis. Samples were recovered postmortem from two epididymides from one animal and prepared for morphological observation after staining with the Hemacolor kit. Morphometric data were obtained from 581 spermatozoa using a CASA-Morph system, rendering 13 morphometric parameters. The principal component (PC) analysis was performed followed by cluster analysis for the establishment of subpopulations. Two PC components were obtained, the first related to size and the second to shape. Three subpopulations were observed, corresponding to elongated and intermediate-size sperm heads and acrosomes, to large heads with large acrosomes, and to small heads with short acrosomes. In conclusion, puma spermatozoa showed no uniform sperm morphology but three clear subpopulations. These results should be used for future work in the establishment of an adequate germplasm bank of this species.

Cannibalism enhances biofilm development in Bacillus subtilis.

PubMed

López, Daniel; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

2009-11-01

Cannibalism is a mechanism to delay sporulation in Bacillus subtilis. Cannibal cells express the skf and sdp toxin systems to lyse a fraction of their sensitive siblings. The lysed cells release nutrients that serve to feed the community, effectively delaying spore formation. Here we provide evidence that the subpopulation of cells that differentiates into cannibals is the same subpopulation that produces the extracellular matrix that holds cells together in biofilms. Cannibalism and matrix formation are both triggered in response to the signalling molecule surfactin. Nutrients released by the cannibalized cells are preferentially used by matrix-producing cells, as they are the only cells expressing resistance to the Skf and Sdp toxins. As a result this subpopulation increases in number and matrix production is enhanced when cannibalism toxins are produced. The cannibal/matrix-producing subpopulation is also generated in response to antimicrobials produced by other microorganisms and may thus constitute a defense mechanism to protect B. subtilis from the action of antibiotics in natural settings.

The role of the maturation stage of thymocytes on the phytohemagglutinin and concanavalin A responses in thymocyte and lymph node lymphocyte cocultures in guinea pig. Effects of pretreatment of thymocytes with thymosin or levamisole.

PubMed

Soppi, E

1981-02-01

Guinea pig thymocytes (TH) and lymph node lymphocytes (LNL) synergized optimally in both phytohemagglutinin (PHA) and concanavalin (Con A) responses in mixtures containing 0.3 x 10(6) TH and 0.2 x 10(6) LNL. Using discontinuous albumin gradient centrifugation thymocytes were separated into two subpopulations (F4 and F6) at different stages of maturation. Immature, PHA and Con A unresponsive F6 thymocytes synergized significantly only in the PHA response. More mature, PHA and Con A responsive F4 thymocytes cooperated well in the Con A response, but only a small synergy was observed in the PHA response. Pretreatment of the unfractionated thymocytes with the low concentration (0.05 microgram/ml) of thymosin decreased significantly their capacity to interact with LNL in both PHA and Con A responses. Preincubation of F4 thymocytes with the high concentration (200 microgram/ml) of thymosin increased the synergy in PHA response. All other combinations with thymosin or levamisole and thymocytes were ineffective on the mitogenic responses in the TH and LNL cocultures. Altogether, the results how that the thymocyte populations that induce synergy in PHA, or in (PHA and) Con A responses represent the two subpopulations of thymocytes with different maturation stages. The differential effects of the two concentrations of thymosin on the thymocytes support further the concept that the thymocytes synergizing in responses to both mitogens are more mature than those synergizing only PHA response. Thus, the ability of thymocytes to interact with LNL is dependent on the maturation stage of thymocytes, and can be utilized to study the differentiation of thymocytes.

Elastin receptor (S-gal) occupancy by elastin peptides modulates T-cell response during murine emphysema.

PubMed

Meghraoui-Kheddar, Aïda; Pierre, Alexandre; Sellami, Mehdi; Audonnet, Sandra; Lemaire, Flora; Le Naour, Richard

2017-09-01

Chronic obstructive pulmonary disease and emphysema are associated with increased elastin peptides (EP) production because of excessive breakdown of lung connective tissue. We recently reported that exposure of mice to EP elicited hallmark features of emphysema. EP effects are largely mediated through a receptor complex that includes the elastin-binding protein spliced-galactosidase (S-gal). In previous studies, we established a correlation between cytokine production and S-gal protein expression in EP-treated immune cells. In this study, we investigated the S-gal-dependent EP effects on T-helper (Th) and T-cytotoxic (Tc) responses during murine EP-triggered pulmonary inflammation. C57BL/6J mice were endotracheally instilled with the valine-glycine-valine-alanine-proline-glycine (VGVAPG) elastin peptide, and, 21 days after treatment, local and systemic T-lymphocyte phenotypes were analyzed at cytokine and transcription factor expression levels by multicolor flow cytometry. Exposure of mice to the VGVAPG peptide resulted in a significant increase in the proportion of the CD4 + and CD8 + T cells expressing the cytokines IFN-γ or IL-17a and the transcription factors T-box expressed in T cells or retinoic acid-related orphan receptor-γt (RORγt) without effects on IL-4 and Gata-binding protein 3 to DNA sequence [A/T]GATA[A/G] expression. These effects were maximized when each T-cell subpopulation was challenged ex vivo with EP, and they were inhibited in vivo when an analogous peptide antagonizing the EP/S-gal interactions was instilled together with the VGVAPG peptide. This study demonstrates that, during murine emphysema, EP-S-gal interactions contribute to a Th-1 and Th-17 proinflammatory T-cell response combined with a Tc-1 response. Our study also highlights the S-gal receptor as a putative pharmacological target to modulate such an immune response. Copyright © 2017 the American Physiological Society.

Dendritic cells rapidly undergo apoptosis in vitro following culture with activated CD4+ Vα24 natural killer T cells expressing CD40L

PubMed Central

Nieda, M; Kikuchi, A; Nicol, A; Koezuka, Y; Ando, Y; Ishihara, S; Lapteva, N; Yabe, T; Tokunaga, K; Tadokoro, K; Juji, T

2001-01-01

Human Vα24 natural killer T (Vα24NKT) cells are activated by α-glycosylceramide-pulsed dendritic cells (DCs) in a CD1d-dependent and T-cell receptor-mediated manner. There are two major subpopulations of Vα24NKT cells, CD4– CD8– Vα24NKT and CD4+ Vα24NKT cells. We have recently shown that activated CD4– CD8– Vα24NKT cells have cytotoxic activity against DCs, but knowledge of the molecules responsible for cytotoxicity of Vα24NKT cells is currently limited. We aimed to investigate whether CD4+ Vα24NKT cells also have cytotoxic activity against DCs and to determine the mechanisms underlying any observed cytotoxic activity. We demonstrated that activated CD4+ Vα24NKT cells [CD40 ligand (CD40L) -positive] have cytotoxic activity against DCs (strongly CD40-positive), but not against monocytes (weakly CD40-positive) or phytohaemagglutinin blast T cells (CD40-negative), and that apoptosis of DCs significantly contributes to the observed cytotoxicity. The apoptosis of DCs following culture with activated CD4+ Vα24NKT cells, but not with resting CD4+ Vα24NKT cells (CD40L-negative), was partially inhibited by anti-CD40L mAb. Direct ligation of CD40 on the DCs by the anti-CD40 antibody also induced apoptosis of DCs. Our results suggest that CD40–CD40L interaction plays an important role in the induction of apoptosis of DCs following culture with activated CD4+ Vα24NKT cells. The apoptosis of DCs from normal donors, triggered by the CD40–CD40L interaction, may contribute to the homeostatic regulation of the normal human immune system, preventing the interminable activation of activated CD4+ Vα24NKT cells by virtue of apoptosis of DCs. PMID:11260318

Genomic epidemiology of Lineage 4 Mycobacterium tuberculosis subpopulations in New York City and New Jersey, 1999-2009.

PubMed

Brown, Tyler S; Narechania, Apurva; Walker, John R; Planet, Paul J; Bifani, Pablo J; Kolokotronis, Sergios-Orestis; Kreiswirth, Barry N; Mathema, Barun

2016-11-21

Whole genome sequencing (WGS) has rapidly become an important research tool in tuberculosis epidemiology and is likely to replace many existing methods in public health microbiology in the near future. WGS-based methods may be particularly useful in areas with less diverse Mycobacterium tuberculosis populations, such as New York City, where conventional genotyping is often uninformative and field epidemiology often difficult. This study applies four candidate strategies for WGS-based identification of emerging M. tuberculosis subpopulations, employing both phylogenomic and population genetics methods. M. tuberculosis subpopulations in New York City and New Jersey can be distinguished via phylogenomic reconstruction, evidence of demographic expansion and subpopulation-specific signatures of selection, and by determination of subgroup-defining nucleotide substitutions. These methods identified known historical outbreak clusters and previously unidentified subpopulations within relatively monomorphic M. tuberculosis endemic clone groups. Neutrality statistics based on the site frequency spectrum were less useful for identifying M. tuberculosis subpopulations, likely due to the low levels of informative genetic variation in recently diverged isolate groups. In addition, we observed that isolates from New York City endemic clone groups have acquired multiple non-synonymous SNPs in virulence- and growth-associated pathways, and relatively few mutations in drug resistance-associated genes, suggesting that overall pathoadaptive fitness, rather than the acquisition of drug resistance mutations, has played a central role in the evolutionary history and epidemiology of M. tuberculosis subpopulations in New York City. Our results demonstrate that some but not all WGS-based methods are useful for detection of emerging M. tuberculosis clone groups, and support the use of phylogenomic reconstruction in routine tuberculosis laboratory surveillance, particularly in areas with relatively less diverse M. tuberculosis populations. Our study also supports the use of wider-reaching phylogenomic and population genomic methods in tuberculosis public health practice, which can support tuberculosis control activities by identifying genetic polymorphisms contributing to epidemiological success in local M. tuberculosis populations and possibly explain why certain isolate groups are apparently more successful in specific host populations.

The effect of Taurolidine on adherent and floating subpopulations of melanoma cells.

PubMed

Shrayer, D P; Lukoff, H; King, T; Calabresi, P

2003-04-01

The annual incidence of malignant melanoma is estimated at 10-12 per 100000 inhabitants in countries of Central Europe and the US, with more recent estimates showing a dramatic upward trend. Taurolidine (Carter/Wallace, Cranberry, NJ) is a novel, potentially effective, antitumor chemotherapeutic agent. We hypothesized that Taurolidine could inhibit the growth, induce apoptosis, affect the cell cycle and change morphology of melanoma cells. We expected this process to be different in adherent and floating subpopulations that may be reflective of solid tumors and their metastases. Analysis of MNT-1 human and B16F10 murine melanoma cells showed that at 72 h the IC(50) of Taurolidine was 25.4+/-3.3 microM for MNT-1 human melanoma cells and 30.9+/-3.6 microM for B16F10 murine melanoma cells. Taurolidine induced DNA fragmentation of melanoma cells in a dose-dependent manner. Taurolidine (75 and 100 microM) induced 52-97% Annexin-V binding (apoptosis), respectively. Evaluation of cell cycle after 72 h exposure to Taurolidine (0-100 microM) revealed that the percentage of melanoma cells in S phase increased from 27 to 40% in the adherent subpopulation and from 33 to 49% in the floating subpopulation. Phase contrast microscopy revealed a marked swelling of melanoma cells and decreasing cell numbers in adherent subpopulation starting at 24 h with 25 microM Taurolidine. Shrinkage of cells dominated at 75-100 microM Taurolidine. Using Cytospin assay in the floating population, we observed swelling of melanoma cells induced by 25-100 micro Taurolidine and appearance of giant (multinuclear) forms resulting from exposure to 75-100 micro Taurolidine. Some floating cells with normal morphology were observed with low concentrations of Taurolidine (0-25 microM). These data show that effects of Taurolidine may be different in adherent and floating subpopulations of melanoma cells. More importantly, floating subpopulations that may contain some viable melanoma cells, may be reflective of potential metastasis after treatment of solid tumors in vivo.

Characteristics and Kinetic Analysis of AQS Transformation and Microbial Goethite Reduction:Insight into "Redox mediator-Microbe-Iron oxide" Interaction Process.

PubMed

Zhu, Weihuang; Shi, Mengran; Yu, Dan; Liu, Chongxuan; Huang, Tinglin; Wu, Fengchang

2016-03-29

The characteristics and kinetics of redox transformation of a redox mediator, anthraquinone-2-sulfonate (AQS), during microbial goethite reduction by Shewanella decolorationis S12, a dissimilatory iron reduction bacterium (DIRB), were investigated to provide insights into "redox mediator-iron oxide" interaction in the presence of DIRB. Two pre-incubation reaction systems of the "strain S12- goethite" and the "strain S12-AQS" were used to investigate the dynamics of goethite reduction and AQS redox transformation. Results show that the concentrations of goethite and redox mediator, and the inoculation cell density all affect the characteristics of microbial goethite reduction, kinetic transformation between oxidized and reduced species of the redox mediator. Both abiotic and biotic reactions and their coupling regulate the kinetic process for "Quinone-Iron" interaction in the presence of DIRB. Our results provide some new insights into the characteristics and mechanisms of interaction among "quinone-DIRB- goethite" under biotic/abiotic driven.

STEM Analysis of Caenorhabditis elegans muscle thick filaments: evidence for microdifferentiated substructures

NASA Technical Reports Server (NTRS)

Muller, S. A.; Haner, M.; Ortiz, I.; Aebi, U.; Epstein, H. F.

2001-01-01

In the thick filaments of body muscle in Caenorhabditis elegans, myosin A and myosin B isoforms and a subpopulation of paramyosin, a homologue of myosin heavy chain rods, are organized about a tubular core. As determined by scanning transmission electron microscopy, the thick filaments show a continuous decrease in mass-per-length (MPL) from their central zones to their polar regions. This is consistent with previously reported morphological studies and suggests that both their content and structural organization are microdifferentiated as a function of position. The cores are composed of a second distinct subpopulation of paramyosin in association with the alpha, beta, and gamma-filagenins. MPL measurements suggest that cores are formed from seven subfilaments containing four strands of paramyosin molecules, rather than the two originally proposed. The periodic locations of the filagenins within different regions and the presence of a central zone where myosin A is located, implies that the cores are also microdifferentiated with respect to molecular content and structure. This differentiation may result from a novel "induced strain" assembly mechanism based upon the interaction of the filagenins, paramyosin and myosin A. The cores may then serve as "differentiated templates" for the assembly of myosin B and paramyosin in the tapering, microdifferentiated polar regions of the thick filaments.

BAD-LAMP defines a subset of early endocytic organelles in subpopulations of cortical projection neurons.

PubMed

David, Alexandre; Tiveron, Marie-Catherine; Defays, Axel; Beclin, Christophe; Camosseto, Voahirana; Gatti, Evelina; Cremer, Harold; Pierre, Philippe

2007-01-15

The brain-associated LAMP-like molecule (BAD-LAMP) is a new member of the family of lysosome associated membrane proteins (LAMPs). In contrast to other LAMPs, which show a widespread expression, BAD-LAMP expression in mice is confined to the postnatal brain and therein to neuronal subpopulations in layers II/III and V of the neocortex. Onset of expression strictly parallels cortical synaptogenesis. In cortical neurons, the protein is found in defined clustered vesicles, which accumulate along neurites where it localizes with phosphorylated epitopes of neurofilament H. In primary neurons, BAD-LAMP is endocytosed, but is not found in classical lysosomal/endosomal compartments. Modification of BAD-LAMP by addition of GFP revealed a cryptic lysosomal retention motif, suggesting that the cytoplasmic tail of BAD-LAMP is actively interacting with, or modified by, molecules that promote its sorting away from lysosomes. Analysis of BAD-LAMP endocytosis in transfected HeLa cells provided evidence that the protein recycles to the plasma membrane through a dynamin/AP2-dependent mechanism. Thus, BAD-LAMP is an unconventional LAMP-like molecule and defines a new endocytic compartment in specific subtypes of cortical projection neurons. The striking correlation between the appearance of BAD-LAMP and cortical synatogenesis points towards a physiological role of this vesicular determinant for neuronal function.

Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges

PubMed Central

Saxena, Amit; Russo, Ilaria; Frangogiannis, Nikolaos G

2015-01-01

In the infarcted myocardium, necrotic cardiomyocytes release danger signals, activating an intense inflammatory response. Inflammatory pathways play a crucial role in regulation of a wide range of cellular processes involved in injury, repair and remodeling of the infarcted heart. Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin (IL)-1, are markedly upregulated in the infarcted myocardium and promote adhesive interactions between endothelial cells and leukocytes, by stimulating chemokine and adhesion molecule expression. Distinct chemokine/chemokine receptor pairs are implicated in recruitment of various leukocyte subpopulations in the infarcted myocardium. Over the last 30 years, extensive experimental work has explored the role of inflammatory signals and the contributions of leukocyte subpopulations, in myocardial infarction. Robust evidence derived from experimental models of myocardial infarction has identified inflammatory targets that may attenuate cardiomyocyte injury, or protect from adverse remodeling. Unfortunately, attempts to translate the promising experimental findings to clinical therapy have failed. This review manuscript discusses the biology of the inflammatory response following myocardial infarction, attempts to identify the causes for the translational failures of the past, and proposes promising new therapeutic directions. Because of their potential involvement in injurious, reparative and regenerative responses, inflammatory cells may hold the key for design of new therapies in myocardial infarction. PMID:26241027

Ecology of Florida black bears in the Okefenokee-Osceola ecosystem

USGS Publications Warehouse

Dobey, S.; Masters, D.V.; Scheick, B.K.; Clark, J.D.; Pelton, M.R.; Sunquist, M.E.

2005-01-01

The U.S. Fish and Wildlife Service (USFWS) concluded in 1998 that listing the Florida black bear as threatened under the Endangered Species Act of 1973 was not warranted. That decision was largely based on the stability and protection afforded to a few subpopulations within the range of the subspecies, which includes the Okefenokee-Osceola subpopulation; our results support that conclusion. However, we suggest that metapopulation processes among the various subpopulations be given greater consideration, with the ultimate goal of managing the sub-species as a unit rather than as an assemblage of independent components. Our study illustrates the importance of travel corridors for maintaining metapopulation processes.

Social interaction in type 2 diabetes computer-mediated environments: How inherent features of the channels influence peer-to-peer interaction.

PubMed

Lewinski, Allison A; Fisher, Edwin B

2016-06-01

Interventions via the internet provide support to individuals managing chronic illness. The purpose of this integrative review was to determine how the features of a computer-mediated environment influence social interactions among individuals with type 2 diabetes. A combination of MeSH and keyword terms, based on the cognates of three broad groupings: social interaction, computer-mediated environments, and chronic illness, was used to search the PubMed, PsychInfo, Sociology Research Database, and Cumulative Index to Nursing and Allied Health Literature databases. Eleven articles met the inclusion criteria. Computer-mediated environments enhance an individual's ability to interact with peers while increasing the convenience of obtaining personalized support. A matrix, focused on social interaction among peers, identified themes across all articles, and five characteristics emerged: (1) the presence of synchronous and asynchronous communication, (2) the ability to connect with similar peers, (3) the presence or absence of a moderator, (4) personalization of feedback regarding individual progress and self-management, and (5) the ability of individuals to maintain choice during participation. Individuals interact with peers to obtain relevant, situation-specific information and knowledge about managing their own care. Computer-mediated environments facilitate the ability of individuals to exchange this information despite temporal or geographical barriers that may be present, thus improving T2D self-management. © The Author(s) 2015.

Assessing mediation using marginal structural models in the presence of confounding and moderation

PubMed Central

Coffman, Donna L.; Zhong, Wei

2012-01-01

This paper presents marginal structural models (MSMs) with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW can be used to take confounding into account, but IPW has several advantages. Regression adjustment of even one confounder of the mediator and outcome that has been influenced by treatment results in biased estimates of the direct effect (i.e., the effect of treatment on the outcome that does not go through the mediator). One advantage of IPW is that it can properly adjust for this type of confounding, assuming there are no unmeasured confounders. Further, we illustrate that IPW estimation provides unbiased estimates of all effects when there is a baseline moderator variable that interacts with the treatment, when there is a baseline moderator variable that interacts with the mediator, and when the treatment interacts with the mediator. IPW estimation also provides unbiased estimates of all effects in the presence of non-randomized treatments. In addition, for testing mediation we propose a test of the null hypothesis of no mediation. Finally, we illustrate this approach with an empirical data set in which the mediator is continuous, as is often the case in psychological research. PMID:22905648

Assessing mediation using marginal structural models in the presence of confounding and moderation.

PubMed

Coffman, Donna L; Zhong, Wei

2012-12-01

This article presents marginal structural models with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW can be used to take confounding into account, but IPW has several advantages. Regression adjustment of even one confounder of the mediator and outcome that has been influenced by treatment results in biased estimates of the direct effect (i.e., the effect of treatment on the outcome that does not go through the mediator). One advantage of IPW is that it can properly adjust for this type of confounding, assuming there are no unmeasured confounders. Further, we illustrate that IPW estimation provides unbiased estimates of all effects when there is a baseline moderator variable that interacts with the treatment, when there is a baseline moderator variable that interacts with the mediator, and when the treatment interacts with the mediator. IPW estimation also provides unbiased estimates of all effects in the presence of nonrandomized treatments. In addition, for testing mediation we propose a test of the null hypothesis of no mediation. Finally, we illustrate this approach with an empirical data set in which the mediator is continuous, as is often the case in psychological research. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Inhibitory Smads and bone morphogenetic protein (BMP) modulate anterior photoreceptor cell number during planarian eye regeneration.

PubMed

González-Sastre, Alejandro; Molina, Ma Dolores; Saló, Emili

2012-01-01

Planarians represent an excellent model to study the processes of body axis and organ re-specification during regeneration. Previous studies have revealed a conserved role for the bone morphogenetic protein (BMP) pathway and its intracellular mediators Smad1/5/8 and Smad4 in planarian dorsoventral (DV) axis re-establishment. In an attempt to gain further insight into the role of this signalling pathway in planarians, we have isolated and functionally characte-rized the inhibitory Smads (I-Smads) in Schmidtea mediterranea. Two I-Smad homologues have been identified: Smed-smad6/7-1 and Smed-smad6/7-2. Expression of smad6/7-1 was detected in the parenchyma, while smad6/7-2 was found to be ex-pressed in the central nervous system and the eyes. Neither single smad6/7-1 and smad6/7-2 nor double smad6/7-1,-2 silencing gave rise to any apparent disruption of the DV axis. However, both regenerating and intact smad6/7-2 (RNAi) planarians showed defects in eye morphogenesis and displayed small, rounded eyes that lacked the anterior subpopulation of photoreceptor cells. The number of pigment cells was also reduced in these animals at later stages of regeneration. In contrast, after low doses of Smed-bmp(RNAi), planarians regenerated larger eyes in which the anterior subpopulation of photoreceptor cells was expanded. Our results suggest that Smed-smad6/7-2 and Smed-bmp control the re-specification and maintenance of anterior photoreceptor cell number in S. mediterranea.

CD8αβ+ γδ T Cells: A Novel T Cell Subset with a Potential Role in Inflammatory Bowel Disease.

PubMed

Kadivar, Mohammad; Petersson, Julia; Svensson, Lena; Marsal, Jan

2016-12-15

γδ T cells have been attributed a wide variety of functions, which in some cases may appear as contradictory. To better understand the enigmatic biology of γδ T cells it is crucial to define the constituting subpopulations. γδ T cells have previously been categorized into two subpopulations: CD8αα + and CD8 - cells. In this study we have defined and characterized a novel subset of human γδ T-cells expressing CD8αβ. These CD8αβ + γδ T cells differed from the previously described γδ T cell subsets in several aspects, including the degree of enrichment within the gut mucosa, the activation status in blood, the type of TCRδ variant used in blood, and small but significant differences in their response to IL-2 stimulation. Furthermore, the novel subset expressed cytotoxic mediators and CD69, and produced IFN-γ and TNF-α. In patients with active inflammatory bowel disease the mucosal frequencies of CD8αβ + γδ T cells were significantly lower as compared with healthy controls, correlated negatively with the degree of disease activity, and increased to normal levels as a result of anti-TNF-α therapy. In conclusion, our results demonstrate that CD8αβ + γδ T cells constitute a novel lymphocyte subset, which is strongly enriched within the gut and may play an important role in gut homeostasis and mucosal healing in inflammatory bowel disease. Copyright © 2016 by The American Association of Immunologists, Inc.

Epidermal cell-shape regulation and subpopulation kinetics during butyrate-induced terminal maturation of normal and SV40-transformed human keratinocytes: epithelial models of differentiation therapy.

PubMed

Staiano-Coico, L; Steinberg, M; Higgins, P J

1990-10-15

Recent data indicate that malignant human epidermal cells may be appropriate targets for sodium butyrate (NaB)-mediated differentiation therapy. The response of pre- and post-crisis populations of SV40-transformed human keratinocytes (SVKs) to this differentiation-inducing agent was assessed, therefore, within the framework of NaB-directed normal human keratinocyte (NHK) maturation. NaB augmented cornified envelope (CE) production in NHK and pre-crisis SVK cultures; the time-course and efficiency of induced maturation were similar in the 2 cell systems. In NHKs, the percentage of amplifying ("B" substate) cells decreased with time in NaB correlating with increases in both "C" stage keratinocytes and CEs. The latter formed over one or 2 layers of nucleated basal-like cells. Inductions were accompanied by immediate cell cycle blocks (in both the G1 and G2/M phases), reorganization within the actin cytoskeleton, and transient early increases in cellular actin content. Increased NHK and pre-crisis SVK cytoskeletal-associated actin reached a maximum approximately 48 hr after NaB addition and preceded development of CEs. The CE precursors, thus, probably reside in the "B" substate. Post-crisis SVKs, in contrast, were refractive to NaB-induced terminal maturation or cell-cycle perturbation, failed to initiate actin filament rearrangements, and retained a basal cell-like phenotype. Stable transformation of human SVKs in post-crisis phase, therefore, appears to be associated with loss of maturation "competence" within the "B" keratinocyte subpopulation.

Unopposed Estrogen Supplementation/Progesterone Deficiency in Post-Reproductive Age Affects the Secretory Profile of Resident Macrophages in a Tissue-Specific Manner in the Rat.

PubMed

Stanojević, Stanislava; Kovačević-Jovanović, Vesna; Dimitrijević, Mirjana; Vujić, Vesna; Ćuruvija, Ivana; Blagojević, Veljko; Leposavić, Gordana

2015-11-01

The influence of unopposed estrogen replacement/isolated progesterone deficiency on macrophage production of pro-inflammatory/anti-inflammatory mediators in the post-reproductive age was studied. Considering that in the rats post-ovariectomy the circulating estradiol, but not progesterone level rises to the values in sham-operated controls, 20-month-old rats ovariectomized at the age of 10 months served as an experimental model. Estrogen and progesterone receptor expression, secretion of pro- and anti-inflammatory cytokines, and arginine metabolism end-products were examined in splenic and peritoneal macrophages under basal conditions and following lipopolysaccharide (LPS) stimulation in vitro. Almost all peritoneal and a subset of splenic macrophages expressed the intracellular progesterone receptor. Ovariectomy diminished cytokine production by splenic (IL-1β) and peritoneal (TNF-α, IL-1β, IL-10) macrophages and increased the production of IL-10 by splenic and TGF-β by peritoneal cells under basal conditions. Following LPS stimulation, splenic macrophages from ovariectomized rats produced less TNF-α and more IL-10, whereas peritoneal macrophages produced less IL-1β and TGF-β than the corresponding cells from sham-operated rats. Ovariectomy diminished urea production in both subpopulations of LPS-stimulated macrophages. Although long-lasting isolated progesterone deficiency in the post-reproductive age differentially affects cytokine production in the macrophages from distinct tissue compartments, in both subpopulations, it impairs the pro-inflammatory/anti-inflammatory cytokine secretory balance. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intestinal lymphangiectasia and thymic hypoplasia.

PubMed Central

Sorensen, R U; Halpin, T C; Abramowsky, C R; Hornick, D L; Miller, K M; Naylor, P; Incefy, G S

1985-01-01

We have evaluated the immunological abnormalities present in a 6 year old patient with primary intestinal and generalized lymphangiectasia confirmed by intestinal, lung and lymph node biopsies. Lymphocyte loss through the gut was confirmed by the detection of lymphocytes in her stool. An increased enteric protein loss was suggested by hypoproteinaemia, peripheral oedema, and a very short half-life for i.v. immune serum globulin (3 days). Lymphocyte subpopulation analysis revealed a selective loss of T lymphocytes, with a proportionally increased loss of the OKT4 positive helper/inducer subpopulation. Functionally, there was a decrease in proliferative responses to some mitogens and to allogeneic cells, and a lack of T cell help for in vitro B lymphocyte differentiation into immunoglobulin secreting cells. Natural killer function was normal. In this patient, a concomitant thymic deficiency was documented by failure to identify thymic tissue on a thymus biopsy and by an absence or decrease of the serum thymic factor (thymulin) and thymosin alpha 1. No compensatory lymphopoiesis was detected in the bone marrow. In an attempt to increase T lymphocyte development, the patient was treated with thymosin fraction 5. Daily treatment with this preparation resulted in a transient clinical improvement which could not be sustained on a weekly thymosin treatment schedule. However, lymphocyte numbers did not increase during this treatment. The findings in this patient support the notion that T lymphocytes are needed to stimulate thymic epithelium. In situations of excessive loss of long lived T lymphocytes a secondary thymic atrophy may occur and further contribute to the development of a deficiency in cell-mediated immunity. Images Fig. 1 Fig. 2 PMID:3971596

Microbial secondary metabolites and their impacts on insect symbioses.

PubMed

Klassen, Jonathan L

2014-10-01

All insects host communities of microbes that interact both with the insect and each other. Secondary metabolites are understood to mediate many of these interactions, although examples having robust genetic, chemical and/or ecological evidence are relatively rare. Here, I review secondary metabolites mediating community interactions in the beewolf, entomopathogenic nematode and fungus-growing ant symbioses, using the logic of Koch's postulates to emphasize well-validated symbiotic functions mediated by these metabolites. I especially highlight how these interaction networks are structured by both ecological and evolutionary processes, and how selection acting on secondary metabolite production can be multidimensional. Copyright © 2014 Elsevier Inc. All rights reserved.

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

PubMed

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Low but significant genetic differentiation underlies biologically meaningful phenotypic divergence in a large Atlantic salmon population.

PubMed

Aykanat, Tutku; Johnston, Susan E; Orell, Panu; Niemelä, Eero; Erkinaro, Jaakko; Primmer, Craig R

2015-10-01

Despite decades of research assessing the genetic structure of natural populations, the biological meaning of low yet significant genetic divergence often remains unclear due to a lack of associated phenotypic and ecological information. At the same time, structured populations with low genetic divergence and overlapping boundaries can potentially provide excellent models to study adaptation and reproductive isolation in cases where high-resolution genetic markers and relevant phenotypic and life history information are available. Here, we combined single nucleotide polymorphism (SNP)-based population inference with extensive phenotypic and life history data to identify potential biological mechanisms driving fine-scale subpopulation differentiation in Atlantic salmon (Salmo salar) from the Teno River, a major salmon river in Europe. Two sympatrically occurring subpopulations had low but significant genetic differentiation (FST  = 0.018) and displayed marked differences in the distribution of life history strategies, including variation in juvenile growth rate, age at maturity and size within age classes. Large, late-maturing individuals were virtually absent from one of the two subpopulations, and there were significant differences in juvenile growth rates and size at age after oceanic migration between individuals in the respective subpopulations. Our findings suggest that different evolutionary processes affect each subpopulation and that hybridization and subsequent selection may maintain low genetic differentiation without hindering adaptive divergence. © 2015 John Wiley & Sons Ltd.

Adaptive designs for subpopulation analysis optimizing utility functions.

PubMed

Graf, Alexandra C; Posch, Martin; Koenig, Franz

2015-01-01

If the response to treatment depends on genetic biomarkers, it is important to identify predictive biomarkers that define (sub-)populations where the treatment has a positive benefit risk balance. One approach to determine relevant subpopulations are subgroup analyses where the treatment effect is estimated in biomarker positive and biomarker negative groups. Subgroup analyses are challenging because several types of risks are associated with inference on subgroups. On the one hand, by disregarding a relevant subpopulation a treatment option may be missed due to a dilution of the treatment effect in the full population. Furthermore, even if the diluted treatment effect can be demonstrated in an overall population, it is not ethical to treat patients that do not benefit from the treatment when they can be identified in advance. On the other hand, selecting a spurious subpopulation increases the risk to restrict an efficacious treatment to a too narrow fraction of a potential benefiting population. We propose to quantify these risks with utility functions and investigate nonadaptive study designs that allow for inference on subgroups using multiple testing procedures as well as adaptive designs, where subgroups may be selected in an interim analysis. The characteristics of such adaptive and nonadaptive designs are compared for a range of scenarios. © 2014 The Authors. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Differential Properties of Human ALP+ Periodontal Ligament Stem Cells vs Their ALP- Counterparts

PubMed Central

Tran, Quynh T; El-Ayachi, Ikbale; Bhatti, Fazal-Ur-Rehman; Bahabri, Rayan; Al-Habib, Mey; Huang, George TJ

2015-01-01

Characterizing subpopulations of stem cells is important to understand stem cell properties. Tissue-nonspecific alkaline phosphatase (ALP) is associated with mineral tissue forming cells as well as stem cells. Information regarding ALP subpopulation of human periodontal ligament stem cells (hPDLSCs) is limited. In the present study, we examined ALP+ and ALP− hPDLSC subpopulations, their surface markers STRO-1 and CD146, and the expression of stemness genes at various cell passages. We found that ALP+ subpopulation had higher levels of STRO-1 (30.6 ± 5.6%) and CD146 (90.4 ± 3.3%) compared to ALP− (STRO-1: 0.5 ± 0.1%; CD146: 75.3 ± 7.2%). ALP+ cells expressed significantly higher levels of stemness associated genes, NANOG, OCT4 and SOX than ALP− cells at low cell passages of 2-3 (p<0.05). ALP+ and ALP− cells had similar osteogenic, chondrogenic and neurogenic potential while ALP−, not ALP+ cells, lacked adipogenic potential. Upon continuous culturing and passaging, ALP+ continued to express higher stemness genes and STRO-1 and CD146 than ALP− cells at ≥passage 19. Under conditions (over-confluence and vitamin C treatment) when ALP+ subpopulation was increased, the stemness gene levels of ALP+ was no longer significantly higher than those in ALP− cells. In conclusion, ALP+ hPDLSCs possess differential properties from their ALP− counterparts. PMID:26807329

Variations of B cell subpopulations in peripheral blood of healthy Mexican population according to age: Relevance for diagnosis of primary immunodeficiencies.

PubMed

Berrón-Ruíz, L; López-Herrera, G; Ávalos-Martínez, C E; Valenzuela-Ponce, C; Ramírez-SanJuan, E; Santoyo-Sánchez, G; Mújica Guzmán, F; Espinosa-Rosales, F J; Santos-Argumedo, L

Peripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population. Peripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naïve, memory with and without isotype switch, double-negative, transitional, and plasmablast cells. We observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age. In order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected. Copyright © 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Geographic variation and genetic structure in the Bahama Oriole (Icterus northropi), a critically endangered synanthropic species

PubMed Central

Person, Carl; Hayes, William K.

2015-01-01

Bird species may exhibit unexpected population structuring over small distances, with gene flow restricted by geographic features such as water or mountains. The Bahama Oriole (Icterus northropi) is a critically endangered, synanthropic island endemic with a declining population of fewer than 300 individuals. It now remains only on Andros Island (The Bahamas), which is riddled with waterways that past studies assumed did not hinder gene flow. We examined 1,858 base pairs of mitochondrial DNA sequenced from four gene regions in 14 birds (roughly 5% of the remaining population) found on the largest land masses of Andros Island (North Andros and Mangrove Cay/South Andros). We sought to discern genetic structuring between the remaining subpopulations and its relationship to current conservation concerns. Four unique haplotypes were identified, with only one shared between the two subpopulations. Nucleotide and haplotype diversity were higher for the North Andros subpopulation than for the Mangrove Cay/South Andros subpopulation. Analysis of molecular variance (AMOVA) yielded a Wright’s fixation index (Fst) of 0.60 (PFst = 0.016), with 40.2% of the molecular variation explained by within-population differences and 59.8% by among-population differences. Based on the mitochondrial regions examined in this study, we suggest the extant subpopulations of Bahama Oriole exhibit significant population structuring over short distances, consistent with some other non-migratory tropical songbird species. PMID:26644974

Collider study on the loop-induced dark matter mediation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsai, Yuhsin, E-mail: yhtsai@umd.edu

2016-06-21

Collider experiments are one of the most promising ways to constrain Dark Matter (DM) interactions. For DM couplings involving light mediators, especially for the loop-mediated interactions, a meaningful interpretation of the results requires to go beyond effective field theory. In this note we discuss the study of the magnetic dipole interacting DM, focusing on a model with anarchic dark flavor structure. By including the momentum-dependent form factors that mediate the coupling – given by the Dark Penguin – in collider processes, we study bounds from monophoton, diphoton, and non-pointing photon searches at the LHC. We also compare our results tomore » constraints from the direct detection experiments.« less

Siblings' mediated learning strategies in families with and without children with intellectual disabilities.

PubMed

Tzuriel, David; Hanuka-Levy, Dikla

2014-11-01

Dyads of siblings in which the younger sibling had an intellectual disability (ID, n  =  25) were videotaped interacting. The ID group was compared with typically developing sibling dyads matched on mental age (n  =  25) and chronological age (n  =  25). We observed the mediation strategies, activation, and antimediation behaviors of older siblings and younger siblings' responsiveness to mediation. Mediation strategies were analyzed by the Observation of Mediation Interaction scale. The ID group scored highest on mediation strategies and lowest on activation and antimediation behaviors. Younger siblings' responsiveness to mediation was highest among the ID group. Mediation for Intentionality and Reciprocity and Meaning were positively associated with the verbal responsiveness of the younger siblings. Activation and antimediation behaviors were negatively associated with the verbal responsiveness.

Communicative interactions involving plants: information, evolution, and ecology.

PubMed

Mescher, Mark C; Pearse, Ian S

2016-08-01

The role of information obtained via sensory cues and signals in mediating the interactions of organisms with their biotic and abiotic environments has been a major focus of work on sensory and behavioral ecology. Information-mediated interactions also have important implications for broader ecological patterns emerging at the community and ecosystem levels that are only now beginning to be explored. Given the extent to which plants dominate the sensory landscapes of terrestrial ecosystems, information-mediated interactions involving plants should be a major focus of efforts to elucidate these broader patterns. Here we explore how such efforts might be enhanced by a clear understanding of information itself-a central and potentially unifying concept in biology that has nevertheless been the subject of considerable confusion-and of its relationship to adaptive evolution and ecology. We suggest that information-mediated interactions should be a key focus of efforts to more fully integrate evolutionary biology and ecology. Copyright © 2016 Elsevier Ltd. All rights reserved.

PREDICTIVE ORGANOPHOSPHORUS (OP) PESTICIDE QSARS AND PBPK/PD MODELS FOR RISK ASSESSMENT OF SUSCEPTIBLE SUB-POPULATIONS

EPA Science Inventory

Successful use of the Exposure Related Dose Estimating Model (ERDEM) in risk assessment of susceptible human sub-populations, e.g., infants and children, requires input of quality experimental data. In the clear absence of quality data, PBPK models can be developed and possibl...

The Impact of Missing Background Data on Subpopulation Estimation

ERIC Educational Resources Information Center

Rutkowski, Leslie

2011-01-01

Although population modeling methods are well established, a paucity of literature appears to exist regarding the effect of missing background data on subpopulation achievement estimates. Using simulated data that follows typical large-scale assessment designs with known parameters and a number of missing conditions, this paper examines the extent…

Predicting Parental Mediation Behaviors: The Direct and Indirect Influence of Parents' Critical Thinking about Media and Attitudes about Parent-Child Interactions

ERIC Educational Resources Information Center

Rasmussen, Eric C.; White, Shawna R.; King, Andy J.; Holiday, Steven; Densley, Rebecca L.

2016-01-01

Many parents fail to interact with their children regularly about media content and past research has identified few predictors of parents' engagement in parental mediation behaviors. This correlational study explored the relationship between parents' critical thinking about media and parents' provision of both active and restrictive mediation of…

Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair.

PubMed

Tilokee, Everad L; Latham, Nicholas; Jackson, Robyn; Mayfield, Audrey E; Ye, Bin; Mount, Seth; Lam, Buu-Khanh; Suuronen, Erik J; Ruel, Marc; Stewart, Duncan J; Davis, Darryl R

2016-07-01

First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal-cell derived factor 1α, which opens the prospect of maximizing up-front paracrine-mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal-cell derived factor 1α. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal-cell derived factor 1α over-expression prevented lv-mediated "loss of cytokines" through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal-cell derived factor 1α enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal-cell derived factor 1α enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal-cell derived factor 1α content paralleled reductions in myocyte apoptosis but did not influence long-term engraftment or the fate of transplanted cells. Transplantation of stromal-cell derived factor 1α transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction. Stem Cells 2016;34:1826-1835. © 2016 AlphaMed Press.

Genome-wide scans between two honeybee populations reveal putative signatures of human-mediated selection.

PubMed

Parejo, M; Wragg, D; Henriques, D; Vignal, A; Neuditschko, M

2017-12-01

Human-mediated selection has left signatures in the genomes of many domesticated animals, including the European dark honeybee, Apis mellifera mellifera, which has been selected by apiculturists for centuries. Using whole-genome sequence information, we investigated selection signatures in spatially separated honeybee subpopulations (Switzerland, n = 39 and France, n = 17). Three different test statistics were calculated in windows of 2 kb (fixation index, cross-population extended haplotype homozygosity and cross-population composite likelihood ratio) and combined into a recently developed composite selection score. Applying a stringent false discovery rate of 0.01, we identified six significant selective sweeps distributed across five chromosomes covering eight genes. These genes are associated with multiple molecular and biological functions, including regulation of transcription, receptor binding and signal transduction. Of particular interest is a selection signature on chromosome 1, which corresponds to the WNT4 gene, the family of which is conserved across the animal kingdom with a variety of functions. In Drosophila melanogaster, WNT4 alleles have been associated with differential wing, cross vein and abdominal phenotypes. Defining phenotypic characteristics of different Apis mellifera ssp., which are typically used as selection criteria, include colour and wing venation pattern. This signal is therefore likely to be a good candidate for human mediated-selection arising from different applied breeding practices in the two managed populations. © 2017 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.

Restricted amide rotation with steric hindrance induced multiple conformations

NASA Astrophysics Data System (ADS)

Krishnan, V. V.; Vazquez, Salvador; Maitra, Kalyani; Maitra, Santanu

2017-12-01

The Csbnd N bond character is dependent directly upon the resonance-contributor structure population driven by the delocalized nitrogen lone-pair of electrons. In the case of N, N-dibenzyl-ortho-toluamide (o-DBET), the molecule adopts subpopulations of conformers with distinct NMR spectral features, particularly at low temperatures. This conformational adaptation is unique to o-DBET, while the corresponding meta- and para- forms do not show such behavior. Variable-temperature (VT) NMR, two-dimensional exchange spectroscopy (EXSY), and qualitative molecular modeling studies are used to demonstrate how multiple competing interactions such as restricted amide rotation and steric hindrance effects can lead to versatile molecular adaptations in the solution state.

Blockade of invariant TCR-CD1d interaction specifically inhibits antibody production against blood group A carbohydrates

PubMed Central

Tazawa, Hirofumi; Irei, Toshimitsu; Tanaka, Yuka; Igarashi, Yuka; Tashiro, Hirotaka

2013-01-01

Previously, we detected B cells expressing receptors for blood group A carbohydrates in the CD11b+CD5+ B-1a subpopulation in mice, similar to that in blood group O or B in humans. In the present study, we demonstrate that CD1d-restricted natural killer T (NKT) cells are required to produce anti-A antibodies (Abs), probably through collaboration with B-1a cells. After immunization of wild-type (WT) mice with human blood group A red blood cells (A-RBCs), interleukin (IL)-5 exclusively and transiently increased and the anti-A Abs were elevated in sera. However, these reactions were not observed in CD1d−/− mice, which lack NKT cells. Administration of anti-mouse CD1d blocking monoclonal Abs (mAb) prior to immunization abolished IL-5 production by NKT cells and anti-A Ab production in WT mice. Administration of anti-IL-5 neutralizing mAb also diminished anti-A Ab production in WT mice, suggesting that IL-5 secreted from NKT cells critically regulates anti-A Ab production by B-1a cells. In nonobese diabetic/severe combined immunodeficient (NOD/SCID/γcnull) mice, into which peripheral blood mononuclear cells from type O human volunteers were engrafted, administration of anti-human CD1d mAb prior to A-RBC immunization completely inhibited anti-A Ab production. Thus, anti-CD1d treatment might constitute a novel approach that could help in evading Ab-mediated rejection in ABO-incompatible transplant recipients. PMID:23943651

Stability and dynamic of strain mediated adatom superlattices on Cu<111 >

NASA Astrophysics Data System (ADS)

Kappus, Wolfgang

2013-03-01

Substrate strain mediated adatom equilibrium density distributions have been calculated for Cu<111 > surfaces using two complementing methods. A hexagonal adatom superlattice in a coverage range up to 0.045 ML is derived for repulsive short range interactions. For zero short range interactions a hexagonal superstructure of adatom clusters is derived in a coverage range about 0.08 ML. Conditions for the stability of the superlattice against formation of dimers or clusters and degradation are analyzed using simple neighborhood models. Such models are also used to investigate the dynamic of adatoms within their superlattice neighborhood. Collective modes of adatom diffusion are proposed from the analogy with bulk lattice dynamics and methods for measurement are suggested. The recently put forward explanation of surface state mediated interactions for superstructures found in scanning tunneling microscopy experiments is put in question and strain mediated interactions are proposed as an alternative.

Two Impurities in a Bose-Einstein Condensate: From Yukawa to Efimov Attracted Polarons

NASA Astrophysics Data System (ADS)

Naidon, Pascal

2018-04-01

The well-known Yukawa and Efimov potentials are two different mediated interaction potentials. The first one arises in quantum field theory from the exchange of virtual particles. The second one is mediated by a real particle resonantly interacting with two other particles. This Letter shows how two impurities immersed in a Bose-Einstein condensate can exhibit both phenomena. For a weak attraction with the condensate, the two impurities form two polarons that interact through a weak Yukawa attraction mediated by virtual excitations. For a resonant attraction with the condensate, the exchanged excitation becomes a real boson and the mediated interaction changes to a strong Efimov attraction that can bind the two polarons. The resulting bipolarons turn into in-medium Efimov trimers made of the two impurities and one boson. Evidence of this physics could be seen in ultracold mixtures of atoms.

A conserved Mediator–CDK8 kinase module association regulates Mediator–RNA polymerase II interaction

PubMed Central

Tsai, Kuang-Lei; Sato, Shigeo; Tomomori-Sato, Chieri; Conaway, Ronald C.; Conaway, Joan W.; Asturias, Francisco J.

2013-01-01

The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a preeminent complex in eukaryotic transcription regulation. We used macromolecular electron microscopy and biochemistry to investigate the subunit organization, structure, and Mediator interaction of the Saccharomyces cerevisiae CKM. We found that interaction of the CKM with Mediator’s Middle module interferes with CTD-dependent RNAPII binding to a previously unknown Middle module CTD-binding site targeted early on in a multi-step holoenzyme formation process. Taken together, our results reveal the basis for CKM repression, clarify the origin of the connection between CKM subunits and the CTD, and suggest that a combination of competitive interactions and conformational changes that facilitate holoenzyme formation underlie the Mediator mechanism. PMID:23563140

Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros

PubMed Central

Valeri, Linda; VanderWeele, Tyler J.

2012-01-01

Mediation analysis is a useful and widely employed approach to studies in the field of psychology and in the social and biomedical sciences. The contributions of this paper are several-fold. First we seek to bring the developments in mediation analysis for non linear models within the counterfactual framework to the psychology audience in an accessible format and compare the sorts of inferences about mediation that are possible in the presence of exposure-mediator interaction when using a counterfactual versus the standard statistical approach. Second, the work by VanderWeele and Vansteelandt (2009, 2010) is extended here to allow for dichotomous mediators and count outcomes. Third, we provide SAS and SPSS macros to implement all of these mediation analysis techniques automatically and we compare the types of inferences about mediation that are allowed by a variety of software macros. PMID:23379553

Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros.

PubMed

Valeri, Linda; Vanderweele, Tyler J

2013-06-01

Mediation analysis is a useful and widely employed approach to studies in the field of psychology and in the social and biomedical sciences. The contributions of this article are several-fold. First we seek to bring the developments in mediation analysis for nonlinear models within the counterfactual framework to the psychology audience in an accessible format and compare the sorts of inferences about mediation that are possible in the presence of exposure-mediator interaction when using a counterfactual versus the standard statistical approach. Second, the work by VanderWeele and Vansteelandt (2009, 2010) is extended here to allow for dichotomous mediators and count outcomes. Third, we provide SAS and SPSS macros to implement all of these mediation analysis techniques automatically, and we compare the types of inferences about mediation that are allowed by a variety of software macros. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

The Effects of Parent-Child Mediated Learning Experience (MLE) Interaction on Young Children's Cognitive Development

ERIC Educational Resources Information Center

Russell, Christina; Amod, Zaytoon; Rosenthal, Lesley

2008-01-01

This study addressed the effect of parent-child Mediated Learning Experience (MLE) interaction on cognitive development in early childhood. It measured the MLE interactions of 14 parents with their preschool children in the contexts of free-play and structured tasks. The children were assessed for their manifest cognitive performance and learning…

Are We Allowed to Blink? Young Children's Leadership and Ownership while Mediating Interactions around Technologies

ERIC Educational Resources Information Center

Arnott, Lorna

2013-01-01

This article describes the formation of children's social interactions around technologies in preschools. This paper presents evidence from a study that explores how 3- to 5-year-old children construct their social interactions through the mediation of their peers while using technological resources. Utilising a systematic and iterative data…

Tail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo.

PubMed

Jeronimo, Célia; Langelier, Marie-France; Bataille, Alain R; Pascal, John M; Pugh, B Franklin; Robert, François

2016-11-03

Mediator is a highly conserved transcriptional coactivator organized into four modules, namely Tail, Middle, Head, and Kinase (CKM). Previous work suggests regulatory roles for Tail and CKM, but an integrated model for these activities is lacking. Here, we analyzed the genome-wide distribution of Mediator subunits in wild-type and mutant yeast cells in which RNA polymerase II promoter escape is blocked, allowing detection of transient Mediator forms. We found that although all modules are recruited to upstream activated regions (UAS), assembly of Mediator within the pre-initiation complex is accompanied by the release of CKM. Interestingly, our data show that CKM regulates Mediator-UAS interaction rather than Mediator-promoter association. In addition, although Tail is required for Mediator recruitment to UAS, Tailless Mediator nevertheless interacts with core promoters. Collectively, our data suggest that the essential function of Mediator is mediated by Head and Middle at core promoters, while Tail and CKM play regulatory roles. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular imaging of drug-modulated protein-protein interactions in living subjects.

PubMed

Paulmurugan, Ramasamy; Massoud, Tarik F; Huang, Jing; Gambhir, Sanjiv S

2004-03-15

Networks of protein interactions mediate cellular responses to environmental stimuli and direct the execution of many different cellular functional pathways. Small molecules synthesized within cells or recruited from the external environment mediate many protein interactions. The study of small molecule-mediated interactions of proteins is important to understand abnormal signal transduction pathways in cancer and in drug development and validation. In this study, we used split synthetic renilla luciferase (hRLUC) protein fragment-assisted complementation to evaluate heterodimerization of the human proteins FRB and FKBP12 mediated by the small molecule rapamycin. The concentration of rapamycin required for efficient dimerization and that of its competitive binder ascomycin required for dimerization inhibition were studied in cell lines. The system was dually modulated in cell culture at the transcription level, by controlling nuclear factor kappaB promoter/enhancer elements using tumor necrosis factor alpha, and at the interaction level, by controlling the concentration of the dimerizer rapamycin. The rapamycin-mediated dimerization of FRB and FKBP12 also was studied in living mice by locating, quantifying, and timing the hRLUC complementation-based bioluminescence imaging signal using a cooled charged coupled device camera. This split reporter system can be used to efficiently screen small molecule drugs that modulate protein-protein interactions and also to assess drugs in living animals. Both are essential steps in the preclinical evaluation of candidate pharmaceutical agents targeting protein-protein interactions, including signaling pathways in cancer cells.

High-Throughput Fluorescence-Based Isolation of Live C. elegans Larvae

PubMed Central

Fernandez, Anita G.; Bargmann, Bastiaan O. R.; Mis, Emily K.; Edgley, Mark. L.; Birnbaum, Kenneth D.; Piano, Fabio

2017-01-01

For the nematode Caenorhabditis elegans, automated selection of animals of specific genotypes from a mixed pool has become essential for genetic interaction or chemical screens. To date, such selection has been accomplished using specialized instruments. However, access to such dedicated equipment is not common. Here we describe live animal fluorescence-activated cell sorting (laFACS), a protocol for automatic selection of live L1 animals using a standard FACS. We show that a FACS can be used for the precise identification of GFP-expressing and non-GFP-expressing sub-populations and can accomplish high-speed sorting of live animals. We have routinely collected 100,000 or more homozygotes from a mixed starting population within two hours and with greater than ninety-nine percent purity. The sorted animals continue to develop normally, making this protocol ideally suited for the isolation of terminal mutants for use in genetic interaction or chemical genetic screens. PMID:22814389

Optimizing Real-Time Vaccine Allocation in a Stochastic SIR Model

PubMed Central

Nguyen, Chantal; Carlson, Jean M.

2016-01-01

Real-time vaccination following an outbreak can effectively mitigate the damage caused by an infectious disease. However, in many cases, available resources are insufficient to vaccinate the entire at-risk population, logistics result in delayed vaccine deployment, and the interaction between members of different cities facilitates a wide spatial spread of infection. Limited vaccine, time delays, and interaction (or coupling) of cities lead to tradeoffs that impact the overall magnitude of the epidemic. These tradeoffs mandate investigation of optimal strategies that minimize the severity of the epidemic by prioritizing allocation of vaccine to specific subpopulations. We use an SIR model to describe the disease dynamics of an epidemic which breaks out in one city and spreads to another. We solve a master equation to determine the resulting probability distribution of the final epidemic size. We then identify tradeoffs between vaccine, time delay, and coupling, and we determine the optimal vaccination protocols resulting from these tradeoffs. PMID:27043931

iELM—a web server to explore short linear motif-mediated interactions

PubMed Central

Weatheritt, Robert J.; Jehl, Peter; Dinkel, Holger; Gibson, Toby J.

2012-01-01

The recent expansion in our knowledge of protein–protein interactions (PPIs) has allowed the annotation and prediction of hundreds of thousands of interactions. However, the function of many of these interactions remains elusive. The interactions of Eukaryotic Linear Motif (iELM) web server provides a resource for predicting the function and positional interface for a subset of interactions mediated by short linear motifs (SLiMs). The iELM prediction algorithm is based on the annotated SLiM classes from the Eukaryotic Linear Motif (ELM) resource and allows users to explore both annotated and user-generated PPI networks for SLiM-mediated interactions. By incorporating the annotated information from the ELM resource, iELM provides functional details of PPIs. This can be used in proteomic analysis, for example, to infer whether an interaction promotes complex formation or degradation. Furthermore, details of the molecular interface of the SLiM-mediated interactions are also predicted. This information is displayed in a fully searchable table, as well as graphically with the modular architecture of the participating proteins extracted from the UniProt and Phospho.ELM resources. A network figure is also presented to aid the interpretation of results. The iELM server supports single protein queries as well as large-scale proteomic submissions and is freely available at http://i.elm.eu.org. PMID:22638578

Characteristics and kinetic analysis of AQS transformation and microbial goethite reduction: Insight into “redox mediator-microbe-iron oxide” interaction process

DOE PAGES

Zhu, Weihuang; Shi, Mengran; Yu, Dan; ...

2016-03-29

Here, the characteristics and kinetics of redox transformation of a redox mediator, anthraquinone-2-sulfonate (AQS), during microbial goethite reduction by Shewanella decolorationis S12, a dissimilatory iron reduction bacterium (DIRB), were investigated to provide insights into “redox mediator-iron oxide” interaction in the presence of DIRB. Two pre-incubation reaction systems of the “strain S12-goethite” and the “strain S12-AQS” were used to investigate the dynamics of goethite reduction and AQS redox transformation. Results show that the concentrations of goethite and redox mediator, and the inoculation cell density all affect the characteristics of microbial goethite reduction, kinetic transformation between oxidized and reduced species of themore » redox mediator. Both abiotic and biotic reactions and their coupling regulate the kinetic process for “Quinone-Iron” interaction in the presence of DIRB. Our results provide some new insights into the characteristics and mechanisms of interaction among “quinone-DIRB- goethite” under biotic/abiotic driven.« less

Correcting Measurement Error in Latent Regression Covariates via the MC-SIMEX Method

ERIC Educational Resources Information Center

Rutkowski, Leslie; Zhou, Yan

2015-01-01

Given the importance of large-scale assessments to educational policy conversations, it is critical that subpopulation achievement is estimated reliably and with sufficient precision. Despite this importance, biased subpopulation estimates have been found to occur when variables in the conditioning model side of a latent regression model contain…

Population dynamics of the endangered Cape Sable seaside-sparrow

USGS Publications Warehouse

Curnutt, J.L.; Mayer, A.L.; Brooks, T.M.; Manne, L.; Bass, O.L.; Fleming, D.M.; Philip, Nott M.; Pimm, S.L.

1998-01-01

The Cape Sable seaside-sparrow (Ammodramus maritimus mirabilis) has disappeared from its only known breeding areas episodically since its discovery early this century. Systematic surveys across its range in the southern Everglades find the sparrow's range to be fragmented into six subpopulations. The sparrow population decreased by 58% between 1992 and 1995, with the near extinction of the western half of the population and the temporary local extinction of some eastern populations. Other similar grassland sparrows have populations that vary considerably from year to year. Yet the decline in the western subpopulation and the local extinction of some of the peripheral populations cannot be explained by natural variability alone. Hurricane Andrew passed over several subpopulations prior to the particularly poor year of 1993. However, the geographical and temporal patterns of subpopulation decline are not consistent with what would be expected following a hurricane. Frequent fires prevent successful breeding as does flooding during the breeding season. Better management can prevent frequent fires and episodic flooding. However, the long-term survival of the sparrow depends on managing the unanticipated risks that attend its small, fragmented population.

A nanobiosensor for dynamic single cell analysis during microvascular self-organization.

PubMed

Wang, S; Sun, J; Zhang, D D; Wong, P K

2016-10-14

The formation of microvascular networks plays essential roles in regenerative medicine and tissue engineering. Nevertheless, the self-organization mechanisms underlying the dynamic morphogenic process are poorly understood due to a paucity of effective tools for mapping the spatiotemporal dynamics of single cell behaviors. By establishing a single cell nanobiosensor along with live cell imaging, we perform dynamic single cell analysis of the morphology, displacement, and gene expression during microvascular self-organization. Dynamic single cell analysis reveals that endothelial cells self-organize into subpopulations with specialized phenotypes to form microvascular networks and identifies the involvement of Notch1-Dll4 signaling in regulating the cell subpopulations. The cell phenotype correlates with the initial Dll4 mRNA expression level and each subpopulation displays a unique dynamic Dll4 mRNA expression profile. Pharmacological perturbations and RNA interference of Notch1-Dll4 signaling modulate the cell subpopulations and modify the morphology of the microvascular network. Taken together, a nanobiosensor enables a dynamic single cell analysis approach underscoring the importance of Notch1-Dll4 signaling in microvascular self-organization.

Flow cytometric techniques for detection of candidate cancer stem cell subpopulations in canine tumour models.

PubMed

Blacking, T M; Waterfall, M; Samuel, K; Argyle, D J

2012-12-01

The cancer stem cell (CSC) hypothesis proposes that tumour growth is maintained by a distinct subpopulation of 'CSC'. This study applied flow cytometric methods, reported to detect CSC in both primary and cultured cancer cells of other species, to identify candidate canine subpopulations. Cell lines representing diverse canine malignancies, and cells derived from spontaneous canine tumours, were evaluated for expression of stem cell-associated surface markers (CD34, CD44, CD117 and CD133) and functional properties [Hoecsht 33342 efflux, aldehyde dehydrogenase (ALDH) activity]. No discrete marker-defined subsets were identified within established cell lines; cells derived directly from spontaneous tumours demonstrated more heterogeneity, although this diminished upon in vitro culture. Functional assays produced variable results, suggesting context-dependency. Flow cytometric methods may be adopted to identify putative canine CSC. Whilst cell lines are valuable in assay development, primary cells may provide a more rewarding model for studying tumour heterogeneity in the context of CSC. However, it will be essential to fully characterize any candidate subpopulations to ensure that they meet CSC criteria. © 2011 Blackwell Publishing Ltd.

Wilms Tumor 1b defines a wound-specific sheath cell subpopulation associated with notochord repair

PubMed Central

Lopez-Baez, Juan Carlos; Zeng, Zhiqiang; Brunsdon, Hannah; Salzano, Angela; Brombin, Alessandro; Wyatt, Cameron; Rybski, Witold; Huitema, Leonie F A; Dale, Rodney M; Kawakami, Koichi; Englert, Christoph; Chandra, Tamir; Schulte-Merker, Stefan

2018-01-01

Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that wt1b+cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. Wt1b+sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, wt1b+and entpd5+ cells constitute separate, tightly-associated subpopulations. Surprisingly, wt1b expression at the site of injury is maintained even into adult stages in developing vertebrae, which form in an untypical manner via a cartilage intermediate. Given that notochord cells are retained in adult intervertebral discs, the identification of novel subpopulations may have important implications for regenerative spine disorder treatments. PMID:29405914

Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

PubMed Central

Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C.

2016-01-01

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/− CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. PMID:26981578

A multipopulation PSO based memetic algorithm for permutation flow shop scheduling.

PubMed

Liu, Ruochen; Ma, Chenlin; Ma, Wenping; Li, Yangyang

2013-01-01

The permutation flow shop scheduling problem (PFSSP) is part of production scheduling, which belongs to the hardest combinatorial optimization problem. In this paper, a multipopulation particle swarm optimization (PSO) based memetic algorithm (MPSOMA) is proposed in this paper. In the proposed algorithm, the whole particle swarm population is divided into three subpopulations in which each particle evolves itself by the standard PSO and then updates each subpopulation by using different local search schemes such as variable neighborhood search (VNS) and individual improvement scheme (IIS). Then, the best particle of each subpopulation is selected to construct a probabilistic model by using estimation of distribution algorithm (EDA) and three particles are sampled from the probabilistic model to update the worst individual in each subpopulation. The best particle in the entire particle swarm is used to update the global optimal solution. The proposed MPSOMA is compared with two recently proposed algorithms, namely, PSO based memetic algorithm (PSOMA) and hybrid particle swarm optimization with estimation of distribution algorithm (PSOEDA), on 29 well-known PFFSPs taken from OR-library, and the experimental results show that it is an effective approach for the PFFSP.

Versatile Action of Picomolar Gradients of Progesterone on Different Sperm Subpopulations

PubMed Central

Uñates, Diego Rafael; Guidobaldi, Héctor Alejandro; Gatica, Laura Virginia; Cubilla, Marisa Angélica; Teves, María Eugenia; Moreno, Ayelén; Giojalas, Laura Cecilia

2014-01-01

High step concentrations of progesterone may stimulate various sperm physiological processes, such as priming and the acrosome reaction. However, approaching the egg, spermatozoa face increasing concentrations of the hormone, as it is secreted by the cumulus cells and then passively diffuses along the cumulus matrix and beyond. In this context, several questions arise: are spermatozoa sensitive to the steroid gradients as they undergo priming and the acrosome reaction? If so, what are the functional gradual concentrations of progesterone? Do spermatozoa in different physiological states respond differentially to steroid gradients? To answer these questions, spermatozoa were confronted with progesterone gradients generated by different hormone concentrations (1 pM to 100 µM). Brief exposure to a 10 pM progesterone gradient stimulated priming for the acrosome reaction in one sperm subpopulation, and simultaneously induced the acrosome reaction in a different sperm subpopulation. This effect was not observed in non-capacitated cells or when progesterone was homogeneously distributed. The results suggest a versatile role of the gradual distribution of very low doses of progesterone, which selectively stimulate the priming and the acrosome reaction in different sperm subpopulations. PMID:24614230

The Origin, Development and Molecular Diversity of Rodent Olfactory Bulb Glutamatergic Neurons Distinguished by Expression of Transcription Factor NeuroD1.

PubMed

Roybon, Laurent; Mastracci, Teresa L; Li, Joyce; Stott, Simon R W; Leiter, Andrew B; Sussel, Lori; Brundin, Patrik; Li, Jia-Yi

2015-01-01

Production of olfactory bulb neurons occurs continuously in the rodent brain. Little is known, however, about cellular diversity in the glutamatergic neuron subpopulation. In the central nervous system, the basic helix-loop-helix transcription factor NeuroD1 (ND1) is commonly associated with glutamatergic neuron development. In this study, we utilized ND1 to identify the different subpopulations of olfactory bulb glutamategic neurons and their progenitors, both in the embryo and postnatally. Using knock-in mice, transgenic mice and retroviral transgene delivery, we demonstrate the existence of several different populations of glutamatergic olfactory bulb neurons, the progenitors of which are ND1+ and ND1- lineage-restricted, and are temporally and regionally separated. We show that the first olfactory bulb glutamatergic neurons produced - the mitral cells - can be divided into molecularly diverse subpopulations. Our findings illustrate the complexity of neuronal diversity in the olfactory bulb and that seemingly homogenous neuronal populations can consist of multiple subpopulations with unique molecular signatures of transcription factors and expressing neuronal subtype-specific markers.

Genetic and morphological characterisation of the Ankole Longhorn cattle in the African Great Lakes region.

PubMed

Ndumu, Deo B; Baumung, Roswitha; Hanotte, Olivier; Wurzinger, Maria; Okeyo, Mwai A; Jianlin, Han; Kibogo, Harrison; Sölkner, Johann

2008-01-01

The study investigated the population structure, diversity and differentiation of almost all of the ecotypes representing the African Ankole Longhorn cattle breed on the basis of morphometric (shape and size), genotypic and spatial distance data. Twentyone morphometric measurements were used to describe the morphology of 439 individuals from 11 sub-populations located in five countries around the Great Lakes region of central and eastern Africa. Additionally, 472 individuals were genotyped using 15 DNA microsatellites. Femoral length, horn length, horn circumference, rump height, body length and fore-limb circumference showed the largest differences between regions. An overall FST index indicated that 2.7% of the total genetic variation was present among sub-populations. The least differentiation was observed between the two sub-populations of Mbarara south and Luwero in Uganda, while the highest level of differentiation was observed between the Mugamba in Burundi and Malagarasi in Tanzania. An estimated membership of four for the inferred clusters from a model-based Bayesian approach was obtained. Both analyses on distance-based and model-based methods consistently isolated the Mugamba sub-population in Burundi from the others.

Why does interactional justice promote organizational loyalty, job performance, and prevent mental impairment? The role of social support and social stressors.

PubMed

Otto, Kathleen; Mamatoglu, Nihal

2015-01-01

Using social exchange theory as a conceptual framework, we investigated the relationship between interactional justice and the outcomes organizational loyalty (affective commitment, turnover intentions), perceived job performance (self-rated performance, personal accomplishment), and mental impairment (cognitive irritation, emotional exhaustion) in an online survey of 218 employees working in the field of computer technology. Specifically, we predicted that interactional justice would heighten the quality of social exchange relationships and therefore expected perceived social support (POS) and bullying to mediate the proposed relationships. We tested our hypotheses applying a latent structural equation model. Our findings revealed that POS mediated the relationship between interactional justice and organizational loyalty, whereas bullying mediated the relationship between interactional justice and mental impairment. Practical implications are discussed concerning how to foster interactional justice and POS and how to weaken bullying behavior.

Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions

PubMed Central

Kawakami, Takahisa; Lichtnekert, Julia; Thompson, Lucas J.; Karna, Prasanthi; Bouabe, Hicham; Hohl, Tobias M.; Heinecke, Jay W.; Ziegler, Steven F.; Nelson, Peter J.; Duffield, Jeremy S.

2013-01-01

Recent reports have highlighted greater complexity, plasticity and functional diversity of mononuclear phagocytes (MPCs), including monocytes, macrophages and dendritic cells (DCs), in our organs, than previously understood. The functions and origins of MPCs resident within healthy organs, especially in the kidney, are less well understood, while studies suggest they play roles in disease states distinct from recruited monocytes. We developed an unbiased approach using flow cytometry to analyze MPCs residing in the normal mouse kidney, and identified five discrete subpopulations according to CD11b/CD11c expression as well as F4/80, CD103, CD14, CD16 and CD64 expression. In addition to distinct marker profiles, these subpopulations have different lineages and expression of genes involved in tissue homeostasis, including angiogenesis. Among them, the CD11bint CD11cint F4/80hi subpopulation notably exhibited high capacity to produce a representative anti-inflammatory cytokine, IL-10. Each subpopulation had different degrees of both macrophage (phagocytosis) and DC (antigen presentation) capacities, with a tendency to promote differentiation of regulatory T cells, while two of these showed expression of transcription factors reported to be highly expressed by classical DCs, and proclivity to exit the kidney following stimulation with LPS. In summary, resident kidney MPCs comprise discrete subpopulations, which cannot be simply classified into the conventional entities, and they produce anti-inflammatory and tissue-homeostatic factors to differing degrees. PMID:23956422

Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells.

PubMed

Morata-Tarifa, Cynthia; Jiménez, Gema; García, María A; Entrena, José M; Griñán-Lisón, Carmen; Aguilera, Margarita; Picon-Ruiz, Manuel; Marchal, Juan A

2016-01-11

Cancer stem cells are responsible for tumor progression, metastasis, therapy resistance and cancer recurrence, doing their identification and isolation of special relevance. Here we show that low adherent breast and colon cancer cells subpopulations have stem-like properties. Our results demonstrate that trypsin-sensitive (TS) breast and colon cancer cells subpopulations show increased ALDH activity, higher ability to exclude Hoechst 33342, enlarged proportion of cells with a cancer stem-like cell phenotype and are enriched in sphere- and colony-forming cells in vitro. Further studies in MDA-MB-231 breast cancer cells reveal that TS subpopulation expresses higher levels of SLUG, SNAIL, VIMENTIN and N-CADHERIN while show a lack of expression of E-CADHERIN and CLAUDIN, being this profile characteristic of the epithelial-to-mesenchymal transition (EMT). The TS subpopulation shows CXCL10, BMI-1 and OCT4 upregulation, differing also in the expression of several miRNAs involved in EMT and/or cell self-renewal such as miR-34a-5p, miR-34c-5p, miR-21-5p, miR-93-5p and miR-100-5p. Furthermore, in vivo studies in immunocompromised mice demonstrate that MDA-MB-231 TS cells form more and bigger xenograft tumors with shorter latency and have higher metastatic potential. In conclusion, this work presents a new, non-aggressive, easy, inexpensive and reproducible methodology to isolate prospectively cancer stem-like cells for subsequent biological and preclinical studies.

A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients.

PubMed

Bloom, R D; Trofe-Clark, J; Wiland, A; Alloway, R R

2013-01-01

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open-label, randomized, two-period (14 d per period), two-sequence, crossover, steady-state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre-study twice-daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0-12 h , Cmax , and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose-normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose-normalized AUC0-12 h , C12 , Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose-normalized AUC0-12 h and C12 with generic vs. reference tacrolimus were within 80-125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non-diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Single-cell RNA-seq of human induced pluripotent stem cells reveals cellular heterogeneity and cell state transitions between subpopulations.

PubMed

Nguyen, Quan; Lukowski, Samuel; Chiu, Han; Senabouth, Anne; Bruxner, Timothy; Christ, Angelika; Palpant, Nathan; Powell, Joseph

2018-05-11

Heterogeneity of cell states represented in pluripotent cultures have not been described at the transcriptional level. Since gene expression is highly heterogeneous between cells, single-cell RNA sequencing can be used to identify how individual pluripotent cells function. Here, we present results from the analysis of single-cell RNA sequencing data from 18,787 individual WTC CRISPRi human induced pluripotent stem cells. We developed an unsupervised clustering method, and through this identified four subpopulations distinguishable on the basis of their pluripotent state including: a core pluripotent population (48.3%), proliferative (47.8%), early-primed for differentiation (2.8%) and late-primed for differentiation (1.1%). For each subpopulation we were able to identify the genes and pathways that define differences in pluripotent cell states. Our method identified four discrete predictor gene sets comprised of 165 unique genes that denote the specific pluripotency states; and using these sets, we developed a multigenic machine learning prediction method to accurately classify single cells into each of the subpopulations. Compared against a set of established pluripotency markers, our method increases prediction accuracy by 10%, specificity by 20%, and explains a substantially larger proportion of deviance (up to 3-fold) from the prediction model. Finally, we developed an innovative method to predict cells transitioning between subpopulations, and support our conclusions with results from two orthogonal pseudotime trajectory methods. Published by Cold Spring Harbor Laboratory Press.

Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia.

PubMed

Dwivedi, Ankit; Khim, Nimol; Reynes, Christelle; Ravel, Patrice; Ma, Laurence; Tichit, Magali; Bourchier, Christiane; Kim, Saorin; Dourng, Dany; Khean, Chanra; Chim, Pheaktra; Siv, Sovannaroth; Frutos, Roger; Lek, Dysoley; Mercereau-Puijalon, Odile; Ariey, Frédéric; Menard, Didier; Cornillot, Emmanuel

2016-06-14

Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008-2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential. To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010-2011 from 16 health centres in malaria endemics areas in Cambodia. Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance. The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia.

Temporal phylogeography of Yersinia pestis in Madagascar: Insights into the long-term maintenance of plague

PubMed Central

Vogler, Amy J.; Andrianaivoarimanana, Voahangy; Telfer, Sandra; Hall, Carina M.; Sahl, Jason W.; Hepp, Crystal M.; Centner, Heather; Andersen, Genevieve; Birdsell, Dawn N.; Rahalison, Lila; Nottingham, Roxanne; Keim, Paul; Rajerison, Minoarisoa

2017-01-01

Background Yersinia pestis appears to be maintained in multiple, geographically separate, and phylogenetically distinct subpopulations within the highlands of Madagascar. However, the dynamics of these locally differentiated subpopulations through time are mostly unknown. To address that gap and further inform our understanding of plague epidemiology, we investigated the phylogeography of Y. pestis in Madagascar over an 18 year period. Methodology/Principal findings We generated whole genome sequences for 31 strains and discovered new SNPs that we used in conjunction with previously identified SNPs and variable-number tandem repeats (VNTRs) to genotype 773 Malagasy Y. pestis samples from 1995 to 2012. We mapped the locations where samples were obtained on a fine geographic scale to examine phylogeographic patterns through time. We identified 18 geographically separate and phylogenetically distinct subpopulations that display spatial and temporal stability, persisting in the same locations over a period of almost two decades. We found that geographic areas with higher levels of topographical relief are associated with greater levels of phylogenetic diversity and that sampling frequency can vary considerably among subpopulations and from year to year. We also found evidence of various Y. pestis dispersal events, including over long distances, but no evidence that any dispersal events resulted in successful establishment of a transferred genotype in a new location during the examined time period. Conclusions/Significance Our analysis suggests that persistent endemic cycles of Y. pestis transmission within local areas are responsible for the long term maintenance of plague in Madagascar, rather than repeated episodes of wide scale epidemic spread. Landscape likely plays a role in maintaining Y. pestis subpopulations in Madagascar, with increased topographical relief associated with increased levels of localized differentiation. Local ecological factors likely affect the dynamics of individual subpopulations and the associated likelihood of observing human plague cases in a given year in a particular location. PMID:28873412

Temporal phylogeography of Yersinia pestis in Madagascar: Insights into the long-term maintenance of plague.

PubMed

Vogler, Amy J; Andrianaivoarimanana, Voahangy; Telfer, Sandra; Hall, Carina M; Sahl, Jason W; Hepp, Crystal M; Centner, Heather; Andersen, Genevieve; Birdsell, Dawn N; Rahalison, Lila; Nottingham, Roxanne; Keim, Paul; Wagner, David M; Rajerison, Minoarisoa

2017-09-01

Yersinia pestis appears to be maintained in multiple, geographically separate, and phylogenetically distinct subpopulations within the highlands of Madagascar. However, the dynamics of these locally differentiated subpopulations through time are mostly unknown. To address that gap and further inform our understanding of plague epidemiology, we investigated the phylogeography of Y. pestis in Madagascar over an 18 year period. We generated whole genome sequences for 31 strains and discovered new SNPs that we used in conjunction with previously identified SNPs and variable-number tandem repeats (VNTRs) to genotype 773 Malagasy Y. pestis samples from 1995 to 2012. We mapped the locations where samples were obtained on a fine geographic scale to examine phylogeographic patterns through time. We identified 18 geographically separate and phylogenetically distinct subpopulations that display spatial and temporal stability, persisting in the same locations over a period of almost two decades. We found that geographic areas with higher levels of topographical relief are associated with greater levels of phylogenetic diversity and that sampling frequency can vary considerably among subpopulations and from year to year. We also found evidence of various Y. pestis dispersal events, including over long distances, but no evidence that any dispersal events resulted in successful establishment of a transferred genotype in a new location during the examined time period. Our analysis suggests that persistent endemic cycles of Y. pestis transmission within local areas are responsible for the long term maintenance of plague in Madagascar, rather than repeated episodes of wide scale epidemic spread. Landscape likely plays a role in maintaining Y. pestis subpopulations in Madagascar, with increased topographical relief associated with increased levels of localized differentiation. Local ecological factors likely affect the dynamics of individual subpopulations and the associated likelihood of observing human plague cases in a given year in a particular location.

Families of transposable elements, population structure and the origin of species.

PubMed

Jurka, Jerzy; Bao, Weidong; Kojima, Kenji K

2011-09-19

Eukaryotic genomes harbor diverse families of repetitive DNA derived from transposable elements (TEs) that are able to replicate and insert into genomic DNA. The biological role of TEs remains unclear, although they have profound mutagenic impact on eukaryotic genomes and the origin of repetitive families often correlates with speciation events. We present a new hypothesis to explain the observed correlations based on classical concepts of population genetics. The main thesis presented in this paper is that the TE-derived repetitive families originate primarily by genetic drift in small populations derived mostly by subdivisions of large populations into subpopulations. We outline the potential impact of the emerging repetitive families on genetic diversification of different subpopulations, and discuss implications of such diversification for the origin of new species. Several testable predictions of the hypothesis are examined. First, we focus on the prediction that the number of diverse families of TEs fixed in a representative genome of a particular species positively correlates with the cumulative number of subpopulations (demes) in the historical metapopulation from which the species has emerged. Furthermore, we present evidence indicating that human AluYa5 and AluYb8 families might have originated in separate proto-human subpopulations. We also revisit prior evidence linking the origin of repetitive families to mammalian phylogeny and present additional evidence linking repetitive families to speciation based on mammalian taxonomy. Finally, we discuss evidence that mammalian orders represented by the largest numbers of species may be subject to relatively recent population subdivisions and speciation events. The hypothesis implies that subdivision of a population into small subpopulations is the major step in the origin of new families of TEs as well as of new species. The origin of new subpopulations is likely to be driven by the availability of new biological niches, consistent with the hypothesis of punctuated equilibria. The hypothesis also has implications for the ongoing debate on the role of genetic drift in genome evolution.

Population dynamics of the Concho water snake in rivers and reservoirs

USGS Publications Warehouse

Whiting, M.J.; Dixon, J.R.; Greene, B.D.; Mueller, J.M.; Thornton, O.W.; Hatfield, J.S.; Nichols, J.D.; Hines, J.E.

2008-01-01

The Concho Water Snake (Nerodia harteri paucimaculata) is confined to the Concho–Colorado River valley of central Texas, thereby occupying one of the smallest geographic ranges of any North American snake. In 1986, N. h. paucimaculata was designated as a federally threatened species, in large part because of reservoir projects that were perceived to adversely affect the amount of habitat available to the snake. During a ten-year period (1987–1996), we conducted capture–recapture field studies to assess dynamics of five subpopulations of snakes in both natural (river) and man-made (reservoir) habitats. Because of differential sampling of subpopulations, we present separate results for all five subpopulations combined (including large reservoirs) and three of the five subpopulations (excluding large reservoirs). We used multistate capture–recapture models to deal with stochastic transitions between pre-reproductive and reproductive size classes and to allow for the possibility of different survival and capture probabilities for the two classes. We also estimated both the finite rate of increase (λ) for a deterministic, stage-based, female-only matrix model using the average litter size, and the average rate of adult population change, λ ˆ, which describes changes in numbers of adult snakes, using a direct capture–recapture approach to estimation. Average annual adult survival was about 0.23 and similar for males and females. Average annual survival for subadults was about 0.14. The parameter estimates from the stage-based projection matrix analysis all yielded asymptotic values of λ < 1, suggesting populations that are not viable. However, the direct estimates of average adult λ for the three subpopulations excluding major reservoirs were λ ˆ  =  1.26, SE ˆ(λ ˆ)  =  0.18 and λ ˆ  =  0.99, SE ˆ(λ ˆ)  =  0.79, based on two different models. Thus, the direct estimation approach did not provide strong evidence of population declines of the riverine subpopulations, but the estimates are characterized by substantial uncertainty.

Genetic Architecture of Aluminum Tolerance in Rice (Oryza sativa) Determined through Genome-Wide Association Analysis and QTL Mapping

PubMed Central

Famoso, Adam N.; Zhao, Keyan; Clark, Randy T.; Tung, Chih-Wei; Wright, Mark H.; Bustamante, Carlos; Kochian, Leon V.; McCouch, Susan R.

2011-01-01

Aluminum (Al) toxicity is a primary limitation to crop productivity on acid soils, and rice has been demonstrated to be significantly more Al tolerant than other cereal crops. However, the mechanisms of rice Al tolerance are largely unknown, and no genes underlying natural variation have been reported. We screened 383 diverse rice accessions, conducted a genome-wide association (GWA) study, and conducted QTL mapping in two bi-parental populations using three estimates of Al tolerance based on root growth. Subpopulation structure explained 57% of the phenotypic variation, and the mean Al tolerance in Japonica was twice that of Indica. Forty-eight regions associated with Al tolerance were identified by GWA analysis, most of which were subpopulation-specific. Four of these regions co-localized with a priori candidate genes, and two highly significant regions co-localized with previously identified QTLs. Three regions corresponding to induced Al-sensitive rice mutants (ART1, STAR2, Nrat1) were identified through bi-parental QTL mapping or GWA to be involved in natural variation for Al tolerance. Haplotype analysis around the Nrat1 gene identified susceptible and tolerant haplotypes explaining 40% of the Al tolerance variation within the aus subpopulation, and sequence analysis of Nrat1 identified a trio of non-synonymous mutations predictive of Al sensitivity in our diversity panel. GWA analysis discovered more phenotype–genotype associations and provided higher resolution, but QTL mapping identified critical rare and/or subpopulation-specific alleles not detected by GWA analysis. Mapping using Indica/Japonica populations identified QTLs associated with transgressive variation where alleles from a susceptible aus or indica parent enhanced Al tolerance in a tolerant Japonica background. This work supports the hypothesis that selectively introgressing alleles across subpopulations is an efficient approach for trait enhancement in plant breeding programs and demonstrates the fundamental importance of subpopulation in interpreting and manipulating the genetics of complex traits in rice. PMID:21829395