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Sample records for integration regulating male

  1. RFX1 maintains testis cord integrity by regulating the expression of Itga6 in male mouse embryos.

    PubMed

    Wang, Bo; Qi, Tao; Chen, Shi-Qin; Ye, Lei; Huang, Zhan-Sen; Li, Hao

    2016-07-01

    Formation and maintenance of testis cords during embryogenesis are essential for establishing testicular structure and function in adults. At least five genes (Wt1, Dhh, Sox8/Sox9, and Dax1) appear to be required for the maintenance of testis cord integrity in mice. Here, we report that RFX1 is specifically expressed in fetal Sertoli cells. Mouse embryos conditionally deficient in Rfx1 (Rfx1(flox/flox) , Amh-Cre) possessed disrupted testis cords, as the basal lamina lining was fragmented or completely absent in some areas of the testes. Spermatogenesis was blocked, leading to complete infertility. Expression of integrin alpha-6 was significantly decreased in Rfx1-deficient testes compared to control testes; indeed, luciferase and chromatin immunoprecipitation assays indicated that RFX1 directly activates transcription of Itga6 (the gene coding for integrin alpha-6). Taken together, RFX1 transcriptionally targets Itga6 in Sertoli cells, thereby, helping maintain the integrity of the basal lamina during testis cord development. Mol. Reprod. Dev. 83: 606-614, 2016. © 2016 Wiley Periodicals, Inc. PMID:27228460

  2. Sensory regulation of C. elegans male mate-searching behaviour

    PubMed Central

    Barrios, Arantza; Nurrish, Stephen; Emmons, Scott W.

    2009-01-01

    Summary How do animals integrate internal drives and external environmental cues to coordinate behaviours? We address this question studying mate-searching behaviour in C. elegans. C. elgans males explore their environment in search of mates (hermaphrodites) and will leave food if mating partners are absent. However, when mates and food coincide, male exploratory behaviour is suppressed and males are retained on the food source. We show that the drive to explore is stimulated by male specific neurons in the tail, the ray neurons. Periodic contact with the hermaphrodite detected through ray neurons changes the male’s behaviour during periods of no contact and prevents the male from leaving the food source. The hermaphrodite signal is conveyed by male-specific interneurons that are post-synaptic to the rays and that send processes to the major integrative center in the head. This study identifies key parts of the neural circuit that regulates a sexual appetitive behaviour in C. elegans. PMID:19062284

  3. Magnetoreception Regulates Male Courtship Activity in Drosophila.

    PubMed

    Wu, Chia-Lin; Fu, Tsai-Feng; Chiang, Meng-Hsuan; Chang, Yu-Wei; Her, Jim-Long; Wu, Tony

    2016-01-01

    The possible neurological and biophysical effects of magnetic fields on animals is an area of active study. Here, we report that courtship activity of male Drosophila increases in a magnetic field and that this effect is regulated by the blue light-dependent photoreceptor cryptochrome (CRY). Naïve male flies exhibited significantly increased courtship activities when they were exposed to a ≥ 20-Gauss static magnetic field, compared with their behavior in the natural environment (0 Gauss). CRY-deficient flies, cryb and crym, did not show an increased courtship index in a magnetic field. RNAi-mediated knockdown of cry in cry-GAL4-positive neurons disrupted the increased male courtship activity in a magnetic field. Genetically expressing cry under the control of cry-GAL4 in the CRY-deficient flies restored the increase in male courtship index that occurred in a magnetic field. Interestingly, artificially activating cry-GAL4-expressing neurons, which include large ventral lateral neurons and small ventral lateral neurons, via expression of thermosensitive cation channel dTrpA1, also increased the male courtship index. This enhancement was abolished by the addition of the cry-GAL80 transgene. Our results highlight the phenomenon of increased male courtship activity caused by a magnetic field through CRY-dependent magnetic sensation in CRY expression neurons in Drosophila. PMID:27195955

  4. Magnetoreception Regulates Male Courtship Activity in Drosophila

    PubMed Central

    Wu, Chia-Lin; Fu, Tsai-Feng; Chiang, Meng-Hsuan; Chang, Yu-Wei; Her, Jim-Long; Wu, Tony

    2016-01-01

    The possible neurological and biophysical effects of magnetic fields on animals is an area of active study. Here, we report that courtship activity of male Drosophila increases in a magnetic field and that this effect is regulated by the blue light-dependent photoreceptor cryptochrome (CRY). Naïve male flies exhibited significantly increased courtship activities when they were exposed to a ≥ 20-Gauss static magnetic field, compared with their behavior in the natural environment (0 Gauss). CRY-deficient flies, cryb and crym, did not show an increased courtship index in a magnetic field. RNAi-mediated knockdown of cry in cry-GAL4-positive neurons disrupted the increased male courtship activity in a magnetic field. Genetically expressing cry under the control of cry-GAL4 in the CRY-deficient flies restored the increase in male courtship index that occurred in a magnetic field. Interestingly, artificially activating cry-GAL4-expressing neurons, which include large ventral lateral neurons and small ventral lateral neurons, via expression of thermosensitive cation channel dTrpA1, also increased the male courtship index. This enhancement was abolished by the addition of the cry-GAL80 transgene. Our results highlight the phenomenon of increased male courtship activity caused by a magnetic field through CRY-dependent magnetic sensation in CRY expression neurons in Drosophila. PMID:27195955

  5. Review: neuroestrogen regulation of socio-sexual behavior of males

    PubMed Central

    Ubuka, Takayoshi; Tsutsui, Kazuyoshi

    2014-01-01

    It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior. PMID:25352775

  6. Integration of male bisexuality and marriage.

    PubMed

    Coleman, E

    1985-01-01

    Eighteen couples who had originally entered therapy because of conflicts created by the husband's bisexuality were studied to determine the dynamics and adjustment of their marriages. All the couples, to varying degrees, had been openly dealing with the husband's bisexuality for at least two years. Through questionnaires and psychological instruments, couples indicated that openness and communication helped the relationship. The greatest difficulties they encountered were in their sexual relationships. Marital satisfaction and adjustment was found to be negatively correlated with increasing age, number of children, later onset of homosexual activities, increased emotional involvement with male partners, increased numbers of people who know about the husband's homosexual activities, and increased sexual dissatisfaction and conflict. Basically, this study reinforced the notion that some marriages can survive by way of open communication, acceptance and understanding, dynamics which help compensate for the inherent conflicts these couples face.

  7. Bodily Integrity and Male Circumcision: An Islamic Perspective

    PubMed Central

    Alahmad, Ghiath; Dekkers, Wim

    2012-01-01

    The notion of bodily integrity forms an important part of the value-structure of many religions and cultures. In this paper, we explore the notion of bodily integrity in Islam using male circumcision as the focus of the discussion. Our aim is to contribute to a better understanding of the Muslim perspective and of the differences and similarities between Western and Islamic ethical structures, in particular, regarding the concept of bodily integrity. PMID:23610746

  8. The Anaphase-Promoting Complex is a dual integrator that regulates both microRNA-mediated transcriptional regulation of Cyclin B1 and degradation of Cyclin B1 during Arabidopsis male gametophyte development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The anaphase-promoting complex/cyclosome (APC/C), an essential ubiquitin protein ligase, regulates mitotic progression and exit by enhancing degradation of cell cycle regulatory proteins, such as CYCB1;1, whose transcripts are upregulated by DUO POLLEN1 (DUO1). DUO1 is required for cell division in ...

  9. The Anaphase-Promoting Complex Is a Dual Integrator That Regulates Both MicroRNA-Mediated Transcriptional Regulation of Cyclin B1 and Degradation of Cyclin B1 during Arabidopsis Male Gametophyte Development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The anaphase-promoting complex/cyclosome (APC/C), an essential ubiquitin protein ligase, regulates mitotic progression and exit by enhancing degradation of cell cycle regulatory proteins, such as CYCB1;1, whose transcripts are upregulated by DUO POLLEN1 (DUO1). DUO1 is required for cell division in ...

  10. Turn the Wheel: Integral School Counseling for Male Adolescents.

    ERIC Educational Resources Information Center

    Forbes, David

    2003-01-01

    This article formulates an overarching, inclusive model of integral counseling that enables school counselors to help male adolescents challenge the norm of conventional masculinity. The model draws from 3 areas: transpersonal counseling, holistic education, and mindful social action. The aim is to move the students' level of self-development and…

  11. Dietary glucose regulates yeast consumption in adult Drosophila males

    PubMed Central

    Lebreton, Sébastien; Witzgall, Peter; Olsson, Marie; Becher, Paul G.

    2014-01-01

    The adjustment of feeding behavior in response to hunger and satiety contributes to homeostatic regulation in animals. The fruit fly Drosophila melanogaster feeds on yeasts growing on overripe fruit, providing nutrients required for adult survival, reproduction and larval growth. Here, we present data on how the nutritional value of food affects subsequent yeast consumption in Drosophila adult males. After a period of starvation, flies showed intensive yeast consumption. In comparison, flies stopped feeding after having access to a nutritive cornmeal diet. Interestingly, dietary glucose was equally efficient as the complex cornmeal diet. In contrast, flies fed with sucralose, a non-metabolizable sweetener, behaved as if they were starved. The adipokinetic hormone and insulin-like peptides regulate metabolic processes in insects. We did not find any effect of the adipokinetic hormone pathway on this modulation. Instead, the insulin pathway was involved in these changes. Flies lacking the insulin receptor (InR) did not respond to nutrient deprivation by increasing yeast consumption. Together these results show the importance of insulin in the regulation of yeast consumption in response to starvation in adult D. melanogaster males. PMID:25566097

  12. Juvenile hormone regulates extreme mandible growth in male stag beetles.

    PubMed

    Gotoh, Hiroki; Cornette, Richard; Koshikawa, Shigeyuki; Okada, Yasukazu; Lavine, Laura Corley; Emlen, Douglas J; Miura, Toru

    2011-01-01

    The morphological diversity of insects is one of the most striking phenomena in biology. Evolutionary modifications to the relative sizes of body parts, including the evolution of traits with exaggerated proportions, are responsible for a vast range of body forms. Remarkable examples of an insect trait with exaggerated proportions are the mandibular weapons of stag beetles. Male stag beetles possess extremely enlarged mandibles which they use in combat with rival males over females. As with other sexually selected traits, stag beetle mandibles vary widely in size among males, and this variable growth results from differential larval nutrition. However, the mechanisms responsible for coupling nutrition with growth of stag beetle mandibles (or indeed any insect structure) remain largely unknown. Here, we demonstrate that during the development of male stag beetles (Cyclommatus metallifer), juvenile hormone (JH) titers are correlated with the extreme growth of an exaggerated weapon of sexual selection. We then investigate the putative role of JH in the development of the nutritionally-dependent, phenotypically plastic mandibles, by increasing hemolymph titers of JH with application of the JH analog fenoxycarb during larval and prepupal developmental periods. Increased JH signaling during the early prepupal period increased the proportional size of body parts, and this was especially pronounced in male mandibles, enhancing the exaggerated size of this trait. The direction of this response is consistent with the measured JH titers during this same period. Combined, our results support a role for JH in the nutrition-dependent regulation of extreme mandible growth in this species. In addition, they illuminate mechanisms underlying the evolution of trait proportion, the most salient feature of the evolutionary diversification of the insects.

  13. Groundwater regulation and integrated planning

    USGS Publications Warehouse

    Quevauviller, Philippe; Batelaan, Okke; Hunt, Randall J.

    2016-01-01

    The complex nature of groundwater and the diversity of uses and environmental interactions call for emerging groundwater problems to be addressed through integrated management and planning approaches. Planning requires different levels of integration dealing with: the hydrologic cycle (the physical process) including the temporal dimension; river basins and aquifers (spatial integration); socioeconomic considerations at regional, national and international levels; and scientific knowledge. The great natural variation in groundwater conditions obviously affects planning needs and options as well as perceptions from highly localised to regionally-based approaches. The scale at which planning is done therefore needs to be carefully evaluated against available policy choices and options in each particular setting. A solid planning approach is based on River Basin Management Planning (RBMP), which covers: (1) objectives that management planning are designed to address; (2) the way various types of measures fit into the overall management planning; and (3) the criteria against which the success or failure of specific strategies or interventions can be evaluated (e.g. compliance with environmental quality standards). A management planning framework is to be conceived as a “living” or iterated document that can be updated, refined and if necessary changed as information and experience are gained. This chapter discusses these aspects, providing an insight into European Union (EU), United States and Australia groundwater planning practices.

  14. Bone endocrine regulation of energy metabolism and male reproduction.

    PubMed

    Karsenty, Gerard

    2011-10-01

    Usually vertebrate physiology is studied within the confined limits of a given organ, if not cell type. This approach has progressively changed with the emergence of mouse genetics that has rejuvenated the concept of a whole body study of physiology. A vivid example of how mouse genetics has profoundly affected our understanding of physiology is skeleton physiology. A genetic approach to bone physiology revealed that bone via osteocalcin, an osteoblast-secreted molecule, is a true endocrine organ regulating energy metabolism and male reproduction. This ongoing body of work that takes bone out of its traditional roles is connecting it to a growing number of peripheral organs. These novel important hormonal connections between bone, energy metabolism and reproduction underscore the concept of functional dependence in physiology and the importance of genetic approaches to identify novel endocrine regulations.

  15. The PSI-U1 snRNP interaction regulates male mating behavior in Drosophila.

    PubMed

    Wang, Qingqing; Taliaferro, J Matthew; Klibaite, Ugne; Hilgers, Valérie; Shaevitz, Joshua W; Rio, Donald C

    2016-05-10

    Alternative pre-mRNA splicing (AS) is a critical regulatory mechanism that operates extensively in the nervous system to produce diverse protein isoforms. Fruitless AS isoforms have been shown to influence male courtship behavior, but the underlying mechanisms are unknown. Using genome-wide approaches and quantitative behavioral assays, we show that the P-element somatic inhibitor (PSI) and its interaction with the U1 small nuclear ribonucleoprotein complex (snRNP) control male courtship behavior. PSI mutants lacking the U1 snRNP-interacting domain (PSIΔAB mutant) exhibit extended but futile mating attempts. The PSIΔAB mutant results in significant changes in the AS patterns of ∼1,200 genes in the Drosophila brain, many of which have been implicated in the regulation of male courtship behavior. PSI directly regulates the AS of at least one-third of these transcripts, suggesting that PSI-U1 snRNP interactions coordinate the behavioral network underlying courtship behavior. Importantly, one of these direct targets is fruitless, the master regulator of courtship. Thus, PSI imposes a specific mode of regulatory control within the neuronal circuit controlling courtship, even though it is broadly expressed in the fly nervous system. This study reinforces the importance of AS in the control of gene activity in neurons and integrated neuronal circuits, and provides a surprising link between a pleiotropic pre-mRNA splicing pathway and the precise control of successful male mating behavior.

  16. E-type cyclins modulate telomere integrity in mammalian male meiosis.

    PubMed

    Manterola, Marcia; Sicinski, Piotr; Wolgemuth, Debra J

    2016-06-01

    We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/-E2-/-) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.

  17. Disrupting Immune Regulation Incurs Transient Costs in Male Reproductive Function

    PubMed Central

    Belloni, Virginia; Sorci, Gabriele; Paccagnini, Eugenio; Guerreiro, Romain; Bellenger, Jérôme; Faivre, Bruno

    2014-01-01

    Background Immune protection against pathogenic organisms has been shown to incur costs. Previous studies investigating the cost of immunity have mostly focused on the metabolic requirements of immune maintenance and activation. In addition to these metabolic costs, the immune system can induce damage to the host if the immune response is mis-targeted or over-expressed. Given its non-specific nature, an over-expressed inflammatory response is often associated with substantial damage for the host. Here, we investigated the cost of an over-expressed inflammatory response in the reproductive function of male mice. Methodology/Principal Findings We experimentally blocked the receptors of an anti-inflammatory cytokine (IL-10) in male mice exposed to a mild inflammatory challenge, with each treatment having an appropriate control group. The experiment was conducted on two age classes, young (3 month old) and old (15 month old) mice, to assess any age-related difference in the cost of a disrupted immune regulation. We found that the concomitant exposure to an inflammatory insult and the blockade of IL-10 induced a reduction in testis mass, compared to the three other groups. The frequency of abnormal sperm morphology was also higher in the group of mice exposed to the inflammatory challenge but did not depend on the blockade of the IL-10. Conclusions Our results provide evidence that immune regulation confers protection against the risk of inflammation-induced infertility during infection. They also suggest that disruption of the effectors involved in the regulation of the inflammatory response can have serious fitness consequences even under mild inflammatory insult and benign environmental conditions. PMID:24400103

  18. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity

    NASA Astrophysics Data System (ADS)

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-09-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

  19. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity

    PubMed Central

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-01-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered. PMID:27585557

  20. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity.

    PubMed

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-09-02

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

  1. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity.

    PubMed

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-01-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered. PMID:27585557

  2. Social regulation of reproduction in male cichlid fishes.

    PubMed

    Maruska, Karen P

    2014-10-01

    Social interactions and relative positions within a dominance hierarchy have helped shape the evolution of reproduction in many animals. Since reproduction is crucial in all animals, and rank typically regulates access to reproductive opportunities, understanding the mechanisms that regulate socially-induced reproductive processes is extremely important. How does position in a dominance hierarchy impact an individual's reproductive behavior, morphology, and physiology? Teleost fishes, and cichlids in particular, are ideally-suited models for studying how social status influences reproduction on multiple levels of biological organization. Here I review the current knowledge on the reproductive behavioral and physiological consequences of relative position in a dominance hierarchy, with a particular focus on male cichlids. Dominant and subordinate social status is typically associated with distinct differences in activity along the entire hypothalamic-pituitary-gonadal axis. Further, when transitions in social status occur between subordinate and dominant individuals, there are plastic changes from whole-organism behavior to molecular-level gene expression modifications that occur quickly. These rapid changes in behavior and physiology have allowed cichlids the flexibility to adapt to and thrive in their often dynamic physical and social environments. Studies in cichlid fishes have, and will continue, to advance our understanding of how the social environment can modulate molecular, cellular, and behavioral outcomes relevant to reproductive success. Future studies that take advantage of the extreme diversity in mating systems, reproductive tactics, and parental care strategies within the cichlid group will help generate hypotheses and careful experimental tests on the mechanisms governing the social control of reproduction in many vertebrates.

  3. Social regulation of male reproductive plasticity in an African cichlid fish.

    PubMed

    Maruska, Karen P; Fernald, Russell D

    2013-12-01

    Social interactions with the outcome of a position in a dominance hierarchy can have profound effects on reproductive behavior and physiology, requiring animals to integrate environmental information with their internal physiological state; but how is salient information from the animal's dynamic social environment transformed into adaptive behavioral, physiological, and molecular-level changes? The African cichlid fish, Astatotilapia burtoni, is ideally suited to understand socially controlled reproductive plasticity because activity of the male reproductive (brain-pituitary-gonad) axis is tightly linked to social status. Males form hierarchies in which a small percentage of brightly colored dominant individuals have an active reproductive axis, defend territories, and spawn with females, while the remaining males are subordinate, drably colored, do not hold a territory, and have a suppressed reproductive system with minimal opportunities for spawning. These social phenotypes are plastic and quickly reversible, meaning that individual males may switch between dominant and subordinate status multiple times within a lifetime. Here, we review the rapid and remarkable plasticity that occurs along the entire reproductive axis when males rise in social rank, a transition that has important implications for the operational sex ratio of the population. When males rise in rank, transformations occur in the brain, pituitary, circulation, and testes over short time-scales (minutes to days). Changes are evident in overt behavior, as well as modifications at the physiological, cellular, and molecular levels that regulate reproductive capacity. Widespread changes triggered by a switch in rank highlight the significance of external social information in shaping internal physiology and reproductive competence.

  4. Social Regulation of Male Reproductive Plasticity in an African Cichlid Fish

    PubMed Central

    Maruska, Karen P.; Fernald, Russell D.

    2013-01-01

    Social interactions with the outcome of a position in a dominance hierarchy can have profound effects on reproductive behavior and physiology, requiring animals to integrate environmental information with their internal physiological state; but how is salient information from the animal’s dynamic social environment transformed into adaptive behavioral, physiological, and molecular-level changes? The African cichlid fish, Astatotilapia burtoni, is ideally suited to understand socially controlled reproductive plasticity because activity of the male reproductive (brain–pituitary–gonad) axis is tightly linked to social status. Males form hierarchies in which a small percentage of brightly colored dominant individuals have an active reproductive axis, defend territories, and spawn with females, while the remaining males are subordinate, drably colored, do not hold a territory, and have a suppressed reproductive system with minimal opportunities for spawning. These social phenotypes are plastic and quickly reversible, meaning that individual males may switch between dominant and subordinate status multiple times within a lifetime. Here, we review the rapid and remarkable plasticity that occurs along the entire reproductive axis when males rise in social rank, a transition that has important implications for the operational sex ratio of the population. When males rise in rank, transformations occur in the brain, pituitary, circulation, and testes over short time-scales (minutes to days). Changes are evident in overt behavior, as well as modifications at the physiological, cellular, and molecular levels that regulate reproductive capacity. Widespread changes triggered by a switch in rank highlight the significance of external social information in shaping internal physiology and reproductive competence. PMID:23613320

  5. Septal regulation of male sexual behavior in rats.

    PubMed

    Gogate, M G; Brid, S V; Wingkar, K C; Kantak, N M

    1995-06-01

    Involvement of septal nuclei in modulation of male sexual behavior in rats was investigated. Sexually active Wistar male rats were assigned to intact, sham, lateral septal nuclei lesioned (LSL), and medial septal nuclei lesioned (MSL) groups. All male rats were tested for sexual behavior in an arena in the presence of a sexually receptive female. Intromission and ejaculation latencies were increased, and mount, intromission, and ejaculation frequencies were decreased in the LSL group compared to the intact group. In contrast, mount and intromission latencies were decreased, and pursuit and mount frequencies were increased in the MSL group compared to the intact group. The results indicate that medial septal nuclei may inhibit and lateral septal nuclei may facilitate male sexual behavior in rats. PMID:7652045

  6. FET proteins regulate lifespan and neuronal integrity

    PubMed Central

    Therrien, Martine; Rouleau, Guy A.; Dion, Patrick A.; Parker, J. Alex

    2016-01-01

    The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting motor neurons. Here, we show that a reduction of FET proteins in the nematode Caenorhabditis elegans causes synaptic dysfunction accompanied by impaired motor phenotypes. FET proteins are also involved in the regulation of lifespan and stress resistance, acting partially through the insulin/IGF-signalling pathway. We propose that FET proteins are involved in the maintenance of lifespan, cellular stress resistance and neuronal integrity. PMID:27117089

  7. The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis.

    PubMed

    Ding, Guo-Lian; Liu, Ye; Liu, Miao-E; Pan, Jie-Xue; Guo, Meng-Xi; Sheng, Jian-Zhong; Huang, He-Feng

    2015-01-01

    The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring. PMID:25814158

  8. The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis

    PubMed Central

    Ding, Guo-Lian; Liu, Ye; Liu, Miao-E; Pan, Jie-Xue; Guo, Meng-Xi; Sheng, Jian-Zhong; Huang, He-Feng

    2015-01-01

    The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring. PMID:25814158

  9. Integrating Membrane Transport with Male Gametophyte Development and Function through Transcriptomics.

    SciTech Connect

    Bock KW; D Honys; JM. Ward; S Padmanaban; EP Nawrocki; KD Hirschi; D Twell; H Sze

    2006-01-01

    Male fertility depends on the proper development of the male gametophyte, successful pollen germination, tube growth and delivery of the sperm cells to the ovule. Previous studies have shown that nutrients like boron, and ion gradients or currents of Ca2+, H+, and K+ are critical for pollen tube growth. However, the molecular identities of transporters mediating these fluxes are mostly unknown. As a first step to integrate transport with pollen development and function, a genome-wide analysis of transporter genes expressed in the male gametophyte at four developmental stages was conducted. About 1269 genes encoding classified transporters were collected from the Arabidopsis thaliana genome. Of 757 transporter genes expressed in pollen, 16% or 124 genes, including AHA6, CNGC18, TIP1.3 and CHX08, are specifically or preferentially expressed relative to sporophytic tissues. Some genes are highly expressed in microspores and bicellular pollen (COPT3, STP2, OPT9); while others are activated only in tricellular or mature pollen (STP11, LHT7). Analyses of entire gene families showed that a subset of genes, including those expressed in sporophytic tissues, were developmentally-regulated during pollen maturation. Early and late expression patterns revealed by transcriptome analysis are supported by promoter::GUS analyses of CHX genes and by other methods. Recent genetic studies based on a few transporters, including plasma membrane H+ pump AHA3, Ca2+ pump ACA9, and K+ channel SPIK, further support the expression patterns and the inferred functions revealed by our analyses. Thus, revealing the distinct expression patterns of specific transporters and unknown polytopic proteins during microgametogenesis provides new insights for strategic mutant analyses necessary to integrate the roles of transporters and potential receptors with male gametophyte development.

  10. Regulation of the malic enzyme gene malE by the transcriptional regulator MalR in Corynebacterium glutamicum.

    PubMed

    Krause, Jens P; Polen, Tino; Youn, Jung-Won; Emer, Denise; Eikmanns, Bernhard J; Wendisch, Volker F

    2012-06-15

    Corynebacterium glutamicum is a Gram-positive nonpathogenic bacterium that is used for the biotechnological production of amino acids. Here, we investigated the transcriptional control of the malE gene encoding malic enzyme (MalE) in C. glutamicum ATCC 13032, which is known to involve the nitrogen regulator AmtR. Gel shift experiments using purified regulators RamA and RamB revealed binding of these regulators to the malE promoter. In DNA-affinity purification experiments a hitherto uncharacterized transcriptional regulator belonging to the MarR family was found to bind to malE promoter DNA and was designated as MalR. C. glutamicum cells overexpressing malR showed reduced MalE activities in LB medium or in minimal media with acetate, glucose, pyruvate or citrate. Deletion of malR positively affected MalE activities during growth in LB medium and minimal media with pyruvate, glucose or the TCA cycle dicarboxylates l-malate, succinate and fumarate. Transcriptional fusion analysis revealed elevated malE promoter activity in the malR deletion mutant during growth in pyruvate minimal medium suggesting that MalR acts as a repressor of malE. Purified MalR bound malE promoter DNA in gel shift experiments. Two MalR binding sites were identified in the malE promoter by mutational analysis. Thus, MalR contributes to the complex transcriptional control of malE which also involves RamA, RamB and AmtR. PMID:22261175

  11. PECAM-1: regulator of endothelial junctional integrity.

    PubMed

    Privratsky, Jamie R; Newman, Peter J

    2014-03-01

    PECAM-1 (also known as CD31) is a cellular adhesion and signaling receptor comprising six extracellular immunoglobulin (Ig)-like homology domains, a short transmembrane domain and a 118 amino acid cytoplasmic domain that becomes serine and tyrosine phosphorylated upon cellular activation. PECAM-1 expression is restricted to blood and vascular cells. In circulating platelets and leukocytes, PECAM-1 functions largely as an inhibitory receptor that, via regulated sequential phosphorylation of its cytoplasmic domain, limits cellular activation responses. PECAM-1 is also highly expressed at endothelial cell intercellular junctions, where it functions as a mechanosensor, as a regulator of leukocyte trafficking and in the maintenance of endothelial cell junctional integrity. In this review, we will describe (1) the functional domains of PECAM-1 and how they contribute to its barrier-enhancing properties, (2) how the physical properties of PECAM-1 influence its subcellular localization and its ability to influence endothelial cell barrier function, (3) various stimuli that initiate PECAM-1 signaling and/or function at the endothelial junction and (4) cross-talk of PECAM-1 with other junctional molecules, which can influence endothelial cell function. PMID:24435645

  12. Regulation of sensory motor circuits used in C. elegans male intromission behavior.

    PubMed

    García, L René

    2014-09-01

    Intromission of a male's copulatory organ into his mate's genital orifice is a behavioral step that is conserved in most terrestrial mating behaviors. The behavior serves to anchor the male to his mate and aids in the transmission of the male's gametes into the female. In all animals, the successful execution of intromission likely involves coordinated sensory/motor regulation coupled with constant self-monitoring. The compact male C. elegans reproductive nervous system provides an accessible experimental model for identification and dissection of the molecular and cellular circuit components that promote different motor outputs required for the transfer of the male's genetic material into the self-fertilizing hermaphrodite. The C. elegans male tail contains forty-one sex-specific muscles and 81 sex-specific neurons, which promote different steps of mating behavior. In this review, I will outline the functional contributions of the male-specific sensory-motor neurons and their postsynaptic muscles that control the motions of the male copulatory spicules during the various phases of intromission behavior and ejaculation. In addition, I will summarize the roles of neurotransmitter receptors and ion channels that regulate the outputs of individual circuit components and describe how the intromission circuit uses these molecules to regulate reproductive behavior during male aging and nutritional deprivation.

  13. GermlncRNA: a unique catalogue of long non-coding RNAs and associated regulations in male germ cell development.

    PubMed

    Luk, Alfred Chun-Shui; Gao, Huayan; Xiao, Sizhe; Liao, Jinyue; Wang, Daxi; Tu, Jiajie; Rennert, Owen M; Chan, Wai-Yee; Lee, Tin-Lap

    2015-01-01

    Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date. A major limitation in studying lncRNA in male germ cell development is the absence of germ cell-specific lncRNA annotation. Current lncRNA annotations are assembled by transcriptome data from heterogeneous tissue sources; specific germ cell transcript information of various developmental stages is therefore under-represented, which may lead to biased prediction or fail to identity important germ cell-specific lncRNAs. GermlncRNA provides the first comprehensive web-based and open-access lncRNA catalogue for three key male germ cell stages, including type A spermatogonia, pachytene spermatocytes and round spermatids. This information has been developed by integrating male germ transcriptome resources derived from RNA-Seq, tiling microarray and GermSAGE. Characterizations on lncRNA-associated regulatory features, potential coding gene and microRNA targets are also provided. Search results from GermlncRNA can be exported to Galaxy for downstream analysis or downloaded locally. Taken together, GermlncRNA offers a new avenue to better understand the role of lncRNAs and associated targets during spermatogenesis. Database URL: http://germlncrna.cbiit.cuhk.edu.hk/ PMID:25982314

  14. GermlncRNA: a unique catalogue of long non-coding RNAs and associated regulations in male germ cell development

    PubMed Central

    Luk, Alfred Chun-Shui; Gao, Huayan; Xiao, Sizhe; Liao, Jinyue; Wang, Daxi; Tu, Jiajie; Rennert, Owen M.; Chan, Wai-Yee; Lee, Tin-Lap

    2015-01-01

    Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date. A major limitation in studying lncRNA in male germ cell development is the absence of germ cell-specific lncRNA annotation. Current lncRNA annotations are assembled by transcriptome data from heterogeneous tissue sources; specific germ cell transcript information of various developmental stages is therefore under-represented, which may lead to biased prediction or fail to identity important germ cell-specific lncRNAs. GermlncRNA provides the first comprehensive web-based and open-access lncRNA catalogue for three key male germ cell stages, including type A spermatogonia, pachytene spermatocytes and round spermatids. This information has been developed by integrating male germ transcriptome resources derived from RNA-Seq, tiling microarray and GermSAGE. Characterizations on lncRNA-associated regulatory features, potential coding gene and microRNA targets are also provided. Search results from GermlncRNA can be exported to Galaxy for downstream analysis or downloaded locally. Taken together, GermlncRNA offers a new avenue to better understand the role of lncRNAs and associated targets during spermatogenesis. Database URL: http://germlncrna.cbiit.cuhk.edu.hk/ PMID:25982314

  15. Hypothalamic integration of body fluid regulation.

    PubMed Central

    Denton, D A; McKinley, M J; Weisinger, R S

    1996-01-01

    The progression of animal life from the paleozoic ocean to rivers and diverse econiches on the planet's surface, as well as the subsequent reinvasion of the ocean, involved many different stresses on ionic pattern, osmotic pressure, and volume of the extracellular fluid bathing body cells. The relatively constant ionic pattern of vertebrates reflects a genetic "set" of many regulatory mechanisms--particularly renal regulation. Renal regulation of ionic pattern when loss of fluid from the body is disproportionate relative to the extracellular fluid composition (e.g., gastric juice with vomiting and pancreatic secretion with diarrhea) makes manifest that a mechanism to produce a biologically relatively inactive extracellular anion HCO3- exists, whereas no comparable mechanism to produce a biologically inactive cation has evolved. Life in the ocean, which has three times the sodium concentration of extracellular fluid, involves quite different osmoregulatory stress to that in freshwater. Terrestrial life involves risk of desiccation and, in large areas of the planet, salt deficiency. Mechanisms integrated in the hypothalamus (the evolutionary ancient midbrain) control water retention and facilitate excretion of sodium, and also control the secretion of renin by the kidney. Over and above the multifactorial processes of excretion, hypothalamic sensors reacting to sodium concentration, as well as circumventricular organs sensors reacting to osmotic pressure and angiotensin II, subserve genesis of sodium hunger and thirst. These behaviors spectacularly augment the adaptive capacities of animals. Instinct (genotypic memory) and learning (phenotypic memory) are melded to give specific behavior apt to the metabolic status of the animal. The sensations, compelling emotions, and intentions generated by these vegetative systems focus the issue of the phylogenetic emergence of consciousness and whether primal awareness initially came from the interoreceptors and vegetative

  16. Tripterygium wilfordii, a Chinese herb effective in male fertility regulation.

    PubMed

    Qian, S Z

    1987-09-01

    A refined extract from the root xylem of Tripterygium wilfordii Hook. f. (the so-called multi-glycosides of the plant), available in the market as tablets for the long-term treatment of rheumatoid arthritis and various skin disorders, has recently been shown to possess a powerful antifertility effect in male rats and in men after oral administration at dose levels not showing apparent toxicity or side effects. Fertility appears to be reversible after cessation of treatment. Moreover, preliminary data indicated that the effective antifertility dose in men is only 1/3 of the recommended dose for the treatment of rheumatoid arthritis or skin diseases. This fact supports additional optimism that the side effects of this small dose will be much less as compared with those of the regular dose level. However, a large amount of further investigation is required before one can predict the future of the drug, which seems to hinge upon the successful isolation of the active principle(s) and the careful toxicological evaluation of the safety of the latter. The present paper is a review article summarizing the chemistry, the general pharmacology and the fertility regulatory effect of the plant. PMID:3315438

  17. Corticosterone regulates multiple colour traits in Lacerta [Zootoca] vivipara males.

    PubMed

    San-Jose, L M; Fitze, P S

    2013-12-01

    Ornamental colours usually evolve as honest signals of quality, which is supported by the fact that they frequently depend on individual condition. It has generally been suggested that some, but not all types of ornamental colours are condition dependent, indicating that different evolutionary mechanisms underlie the evolution of multiple types of ornamental colours even when these are exhibited by the same species. Stress hormones, which negatively affect condition, have been shown to affect colour traits based on different pigments and structures, suggesting that they mediate condition dependence of multiple ornament types both among and within individuals. However, studies investigating effects of stress hormones on different ornament types within individuals are lacking, and thus, evidence for this hypothesis is scant. Here, we investigated whether corticosterone mediates condition dependence of multiple ornaments by manipulating corticosterone levels and body condition (via food availability) using a two-factorial design and by assessing their effect on multiple colour traits in male common lizards. Corticosterone negatively affected ventral melanin- and carotenoid-based coloration, whereas food availability did not affect coloration, despite its significant effect on body condition. The corticosterone effect on melanin- and carotenoid-based coloration demonstrates the condition dependence of both ornaments. Moreover, corticosterone affected ventral coloration and had no effect on the nonsexually selected dorsal coloration, showing specific effects of corticosterone on ornamental ventral colours. This suggests that corticosterone simultaneously mediates condition dependence of multiple colour traits and that it therefore accounts for covariation among them, which may influence their evolution via correlational selection.

  18. Molecular regulation of hypothalamus-pituitary-gonads axis in males.

    PubMed

    Jin, Jia-Min; Yang, Wan-Xi

    2014-11-01

    The hypothalamic-pituitary-gonadal axis (HPG) plays vital roles in reproduction and steroid hormone production in both sexes. The focus of this review is upon gene structures, receptor structures and the signaling pathways of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The hormones' functions in reproduction as well as consequences resulting from mutations are also summarized. Specific characteristics of hormones such as the pulsatile secretions of GnRH are also covered. The different regulators of the HPG axis are introduced including kisspeptin, activin, inhibin, follistatin, androgens and estrogen. This review includes not only their basic information, but also their unique function in the HPG axis. Here we view the HPG axis as a whole, so relations between ligands and receptors are well described crossing different levels of the HPG axis. Hormone interactions and transformations are also considered. The major information of this article is depicted in three figures summarizing the current discoveries on the HPG axis. This article systematically introduces the basic knowledge of the HPG axis and provides information of the current advances relating to reproductive hormones.

  19. HIV Risk and Protection among Gay Male Couples: The Role of Gay Community Integration

    ERIC Educational Resources Information Center

    Fergus, Stevenson; Lewis, Megan A.; Darbes, Lynae A.; Butterfield, Rita M.

    2005-01-01

    This study examined the association between different types of integration in the gay community and HIV risk among gay male couples. Previous research linking gay community integration and involvement among couples to HIV risk has been equivocal. Each partner in 59 gay couples completed a separate anonymous questionnaire that assessed two types of…

  20. Tribolium castaneum Transformer-2 regulates sex determination and development in both males and females.

    PubMed

    Shukla, Jayendra Nath; Palli, Subba Reddy

    2013-12-01

    Tribolium castaneum Transformer (TcTra) is essential for female sex determination and maintenance through the regulation of sex-specific splicing of doublesex (dsx) pre-mRNA. In females, TcTra also regulates the sex-specific splicing of its own pre-mRNA to ensure continuous production of functional Tra protein. Transformer protein is absent in males and hence dsx pre-mRNA is spliced in a default mode. The mechanisms by which males inhibit the production of functional Tra protein are not known. Here, we report on functional characterization of transformer-2 (tra-2) gene (an ortholog of Drosophila transformer-2) in T. castaneum. RNA interference-mediated knockdown in the expression of gene coding for tra-2 in female pupae or adults resulted in the production of male-specific isoform of dsx and both female and male isoforms of tra suggesting that Tra-2 is essential for the female-specific splicing of tra and dsx pre-mRNAs. Interestingly, knockdown of tra-2 in males did not affect the splicing of dsx but resulted in the production of both female and male isoforms of tra suggesting that Tra-2 suppresses female-specific splicing of tra pre-mRNA in males. This dual regulation of sex-specific splicing of tra pre-mRNA ensures a tight regulation of sex determination and maintenance. These data suggest a critical role for Tra-2 in suppression of female sex determination cascade in males. In addition, RNAi studies showed that Tra-2 is also required for successful embryonic and larval development in both sexes.

  1. Suppressed expression of RETROGRADE-REGULATED MALE STERILITY restores pollen fertility in cytoplasmic male sterile rice plants

    PubMed Central

    Fujii, Sota; Toriyama, Kinya

    2009-01-01

    Conflict/reconciliation between mitochondria and nuclei in plants is manifested by the fate of pollen (viable or nonviable) in the cytoplasmic male sterility (CMS)/fertility restoration (Rf) system. Through positional cloning, we identified a nuclear candidate gene, RETROGRADE-REGULATED MALE STERILITY (RMS) for Rf17, a fertility restorer gene for Chinese wild rice (CW)-type CMS in rice (Oryza sativa L.). RNA interference-mediated gene silencing of RMS restored fertility to a CMS plant, whereas its overexpression in the fertility restorer line induced pollen abortion. The mRNA expression level of RMS in mature anthers depended on cytoplasmic genotype, suggesting that RMS is a candidate gene to be regulated via retrograde signaling. We found that a reduced-expression allele of the RMS gene restored fertility in haploid pollen, whereas a normal-expression allele caused pollen to die in the CW-type CMS. RMS encodes a mitochondrial protein, 178 aa in length, of unknown function, unlike the majority of other Rf genes cloned thus far, which encode pentatricopeptide repeat proteins. The unique features of RMS provide novel insights into retrograde signaling and CMS. PMID:19458265

  2. Evidence for opioid involvement in the regulation of song production in male European starlings (Sturnus vulgaris).

    PubMed

    Riters, Lauren V; Schroeder, Molly B; Auger, Catherine J; Eens, Marcel; Pinxten, Rianne; Ball, Gregory F

    2005-02-01

    Many social animals vocalize at high rates, suggesting that vocal communication is highly motivated and rewarding. In songbirds, much is known about the neural control of vocal behavior; however, little is known about neurobiological mechanisms regulating the motivation to communicate. This study examined a possible role for opioid neuropeptides in motivation and reward associated with song production in male European starlings (Sturnus vulgaris). Peripheral opioid blockade facilitated male song production. Furthermore, methionine-enkephalin immunolabeled fiber densities within brain regions in which opioids are known to regulate motivation and reward (i.e., the medial preoptic nucleus and ventral tegmental area) related positively to male song production. These data suggest that song production might be regulated by opioid activity within motivation and reward neural systems. PMID:15727529

  3. Photoperiod and water temperature regulation of seasonal reproduction in male round stingrays (Urobatis halleri).

    PubMed

    Mull, Christopher G; Lowe, Christopher G; Young, Kelly A

    2008-12-01

    This study characterizes the seasonal reproductive cycle of male round stingrays (Urobatis halleri) in Seal Beach, California. Mature round stingrays were collected monthly by beach seine near the San Gabriel River outfall from August 2004-September 2006, and rays were assessed for gametogenesis and steroid hormone levels. Male round stingrays exhibit a seasonal pattern of increased gonadosomatic index (GSI), spermatogenesis, and production of testosterone (T) and 11-ketotestosterone (11-KT). Based on GSI, the male reproductive cycle was broken into three distinct phases. TUNEL positive staining was only observed in the Sertoli cells of mature spermatocysts during the degenerative testicular phase, suggesting that Sertoli cell death potentially plays a role in testicular degeneration and the regulation of sperm release. GSI, T, and 11-KT were all inversely correlated with daylength, while only T was inversely correlated with temperature. Captive male round stingrays subjected to water temperatures of 25 degrees C showed a significant decrease in plasma testosterone concentrations, but the same males exposed to ambient water temperatures (18 degrees -20 degrees C) exhibited T concentrations observed in wild male round stingrays during the recrudescent phase. Together, these findings suggest that temperature plays an important role in the regulation of testosterone, and may serve as an ultimate cue for reproduction in male round stingrays.

  4. Self- and Social Regulation in Learning Contexts: An Integrative Perspective

    ERIC Educational Resources Information Center

    Volet, Simone; Vauras, Marja; Salonen, Pekka

    2009-01-01

    This article outlines the rationale for an integrative perspective of self- and social regulation in learning contexts. The role of regulatory mechanisms in self- and social regulation models is examined, leading to the view that in real time collaborative learning, individuals and social entities should be conceptualized as self-regulating and…

  5. Epigenetic regulation of the RHOX homeobox gene cluster and its association with human male infertility.

    PubMed

    Richardson, Marcy E; Bleiziffer, Andreas; Tüttelmann, Frank; Gromoll, Jörg; Wilkinson, Miles F

    2014-01-01

    The X-linked RHOX cluster encodes a set of homeobox genes that are selectively expressed in the reproductive tract. Members of the RHOX cluster regulate target genes important for spermatogenesis promote male fertility in mice. Studies show that demethylating agents strongly upregulate the expression of mouse Rhox genes, suggesting that they are regulated by DNA methylation. However, whether this extends to human RHOX genes, whether DNA methylation directly regulates RHOX gene transcription and how this relates to human male infertility are unknown. To address these issues, we first defined the promoter regions of human RHOX genes and performed gain- and loss-of-function experiments to determine whether human RHOX gene transcription is regulated by DNA methylation. Our results indicated that DNA methylation is necessary and sufficient to silence human RHOX gene expression. To determine whether RHOX cluster methylation associates with male infertility, we evaluated the methylation status of RHOX genes in sperm from a large cohort of infertility patients. Linear regression analysis revealed a strong association between RHOX gene cluster hypermethylation and three independent types of semen abnormalities. Hypermethylation was restricted specifically to the RHOX cluster; we did not observe it in genes immediately adjacent to it on the X chromosome. Our results strongly suggest that human RHOX homeobox genes are under an epigenetic control mechanism that is aberrantly regulated in infertility patients. We propose that hypermethylation of the RHOX gene cluster serves as a marker for idiopathic infertility and that it is a candidate to exert a causal role in male infertility.

  6. 7α-Hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail.

    PubMed

    Ogura, Yuki; Haraguchi, Shogo; Nagino, Koki; Ishikawa, Kei; Fukahori, Yoko; Tsutsui, Kazuyoshi

    2016-02-01

    In the Japanese quail, 7α-hydroxypregnenolone, a previously undescribed avian neurosteroid, is actively produced in the brain. 7α-Hydroxypregnenolone acts as a novel neuronal activator to stimulate locomotor activity of quail. Therefore, in this study, we determined whether 7α-hydroxypregnenolone changes the expression of sexual behavior in Japanese quail. We first measured diurnal changes in sexual behavior of male quail exposed to a long-day photoperiod. We found that sexual behavior of male quail was high in the morning when endogenous 7α-hydroxypregnenolone level is high. Subsequently, we centrally administered 7α-hydroxypregnenolone in the evening when endogenous 7α-hydroxypregnenolone level is low. In the 30 min after intracerebroventricular (ICV) injection, 7α-hydroxypregnenolone dose dependently increased the frequency of sexual behavior of male quail. However, 7β-hydroxypregnenolone, a stereoisomer of 7α-hydroxypregnenolone, did not effect on the frequency of sexual behavior of male quail. In addition, to confirm the action of 7α-hydroxypregnenolone on sexual behavior, male birds received an ICV injection of ketoconazole, an inhibitor of cytochrome P450s, and behavioral experiments were performed in the morning. Ketoconazole significantly decreased the frequency of sexual behavior of male quail, whereas administration of 7α-hydroxypregnenolone to ketoconazole-treated males increased the frequency of their sexual behavior. These results indicate that 7α-hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail.

  7. Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

    PubMed Central

    Auger, Jacques; Eustache, Florence; Rouiller-Fabre, Virginie; Canivenc-Lavier, Marie Chantal; Livera, Gabriel

    2014-01-01

    In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance (EAS) exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action (MOA) of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool (together with the epidemiological approach) for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction. PMID:24369134

  8. Integrative regulation of human brain blood flow

    PubMed Central

    Willie, Christopher K; Tzeng, Yu-Chieh; Fisher, Joseph A; Ainslie, Philip N

    2014-01-01

    Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research. PMID:24396059

  9. Epigenetic regulation of the RHOX homeobox gene cluster and its association with human male infertility

    PubMed Central

    Richardson, Marcy E.; Bleiziffer, Andreas; Tüttelmann, Frank; Gromoll, Jörg; Wilkinson, Miles F.

    2014-01-01

    The X-linked RHOX cluster encodes a set of homeobox genes that are selectively expressed in the reproductive tract. Members of the RHOX cluster regulate target genes important for spermatogenesis promote male fertility in mice. Studies show that demethylating agents strongly upregulate the expression of mouse Rhox genes, suggesting that they are regulated by DNA methylation. However, whether this extends to human RHOX genes, whether DNA methylation directly regulates RHOX gene transcription and how this relates to human male infertility are unknown. To address these issues, we first defined the promoter regions of human RHOX genes and performed gain- and loss-of-function experiments to determine whether human RHOX gene transcription is regulated by DNA methylation. Our results indicated that DNA methylation is necessary and sufficient to silence human RHOX gene expression. To determine whether RHOX cluster methylation associates with male infertility, we evaluated the methylation status of RHOX genes in sperm from a large cohort of infertility patients. Linear regression analysis revealed a strong association between RHOX gene cluster hypermethylation and three independent types of semen abnormalities. Hypermethylation was restricted specifically to the RHOX cluster; we did not observe it in genes immediately adjacent to it on the X chromosome. Our results strongly suggest that human RHOX homeobox genes are under an epigenetic control mechanism that is aberrantly regulated in infertility patients. We propose that hypermethylation of the RHOX gene cluster serves as a marker for idiopathic infertility and that it is a candidate to exert a causal role in male infertility. PMID:23943794

  10. Prenatal nicotine exposure alters postnatal cardiorespiratory integration in young male but not female rats

    PubMed Central

    Boychuk, Carie R.; Hayward, Linda F.

    2011-01-01

    The present study tested the hypothesis that prenatal nicotine exposure (PNE) induces sex specific alternations in indices of cardiorespiratory coupling during early development. Rat pups exposed to either nicotine (6mg/kg/day) or saline (control) in utero were chronically instrumented with ECG electrodes for measurement of heart rate (HR) and respiratory frequency (RF) was monitored by whole body plethysmography on postnatal days (P)13, P16 and P26. PNE had no identifiable effect on resting respiratory frequency (RF) in either sex. There was however a strong trend (p=0.057) for resting HR to be elevated by PNE in male offspring only. Alternatively, the HR response to hypoxia (10% O2), was significantly blunted at P13 but significantly elevated at P26 s in the absence of any significant change in RF in PNE males only. Indicators of respiratory sinus arrhythmia (RSA) were also significantly reduced in P26 PNE males. No significant effects of PNE on HR, RF or RSA were identified in female offspring at any age. Our results demonstrate that PNE induces very specific changes in cardiorespiratory integration at select postnatal ages and these changes are more prominent in males. Additionally, alternations in cardiorespiratory integration appear to persist into later development in males only, potentially increasing the risk for cardiovascular diseases such as hypertension later in life. PMID:21945005

  11. Maladaptive and adaptive emotion regulation through music: a behavioral and neuroimaging study of males and females.

    PubMed

    Carlson, Emily; Saarikallio, Suvi; Toiviainen, Petri; Bogert, Brigitte; Kliuchko, Marina; Brattico, Elvira

    2015-01-01

    Music therapists use guided affect regulation in the treatment of mood disorders. However, self-directed uses of music in affect regulation are not fully understood. Some uses of music may have negative effects on mental health, as can non-music regulation strategies, such as rumination. Psychological testing and functional magnetic resonance imaging (fMRI) were used explore music listening strategies in relation to mental health. Participants (n = 123) were assessed for depression, anxiety and Neuroticism, and uses of Music in Mood Regulation (MMR). Neural responses to music were measured in the medial prefrontal cortex (mPFC) in a subset of participants (n = 56). Discharge, using music to express negative emotions, related to increased anxiety and Neuroticism in all participants and particularly in males. Males high in Discharge showed decreased activity of mPFC during music listening compared with those using less Discharge. Females high in Diversion, using music to distract from negative emotions, showed more mPFC activity than females using less Diversion. These results suggest that the use of Discharge strategy can be associated with maladaptive patterns of emotional regulation, and may even have long-term negative effects on mental health. This finding has real-world applications in psychotherapy and particularly in clinical music therapy.

  12. Maladaptive and adaptive emotion regulation through music: a behavioral and neuroimaging study of males and females

    PubMed Central

    Carlson, Emily; Saarikallio, Suvi; Toiviainen, Petri; Bogert, Brigitte; Kliuchko, Marina; Brattico, Elvira

    2015-01-01

    Music therapists use guided affect regulation in the treatment of mood disorders. However, self-directed uses of music in affect regulation are not fully understood. Some uses of music may have negative effects on mental health, as can non-music regulation strategies, such as rumination. Psychological testing and functional magnetic resonance imaging (fMRI) were used explore music listening strategies in relation to mental health. Participants (n = 123) were assessed for depression, anxiety and Neuroticism, and uses of Music in Mood Regulation (MMR). Neural responses to music were measured in the medial prefrontal cortex (mPFC) in a subset of participants (n = 56). Discharge, using music to express negative emotions, related to increased anxiety and Neuroticism in all participants and particularly in males. Males high in Discharge showed decreased activity of mPFC during music listening compared with those using less Discharge. Females high in Diversion, using music to distract from negative emotions, showed more mPFC activity than females using less Diversion. These results suggest that the use of Discharge strategy can be associated with maladaptive patterns of emotional regulation, and may even have long-term negative effects on mental health. This finding has real-world applications in psychotherapy and particularly in clinical music therapy. PMID:26379529

  13. Maladaptive and adaptive emotion regulation through music: a behavioral and neuroimaging study of males and females.

    PubMed

    Carlson, Emily; Saarikallio, Suvi; Toiviainen, Petri; Bogert, Brigitte; Kliuchko, Marina; Brattico, Elvira

    2015-01-01

    Music therapists use guided affect regulation in the treatment of mood disorders. However, self-directed uses of music in affect regulation are not fully understood. Some uses of music may have negative effects on mental health, as can non-music regulation strategies, such as rumination. Psychological testing and functional magnetic resonance imaging (fMRI) were used explore music listening strategies in relation to mental health. Participants (n = 123) were assessed for depression, anxiety and Neuroticism, and uses of Music in Mood Regulation (MMR). Neural responses to music were measured in the medial prefrontal cortex (mPFC) in a subset of participants (n = 56). Discharge, using music to express negative emotions, related to increased anxiety and Neuroticism in all participants and particularly in males. Males high in Discharge showed decreased activity of mPFC during music listening compared with those using less Discharge. Females high in Diversion, using music to distract from negative emotions, showed more mPFC activity than females using less Diversion. These results suggest that the use of Discharge strategy can be associated with maladaptive patterns of emotional regulation, and may even have long-term negative effects on mental health. This finding has real-world applications in psychotherapy and particularly in clinical music therapy. PMID:26379529

  14. KATNAL1 Regulation of Sertoli Cell Microtubule Dynamics Is Essential for Spermiogenesis and Male Fertility

    PubMed Central

    Smith, Lee B.; Milne, Laura; Nelson, Nancy; Eddie, Sharon; Brown, Pamela; Atanassova, Nina; O'Bryan, Moira K.; O'Donnell, Liza; Rhodes, Danielle; Wells, Sara; Napper, Diane; Nolan, Patrick; Lalanne, Zuzanna; Cheeseman, Michael; Peters, Josephine

    2012-01-01

    Spermatogenesis is a complex process reliant upon interactions between germ cells (GC) and supporting somatic cells. Testicular Sertoli cells (SC) support GCs during maturation through physical attachment, the provision of nutrients, and protection from immunological attack. This role is facilitated by an active cytoskeleton of parallel microtubule arrays that permit transport of nutrients to GCs, as well as translocation of spermatids through the seminiferous epithelium during maturation. It is well established that chemical perturbation of SC microtubule remodelling leads to premature GC exfoliation demonstrating that microtubule remodelling is an essential component of male fertility, yet the genes responsible for this process remain unknown. Using a random ENU mutagenesis approach, we have identified a novel mouse line displaying male-specific infertility, due to a point mutation in the highly conserved ATPase domain of the novel KATANIN p60-related microtubule severing protein Katanin p60 subunit A-like1 (KATNAL1). We demonstrate that Katnal1 is expressed in testicular Sertoli cells (SC) from 15.5 days post-coitum (dpc) and that, consistent with chemical disruption models, loss of function of KATNAL1 leads to male-specific infertility through disruption of SC microtubule dynamics and premature exfoliation of spermatids from the seminiferous epithelium. The identification of KATNAL1 as an essential regulator of male fertility provides a significant novel entry point into advancing our understanding of how SC microtubule dynamics promotes male fertility. Such information will have resonance both for future treatment of male fertility and the development of non-hormonal male contraceptives. PMID:22654668

  15. Juvenile hormone regulation of male accessory gland activity in the red flour beetle, Tribolium castaneum

    PubMed Central

    Parthasarathy, R.; Tan, A.; Sun, Z.; Chen, J.; Rainkin, M.; Palli, S. R.

    2009-01-01

    Male accessory gland proteins (Acps) act as key modulators of reproductive success in insects by influencing the female reproductive physiology and behavior. We used custom microarrays and identified 112 genes that were highly expressed in male accessory glands (MAG) in the red flour beetle, Tribolium castaneum. Out of these 112 identified genes, 59 of them contained sequences coding for signal peptide and cleavage site and the remaining 53 contained transmembrane domains. The expression of 14 these genes in the MAG but not in other tissues of male or female was confirmed by quantitative real-time PCR. In virgin males, juvenile hormone (JH) levels increased from second day post adult emergence (PAE), remained high on third day PAE and declined on fourth day PAE. The ecdysteroid titers were high soon after adult emergence but declined to minimal levels from 1-5 days PAE. Feeding of juvenile hormone analog, hydroprene, but not the ecdysteroid analog, RH-2485, showed an increase in size of MAGs, as well as an increase in total RNA and protein content of MAG. Hydroprene treatment also increased the expression Acp genes in the MAG. RNAi-mediated knock-down in the expression of JHAMT gene decreased the size of MAGs and expression of Acps. JH deficiency influenced male reproductive fitness as evidenced by a less vigor in mating behavior, poor sperm transfer, low egg and the progeny production by females mated with the JH deficient males. These data suggest a critical role for JH in the regulation of male reproduction especially through MAG secretions. PMID:19324087

  16. Understanding the Relationships among Racial Identity, Self-Efficacy, Institutional Integration and Academic Achievement of Black Males Attending Research Universities

    ERIC Educational Resources Information Center

    Reid, Karl W.

    2013-01-01

    This study asserts that African American males with higher grade point averages (GPAs) in college are also academically and socially integrated into campus and hold racial identity attitudes and self-efficacy beliefs that facilitate their level of institutional integration. The statistical study of 190 African American males attending five…

  17. Lactate Regulates Rat Male Germ Cell Function through Reactive Oxygen Species

    PubMed Central

    Galardo, María Noel; Regueira, Mariana; Riera, María Fernanda; Pellizzari, Eliana Herminia; Cigorraga, Selva Beatriz; Meroni, Silvina Beatriz

    2014-01-01

    Besides giving structural support, Sertoli cells regulate the fate of germ cells by supplying a variety of factors. These factors include hormones, several pro- and anti-apoptotic agents and also energetic substrates. Lactate is one of the compounds produced by Sertoli cells, which is utilized as an energetic substrate by germ cells, particularly spermatocytes and spermatids. Beyond its function as an energy source, some studies have proposed a role of lactate in the regulation of gene expression not strictly related to the energetic state of the cells. The general hypothesis that motivated this investigation was that lactate affects male germ cell function, far beyond its well-known role as energetic substrate. To evaluate this hypothesis we investigated: 1) if lactate was able to regulate germ cell gene expression and if reactive oxygen species (ROS) participated in this regulation, 2) if different signal transduction pathways were modified by the production of ROS in response to lactate and 3) possible mechanisms that may be involved in lactate stimulation of ROS production. In order to achieve these goals, cultures of germ cells obtained from male 30-day old rats were exposed to 10 or 20 mM lactate. Increases in lactate dehydrogenase (LDH) C and monocarboxylate transporter (MCT)2 expression, in Akt and p38-MAPK phosphorylation levels and in ROS production were observed. These effects were impaired in the presence of a ROS scavenger. Lactate stimulated ROS production was also inhibited by a LDH inhibitor or a NAD(P)H oxidase (NOX) inhibitor. NOX4 expression was identified in male germ cells. The results obtained herein are consistent with a scenario where lactate, taken up by germ cells, becomes oxidized to pyruvate with the resultant increase in NADH, which is a substrate for NOX4. ROS, products of NOX4 activity, may act as second messengers regulating signal transduction pathways and gene expression. PMID:24498241

  18. Alcohol Use Among Female Sex Workers and Male Clients: An Integrative Review of Global Literature

    PubMed Central

    Li, Qing; Li, Xiaoming; Stanton, Bonita

    2010-01-01

    Aims: To review the patterns, contexts and impacts of alcohol use associated with commercial sex reported in the global literature. Methods: We identified peer-reviewed English-language articles from 1980 to 2008 reporting alcohol consumption among female sex workers (FSWs) or male clients. We retrieved 70 articles describing 76 studies, in which 64 were quantitative (52 for FSWs, 12 for male clients) and 12 qualitative. Results: Studies increased over the past three decades, with geographic concentration of the research in Asia and North America. Alcohol use was prevalent among FSWs and clients. Integrating quantitative and qualitative studies, multilevel contexts of alcohol use in the sex work environment were identified, including workplace and occupation-related use, the use of alcohol to facilitate the transition into and practice of commercial sex among both FSWs and male clients, and self-medication among FSWs. Alcohol use was associated with adverse physical health, illicit drug use, mental health problems, and victimization of sexual violence, although its associations with HIV/sexually transmitted infections and unprotected sex among FSWs were inconclusive. Conclusions: Alcohol use in the context of commercial sex is prevalent, harmful among FSWs and male clients, but under-researched. Research in this area in more diverse settings and with standardized measures is required. The review underscores the importance of integrated intervention for alcohol use and related problems in multilevel contexts and with multiple components in order to effectively reduce alcohol use and its harmful effects among FSWs and their clients. PMID:20089544

  19. Cytological, molecular mechanisms and temperature stress regulating production of diploid male gametes in Dianthus caryophyllus L.

    PubMed

    Zhou, Xuhong; Mo, Xijun; Gui, Min; Wu, Xuewei; Jiang, Yalian; Ma, Lulin; Shi, Ziming; Luo, Ying; Tang, Wenru

    2015-12-01

    In plant evolution, because of its key role in sexual polyploidization or whole genome duplication events, diploid gamete formation is considered as an important component in diversification and speciation. Environmental stress often triggers unreduced gamete production. However, the molecular, cellular mechanisms and adverse temperature regulating diplogamete production in carnation remain poorly understood. Here, we investigate the cytological basis for 2n male gamete formation and describe the isolation and characterization of the first gene, DcPS1 (Dianthus Caryophyllus Parallel Spindle 1). In addition, we analyze influence of temperature stress on diploid gamete formation and transcript levels of DcPS1. Cytological evidence indicated that 2n male gamete formation is attributable to abnormal spindle orientation at male meiosis II. DcPS1 protein is conserved throughout the plant kingdom and carries domains suggestive of a regulatory function. DcPS1 expression analysis show DcPS1 gene probably have a role in 2n pollen formation. Unreduced pollen formation in various cultivation was sensitive to high or low temperature which was probably regulated by the level of DcPS1 transcripts. In a broader perspective, these findings can have potential applications in fundamental polyploidization research and plant breeding programs.

  20. SCML2 Establishes the Male Germline Epigenome through Regulation of Histone H2A Ubiquitination

    PubMed Central

    Hasegawa, Kazuteru; Sin, Ho-Su; Maezawa, So; Broering, Tyler J.; Kartashov, Andrey V.; Alavattam, Kris G.; Ichijima, Yosuke; Zhang, Fan; Bacon, W. Clark; Greis, Kenneth D.; Andreassen, Paul R.; Barski, Artem; Namekawa, Satoshi H.

    2015-01-01

    SUMMARY Gametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells. PMID:25703348

  1. Octopamine neuromodulation regulates Gr32a-linked aggression and courtship pathways in Drosophila males.

    PubMed

    Andrews, Jonathan C; Fernández, María Paz; Yu, Qin; Leary, Greg P; Leung, Adelaine K W; Kavanaugh, Michael P; Kravitz, Edward A; Certel, Sarah J

    2014-05-01

    Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-Fru(M) neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway.

  2. Doublesex Regulates the Connectivity of a Neural Circuit Controlling Drosophila Male Courtship Song.

    PubMed

    Shirangi, Troy R; Wong, Allan M; Truman, James W; Stern, David L

    2016-06-20

    It is unclear how regulatory genes establish neural circuits that compose sex-specific behaviors. The Drosophila melanogaster male courtship song provides a powerful model to study this problem. Courting males vibrate a wing to sing bouts of pulses and hums, called pulse and sine song, respectively. We report the discovery of male-specific thoracic interneurons-the TN1A neurons-that are required specifically for sine song. The TN1A neurons can drive the activity of a sex-non-specific wing motoneuron, hg1, which is also required for sine song. The male-specific connection between the TN1A neurons and the hg1 motoneuron is regulated by the sexual differentiation gene doublesex. We find that doublesex is required in the TN1A neurons during development to increase the density of the TN1A arbors that interact with dendrites of the hg1 motoneuron. Our findings demonstrate how a sexual differentiation gene can build a sex-specific circuit motif by modulating neuronal arborization. PMID:27326931

  3. Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis

    PubMed Central

    Schellino, Roberta; Trova, Sara; Cimino, Irene; Farinetti, Alice; Jongbloets, Bart C.; Pasterkamp, R. Jeroen; Panzica, Giancarlo; Giacobini, Paolo; De Marchis, Silvia; Peretto, Paolo

    2016-01-01

    Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits. PMID:27782186

  4. Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development.

    PubMed

    Marcorelles, Pascale; Gillet, Danièle; Friocourt, Gaëlle; Ledé, Françoise; Samaison, Laura; Huguen, Geneviève; Ferec, Claude

    2012-03-01

    Sterility due to bilateral destruction in utero or in early infancy resulting in congenital absence of the vas deferens is the rule in male patients with cystic fibrosis. To understand the developmental pattern of this anomaly, the microscopic morphology of the male excretory system was analyzed during development and the expression of the cystic fibrosis transmembrane conductance regulator protein was explored by immunohistochemistry. We observed that cystic fibrosis fetuses had no excretory ducts agenesis or obstruction until 22 weeks of gestation. However, a focal inflammatory pattern and mucinous plugs in the oldest cystic fibrosis case suggested a disruptive mechanism. Immunolabeling of cytoplasmic epithelial cystic fibrosis transmembrane conductance regulator protein was demonstrated in all cystic fibrosis and control cases with a similar pattern of expression of the protein between age-matched controls and cystic fibrosis cases. At midgestation, an apical intensification appeared in both cystic fibrosis and control cases and was stable during the remainder of fetal life. No gradient of intensity could be detected between the different segments of the excretory tract. These findings are different from those reported in adults. The absence of any morphologic anomaly until 22 weeks of gestation, the focal destruction of the epithelial structures during the second trimester, and the chronological pattern of expression of cystic fibrosis transmembrane conductance regulator are of interest for a better understanding of the pathophysiology of this disease.

  5. A long noncoding RNA regulates photoperiod-sensitive male sterility, an essential component of hybrid rice.

    PubMed

    Ding, Jihua; Lu, Qing; Ouyang, Yidan; Mao, Hailiang; Zhang, Pingbo; Yao, Jialing; Xu, Caiguo; Li, Xianghua; Xiao, Jinghua; Zhang, Qifa

    2012-02-14

    Hybrid rice has greatly contributed to the global increase of rice productivity. A major component that facilitated the development of hybrids was a mutant showing photoperiod-sensitive male sterility (PSMS) with its fertility regulated by day length. Transcriptome studies have shown that large portions of the eukaryotic genomic sequences are transcribed to long noncoding RNAs (lncRNAs). However, the potential roles for only a few lncRNAs have been brought to light at present. Thus, great efforts have to be invested to understand the biological functions of lncRNAs. Here we show that a lncRNA of 1,236 bases in length, referred to as long-day-specific male-fertility-associated RNA (LDMAR), regulates PSMS in rice. We found that sufficient amount of the LDMAR transcript is required for normal pollen development of plants grown under long-day conditions. A spontaneous mutation causing a single nucleotide polymorphism (SNP) between the wild-type and mutant altered the secondary structure of LDMAR. This change brought about increased methylation in the putative promoter region of LDMAR, which reduced the transcription of LDMAR specifically under long-day conditions, resulting in premature programmed cell death (PCD) in developing anthers, thus causing PSMS. Thus, a lncRNA could directly exert a major effect on a trait like a structure gene, and a SNP could alter the function of a lncRNA similar to amino acid substitution in structural genes. Molecular elucidating of PSMS has important implications for understanding molecular mechanisms of photoperiod regulation of many biological processes and also for developing male sterile germplasms for hybrid crop breeding.

  6. A long noncoding RNA regulates photoperiod-sensitive male sterility, an essential component of hybrid rice

    PubMed Central

    Ding, Jihua; Lu, Qing; Ouyang, Yidan; Mao, Hailiang; Zhang, Pingbo; Yao, Jialing; Xu, Caiguo; Li, Xianghua; Xiao, Jinghua; Zhang, Qifa

    2012-01-01

    Hybrid rice has greatly contributed to the global increase of rice productivity. A major component that facilitated the development of hybrids was a mutant showing photoperiod-sensitive male sterility (PSMS) with its fertility regulated by day length. Transcriptome studies have shown that large portions of the eukaryotic genomic sequences are transcribed to long noncoding RNAs (lncRNAs). However, the potential roles for only a few lncRNAs have been brought to light at present. Thus, great efforts have to be invested to understand the biological functions of lncRNAs. Here we show that a lncRNA of 1,236 bases in length, referred to as long-day–specific male-fertility–associated RNA (LDMAR), regulates PSMS in rice. We found that sufficient amount of the LDMAR transcript is required for normal pollen development of plants grown under long-day conditions. A spontaneous mutation causing a single nucleotide polymorphism (SNP) between the wild-type and mutant altered the secondary structure of LDMAR. This change brought about increased methylation in the putative promoter region of LDMAR, which reduced the transcription of LDMAR specifically under long-day conditions, resulting in premature programmed cell death (PCD) in developing anthers, thus causing PSMS. Thus, a lncRNA could directly exert a major effect on a trait like a structure gene, and a SNP could alter the function of a lncRNA similar to amino acid substitution in structural genes. Molecular elucidating of PSMS has important implications for understanding molecular mechanisms of photoperiod regulation of many biological processes and also for developing male sterile germplasms for hybrid crop breeding. PMID:22308482

  7. Specific regulation of male rat liver cytosolic estrogen receptor by the modulator of the glucocorticoid receptor.

    PubMed

    Celiker, M Y; Haas, A; Saunders, D; Litwack, G

    1993-08-31

    Modulator is a novel low-molecular-weight organic compound that regulates activities of glucocorticoid and mineralocorticoid receptors as well as protein kinase C. In this study we show that male rat liver cytosolic estrogen receptor activation is inhibited by modulator in a dose-dependent manner. Fifty percent inhibition is obtained with 1 unit/ml modulator purified from bovine liver which is within the physiological concentration for modulator. However, sheep uterine cytosolic estrogen and androgen receptors are insensitive to regulation by modulator. Exogenous sodium molybdate treatment inhibits activation of all of these receptors of liver or uterus origin in an identical manner, further differentiating the effects of modulator and the molybdate anion. PMID:8363596

  8. The Lombard effect in male ultrasonic frogs: Regulating antiphonal signal frequency and amplitude in noise.

    PubMed

    Shen, Jun-Xian; Xu, Zhi-Min

    2016-01-01

    Acoustic communication in noisy environments presents a significant challenge for vocal animals because noise can interfere with animal acoustic signals by decreasing signal-to-noise ratios and masking signals. Birds and mammals increase call intensity or frequency as noise levels increase, but it is unclear to what extend this behavior is shared by frogs. Concave-eared torrent frogs (Odorrana tormota) have evolved the capacity to produce various calls containing ultrasonic harmonics and to communicate beside noisy streams. However, it is largely unclear how frogs regulate vocalization in response to increasing noise levels. We exposed male frogs to various levels of noise with playback of conspecific female courtship calls and recorded antiphonal signals and spontaneous short calls. Males were capable of rapidly adjusting fundamental frequency and amplitude of antiphonal signals as noise levels increased. The increment in fundamental frequency and amplitude was approximately 0.5 kHz and 3 dB with every 10 dB increase in noise level, indicating the presence of noise-dependent signal characteristics. Males showed the noise-tolerant adaption in response to female calls in noise level from 40 to 90 dB SPL. The results suggest that the noise-dependent signal characteristics in O. tormota have evolved as a strategy to cope with varying torrent noise. PMID:27345957

  9. Subacute toxicity assessment of diflubenzuron, an insect growth regulator, in adult male rats.

    PubMed

    de Barros, Aline Lima; Cavalheiro, Gabriela Finoto; de Souza, Alexsandra Vila Maior; Traesel, Giseli Karenina; Anselmo-Franci, Janete A; Kassuya, Cândida Aparecida Leite; Arena, Arielle Cristina

    2016-04-01

    Diflubenzuron (DFB), an insecticide and acaricide insect growth regulator, can be used in agriculture against insect predators and in public health programs, to control insects and vectors, mainly Aedes aegypti larvae. Due to the lack of toxicological assessments of this compound, the objective of the present study was to evaluate the toxicological effects of subacute exposure to the DFB insecticide in adult male rats. Adult male rats were exposed (gavage) to 0, 2, 4, or 8 mg/kg of DFB for 28 days. No clinical signs of toxicity were observed in the DFB-treated animals of the experimental groups. However, there was an increase in serum levels of alanine aminotransferase in the group that received 8 mg/kg/DFB/day and urea at doses of 4 and 8 mg/kg/DFB/day, without altering other biochemical or hematological parameters. The subacute exposure to the lowest dose of DFB caused significant decrease in testis weight, daily sperm production, and in number of sperm in the epididymis in relation to the control group. However, no alterations were observed in the sperm morphology, testicular, epididymis, liver and kidney histology, or testosterone levels. These findings unveiled the hazardous effects of DFB on male reproduction after the subacute exposure and special attention should be addressed to the effects of low doses of this pesticide.

  10. The Sex Determination Gene transformer Regulates Male-Female Differences in Drosophila Body Size.

    PubMed

    Rideout, Elizabeth J; Narsaiya, Marcus S; Grewal, Savraj S

    2015-12-01

    Almost all animals show sex differences in body size. For example, in Drosophila, females are larger than males. Although Drosophila is widely used as a model to study growth, the mechanisms underlying this male-female difference in size remain unclear. Here, we describe a novel role for the sex determination gene transformer (tra) in promoting female body growth. Normally, Tra is expressed only in females. We find that loss of Tra in female larvae decreases body size, while ectopic Tra expression in males increases body size. Although we find that Tra exerts autonomous effects on cell size, we also discovered that Tra expression in the fat body augments female body size in a non cell-autonomous manner. These effects of Tra do not require its only known targets doublesex and fruitless. Instead, Tra expression in the female fat body promotes growth by stimulating the secretion of insulin-like peptides from insulin producing cells in the brain. Our data suggest a model of sex-specific growth in which body size is regulated by a previously unrecognized branch of the sex determination pathway, and identify Tra as a novel link between sex and the conserved insulin signaling pathway.

  11. The Lombard effect in male ultrasonic frogs: Regulating antiphonal signal frequency and amplitude in noise

    PubMed Central

    Shen, Jun-Xian; Xu, Zhi-Min

    2016-01-01

    Acoustic communication in noisy environments presents a significant challenge for vocal animals because noise can interfere with animal acoustic signals by decreasing signal-to-noise ratios and masking signals. Birds and mammals increase call intensity or frequency as noise levels increase, but it is unclear to what extend this behavior is shared by frogs. Concave-eared torrent frogs (Odorrana tormota) have evolved the capacity to produce various calls containing ultrasonic harmonics and to communicate beside noisy streams. However, it is largely unclear how frogs regulate vocalization in response to increasing noise levels. We exposed male frogs to various levels of noise with playback of conspecific female courtship calls and recorded antiphonal signals and spontaneous short calls. Males were capable of rapidly adjusting fundamental frequency and amplitude of antiphonal signals as noise levels increased. The increment in fundamental frequency and amplitude was approximately 0.5 kHz and 3 dB with every 10 dB increase in noise level, indicating the presence of noise-dependent signal characteristics. Males showed the noise-tolerant adaption in response to female calls in noise level from 40 to 90 dB SPL. The results suggest that the noise-dependent signal characteristics in O. tormota have evolved as a strategy to cope with varying torrent noise. PMID:27345957

  12. Pituitary androgen receptor signalling regulates prolactin but not gonadotrophins in the male mouse.

    PubMed

    O'Hara, Laura; Curley, Michael; Tedim Ferreira, Maria; Cruickshanks, Lyndsey; Milne, Laura; Smith, Lee B

    2015-01-01

    Production of the androgen testosterone is controlled by a negative feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. Stimulation of testicular Leydig cells by pituitary luteinising hormone (LH) is under the control of hypothalamic gonadotrophin releasing hormone (GnRH), while suppression of LH secretion by the pituitary is controlled by circulating testosterone. Exactly how androgens exert their feedback control of gonadotrophin secretion (and whether this is at the level of the pituitary), as well as the role of AR in other pituitary cell types remains unclear. To investigate these questions, we exploited a transgenic mouse line (Foxg1 Cre/+; AR fl/y) which lacks androgen receptor in the pituitary gland. Both circulating testosterone and gonadotrophins are unchanged in adulthood, demonstrating that AR signalling is dispensable in the male mouse pituitary for testosterone-dependent regulation of LH secretion. In contrast, Foxg1 Cre/+; AR fl/y males have a significant increase in circulating prolactin, suggesting that, rather than controlling gonadotrophins, AR-signalling in the pituitary acts to suppress aberrant prolactin production in males.

  13. Pituitary Androgen Receptor Signalling Regulates Prolactin but Not Gonadotrophins in the Male Mouse

    PubMed Central

    O’Hara, Laura; Curley, Michael; Tedim Ferreira, Maria; Cruickshanks, Lyndsey; Milne, Laura; Smith, Lee B.

    2015-01-01

    Production of the androgen testosterone is controlled by a negative feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. Stimulation of testicular Leydig cells by pituitary luteinising hormone (LH) is under the control of hypothalamic gonadotrophin releasing hormone (GnRH), while suppression of LH secretion by the pituitary is controlled by circulating testosterone. Exactly how androgens exert their feedback control of gonadotrophin secretion (and whether this is at the level of the pituitary), as well as the role of AR in other pituitary cell types remains unclear. To investigate these questions, we exploited a transgenic mouse line (Foxg1Cre/+; ARfl/y) which lacks androgen receptor in the pituitary gland. Both circulating testosterone and gonadotrophins are unchanged in adulthood, demonstrating that AR signalling is dispensable in the male mouse pituitary for testosterone-dependent regulation of LH secretion. In contrast, Foxg1Cre/+; ARfl/y males have a significant increase in circulating prolactin, suggesting that, rather than controlling gonadotrophins, AR-signalling in the pituitary acts to suppress aberrant prolactin production in males. PMID:25799562

  14. The Lombard effect in male ultrasonic frogs: Regulating antiphonal signal frequency and amplitude in noise.

    PubMed

    Shen, Jun-Xian; Xu, Zhi-Min

    2016-01-01

    Acoustic communication in noisy environments presents a significant challenge for vocal animals because noise can interfere with animal acoustic signals by decreasing signal-to-noise ratios and masking signals. Birds and mammals increase call intensity or frequency as noise levels increase, but it is unclear to what extend this behavior is shared by frogs. Concave-eared torrent frogs (Odorrana tormota) have evolved the capacity to produce various calls containing ultrasonic harmonics and to communicate beside noisy streams. However, it is largely unclear how frogs regulate vocalization in response to increasing noise levels. We exposed male frogs to various levels of noise with playback of conspecific female courtship calls and recorded antiphonal signals and spontaneous short calls. Males were capable of rapidly adjusting fundamental frequency and amplitude of antiphonal signals as noise levels increased. The increment in fundamental frequency and amplitude was approximately 0.5 kHz and 3 dB with every 10 dB increase in noise level, indicating the presence of noise-dependent signal characteristics. Males showed the noise-tolerant adaption in response to female calls in noise level from 40 to 90 dB SPL. The results suggest that the noise-dependent signal characteristics in O. tormota have evolved as a strategy to cope with varying torrent noise.

  15. A role for preoptic glutamate in the regulation of male reproductive behavior.

    PubMed

    Dominguez, Juan M

    2009-02-01

    Although much progress has been made toward understanding the role of the medial preoptic area (MPOA) in the regulation of male reproductive behaviors, the precise mechanisms responsible for its activation during mating are largely unclear. Several studies implicate glutamate in this response. However, not until recently was there direct evidence supporting this hypothesis. Results obtained using in vivo microdialysis showed that levels of glutamate increased in the MPOA during mating, particularly with ejaculation. Levels then decreased rapidly following ejaculation, during a period of sexual quiescence. The magnitude of this decrease correlated with time spent in quiescence. Additionally, central administration of glutamate uptake inhibitors increased levels of glutamate and facilitated behavior. Glutamate activation of N-methyl-D-aspartate (NMDA) receptors in the MPOA is at least partly responsible for behavioral effects evoked by increase glutamate. This is evidenced by histological analysis of the MPOA, which shows that nearly all cells containing mating-induced Fos also contained NMDA receptors. Mating also increased phosphorylation of NMDA receptors, indicating receptor activation. Finally, bilateral microinjections of NMDA receptor antagonists inhibited copulation. This neurochemical, anatomical, and behavioral evidence points to a key role of preoptic glutamate in the regulation of sexual behavior in males. The implications of these findings are discussed.

  16. Zona occludens-2 is critical for blood-testis barrier integrity and male fertility.

    PubMed

    Xu, Jianliang; Anuar, Farhana; Ali, Safiah Mohamed; Ng, Mei Yong; Phua, Dominic C Y; Hunziker, Walter

    2009-10-01

    Tight junction integral membrane proteins such as claudins and occludin are tethered to the actin cytoskeleton by adaptor proteins, notably the closely related zonula occludens (ZO) proteins ZO-1, ZO-2, and ZO-3. All three ZO proteins have recently been inactivated in mice. Although ZO-3 knockout mice lack an obvious phenotype, animals deficient in ZO-1 or ZO-2 show early embryonic lethality. Here, we rescue the embryonic lethality of ZO-2 knockout mice by injecting ZO-2(-/-) embryonic stem (ES) cells into wild-type blastocysts to generate viable ZO-2 chimera. ZO-2(-/-) ES cells contribute extensively to different tissues of the chimera, consistent with an extraembryonic requirement for ZO-2 rather than a critical role in epiblast development. Adult chimera present a set of phenotypes in different organs. In particular, male ZO-2 chimeras show reduced fertility and pathological changes in the testis. Lanthanum tracer experiments show a compromised blood-testis barrier. Expression levels of ZO-1, ZO-3, claudin-11, and occludin are not apparently affected. ZO-1 and occludin still localize to the blood-testis barrier region, but claudin-11 is less well restricted and the localization of connexin-43 is perturbed. The critical role of ZO-2 for male fertility and blood-testis barrier integrity thus provides a first example for a nonredundant role of an individual ZO protein in adult mice.

  17. How can flexibility be integrated into coexistence regulations? A review.

    PubMed

    Devos, Yann; Dillen, Koen; Demont, Matty

    2014-02-01

    Member states in the European Union (EU) implemented both ex ante coexistence regulations and ex post liability schemes to ensure that genetically modified (GM) and non-GM crops can be cultivated side by side without excluding any agricultural option. Although proportionate coexistence is best achieved if regulated in a flexible manner, most implemented coexistence regulations merely rely on rigid measures. Flexible coexistence regulations, however, would reduce the regulatory burden on certain agricultural options and avoid jeopardizing economic incentives for coexistence. Flexibility can be integrated at: (i) the regulatory level by relaxing the rigidity of coexistence measures in ex ante regulations, yet without offsetting incentives to implement coexistence measures; (ii) the farm level by recommending the use of pollen barriers instead of large and fixed isolation distances; and (iii) the national/regional level by allowing diversified coexistence measures, which are adapted to the heterogeneity of farming in the EU. Owing to difficulties of implementation, the adoption of flexible and proportionate coexistence regulations will inevitably entail challenges.

  18. An Integrative Theory-Driven Positive Emotion Regulation Intervention

    PubMed Central

    Weytens, Fanny; Luminet, Olivier; Verhofstadt, Lesley L.; Mikolajczak, Moïra

    2014-01-01

    Over the past fifteen years, positive psychology research has validated a set of happiness enhancing techniques. These techniques are relatively simple exercises that allow happiness seekers to mimic thoughts and behavior of naturally happy people, in order to increase their level of well-being. Because research has shown that the joint use of these exercises increases their effects, practitioners who want to help happiness seekers need validated interventions that combine several of these techniques. To meet this need, we have developed and tested an integrative intervention (Positive Emotion Regulation program – PER program) incorporating a number of validated techniques structured around a theoretical model: the Process Model of Positive Emotion Regulation. To test the effectiveness of this program and to identify its added value relative to existing interventions, 113 undergraduate students were randomly assigned to a 6-week positive emotion regulation pilot program, a loving-kindness meditation training program, or a wait-list control group. Results indicate that fewer participants dropped out from the PER program than from the Loving-Kindness Meditation training. Furthermore, subjects in the PER group showed a significant increase in subjective well-being and life satisfaction and a significant decrease in depression and physical symptoms when compared to controls. Our results suggest that the Process Model of Positive Emotion Regulation can be an effective option to organize and deliver positive integrative interventions. PMID:24759870

  19. Regulating the balance between differentiation and apoptosis: role of CREM in the male germ cells.

    PubMed

    Sassone-Corsi, P

    1998-01-01

    Various endocrine and neuronal functions are governed by the cAMP-dependent signaling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signaling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members which may act as activators or repressors. These factors contain the basic domain/leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREBs requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. The gene CREM encodes various transcription factors which play key physiological and developmental roles within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREMtau is highly expressed in postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes which are under the hormonal control of the hypothalamic-pituitary axis. We have addressed the specific role of CREM in spermiogenesis using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium from mutant male mice reveals that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent while there is a significant increase in apoptotic germ cells. A series of postmeiotic germ cell-specific genes are not expressed. Mutant male mice completely lack spermatozoa. This phenotype is reminiscent of cases of human infertility.

  20. Regulation of the corpora allata in male larvae of the cockroach Diploptera punctata

    SciTech Connect

    Paulson, C.R.

    1986-01-01

    The regulation of corpora allata was studied in final instar males of Diploptera punctata. The glands were manipulated in vivo and removed to determine the effect by in vitro radiochemical assay for juvenile hormone synthesis. Corpora allata were also treated with putative regulatory factors in vitro. During the final stadium the corpora allata were inhibited both by nerves and by humoral factors. Neural inhibition was shown by an increase in juvenile hormone synthesis following denervation of the corpora allata. This operation elicited an extra larval instar. Humoral inhibition was shown by the decline in juvenile hormone synthesis of adult female corpora allata following transplantation into final instar larval hosts, and conversely the increase in juvenile hormone synthesis by larval corpora allata following implantation into adult females. Humoral inhibition was prevented by decapitation of larvae prior to the head critical period for molting and restored by implantation of a larval brain, showing that the brain is the source of this inhibition.

  1. Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline.

    PubMed

    Xie, Jing; Wooten, Matthew; Tran, Vuong; Chen, Bi-Chang; Pozmanter, Caitlin; Simbolon, Christine; Betzig, Eric; Chen, Xin

    2015-11-01

    A long-standing question concerns how stem cells maintain their identity through multiple divisions. Previously, we reported that pre-existing and newly synthesized histone H3 are asymmetrically distributed during Drosophila male germline stem cell (GSC) asymmetric division. Here, we show that phosphorylation at threonine 3 of H3 (H3T3P) distinguishes pre-existing versus newly synthesized H3. Converting T3 to the unphosphorylatable residue alanine (H3T3A) or to the phosphomimetic aspartate (H3T3D) disrupts asymmetric H3 inheritance. Expression of H3T3A or H3T3D specifically in early-stage germline also leads to cellular defects, including GSC loss and germline tumors. Finally, compromising the activity of the H3T3 kinase Haspin enhances the H3T3A but suppresses the H3T3D phenotypes. These studies demonstrate that H3T3P distinguishes sister chromatids enriched with distinct pools of H3 in order to coordinate asymmetric segregation of "old" H3 into GSCs and that tight regulation of H3T3 phosphorylation is required for male germline activity. PMID:26522592

  2. [Exploration of regulating blood lipids metabolism by integrative medicine].

    PubMed

    Liu, Shan-shan; Wu, Wei; Qing, Li-jin

    2015-02-01

    Hyperlipidemia is an important risk factor of cardio-/cerebrovascular disease, and reducing lipids has become an important project for itsclinical preventing and treating. Western medicine, with its confirmative efficacy and clear mechanism, has played an irreplaceable role. Along with the development of modern medicine, integrative medicine has gradually become a growing trend in regulating blood lipids metabolism. It not only could make up the insufficient power for Chinese medicine in lowering lipids, but also could reduce adverse reactions and economic costs brought by long-term administration of Western medicine. As a modern practitioner of Chinese medicine, we should keep clear that integrative medicine regulating blood lipids metabolism does not mean a simple combination of traditional Chinese medicine and Western medicine. We should treat it guided by systematic theories. We combine disease identification and syndrome differentiation, guide lipids lowering by integrative medicine including selecting Western drugs for blood lipids lowering, Chinese medical prescriptions for syndrome typing, and effective Chinese herbs based on modern pharmacologies.

  3. Regulation of Sclerostin Production in Human Male Osteocytes by Androgens: Experimental and Clinical Evidence.

    PubMed

    Di Nisio, Andrea; De Toni, Luca; Speltra, Elena; Rocca, Maria Santa; Taglialavoro, Giuseppe; Ferlin, Alberto; Foresta, Carlo

    2015-12-01

    In this study we aimed to elucidate a possible role of T in the regulation of sclerostin, a glycoprotein secreted by osteocytes known to regulate bone mass. To this end, we evaluated the effect of T stimulation on sclerostin production and gene expression in human cultured osteocytes. In addition, we evaluated serum sclerostin levels in a cohort of 20 hypogonadal male patients, compared with 20 age-matched eugonadal controls. Stimulation with DHT decreased sclerostin expression in cultured osteocytes in a time- and dose-dependent manner. Confirming a direct androgen receptor-mediated effect on sclerostin production, flutamide coincubation and silencing of androgen receptor gene in osteocytes abolished the DHT effects. In addition, hypogonadal patients showed higher serum sclerostin levels with respect to controls (145.87 ± 50.83 pg/mL vs 84.02 ± 32.15 pg/mL; P < .001) and in both probands and controls, serum T levels were negatively correlated with sclerostin (R = -0.664, P = 0.007, and R = -0.447, P = .045, respectively). Finally, multiple stepwise regression analysis showed that T represented the only independent predictor of sclerostin levels. In conclusion, by showing a direct correlation between T and sclerostin, both in vivo and in vitro, this study adds further support to the emerging clinical and experimental studies focusing on sclerostin as a therapeutic target for osteoporosis treatment.

  4. Regulation of paraoxonase 1 (PON1) in PCB 126-exposed male Sprague Dawley rats

    PubMed Central

    Shen, Hua; Robertson, Larry W.; Ludewig, Gabriele

    2012-01-01

    3,3′,4,4′,5-Pentachlorobiphenyl (PCB 126), an aryl hydrocarbon receptor (AhR) agonist and most potent dioxin-like PCB congener, significantly alters gene expression, lipid metabolism, and oxidative stress in the liver. PON1, an antioxidant and anti-atherogenic enzyme, is produced in the liver and secreted into the blood where it is incorporated into high density lipoprotein (HDL) and protects LDL and cellular membranes against lipid peroxidation. To explore the regulation of PON1, male Sprague-Dawley rats were treated with ip injections of 0, 1 or 5 μmol/kg PCB 126 and euthanized up to two weeks afterwards. Serum total and HDL-cholesterol were increased by low dose and decreased by high dose exposure, while LDL-cholesterol was unchanged. PCB 126 significantly increased hepatic PON1 gene expression and liver and serum PON1 activities. Liver and serum thiobarbituric acid reactive substances levels were not elevated except for high dose and long exposure times. Serum antioxidant capacity was unchanged across all exposure doses and time points. This study, the first describing the regulation of gene expression of PON1 by a PCB congener, raises interesting questions whether elevated PON1 is able to ameliorate PCB 126-induced lipid peroxidation and whether serum PON1 levels may serve as a new biomarker of exposure to dioxin-like compounds. PMID:22266287

  5. Chlordimeform-induced alterations in endocrine regulation within the male rat reproductive system.

    PubMed

    Goldman, J M; Cooper, R L; Laws, S C; Rehnberg, G L; Edwards, T L; McElroy, W K; Hein, J F

    1990-06-01

    The acaricide chlordimeform has been reported to have adverse effects in mammals that may be mediated by an interaction with alpha-adrenergic receptors. Since the hormonal signals involved in the regulation of reproductive function are themselves under hypothalamic adrenergic control, the present study was designed to investigate the effects of acute exposure to this compound on the hypothalamic-pituitary-testicular axis. Male rats given two intraperitoneal injections of chlordimeform-HCl (20 or 50 mg/kg) spaced 12 hr apart showed 24-hr declines in serum gonadotropins at 50 mg/kg that were paralleled by a drop in testosterone. These changes returned to control levels by 96 hr. Thyroid-stimulating hormone exhibited a dose-response decline that was accompanied by a similar decrease in serum thyroid hormone levels. The norepinephrine-stimulated secretion in vitro of gonadotropin-releasing hormone from hypothalamic explants was suppressed at the higher dose, while LH release from pituitary fragments in culture was unaffected. Although measurements of the in vitro release of other pituitary hormones suggest that there could be some direct pituitary effects of the compound, it appears likely that chlordimeform is able to influence endocrine regulation adversely within the reproductive system by interfering with hypothalamic alpha-adrenergic activity.

  6. Chronic unpredictable stress regulates visceral adipocyte‐mediated glucose metabolism and inflammatory circuits in male rats

    PubMed Central

    Karagiannides, Iordanes; Golovatscka, Viktoriya; Bakirtzi, Kyriaki; Sideri, Aristea; Salas, Martha; Stavrakis, Dimitris; Polytarchou, Christos; Iliopoulos, Dimitrios; Pothoulakis, Charalabos; Bradesi, Sylvie

    2014-01-01

    Abstract Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte‐associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high‐throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High‐throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress‐related disease states. PMID:24819750

  7. Ephrin-A5 regulates inter-male aggression in mice.

    PubMed

    Sheleg, Michal; Yochum, Carrie L; Richardson, Jason R; Wagner, George C; Zhou, Renping

    2015-06-01

    The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5(-/-)) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5(-/-) mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5(-/-) mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice.

  8. Steroidogenic factor 1 differentially regulates fetal and adult leydig cell development in male mice.

    PubMed

    Karpova, Tatiana; Ravichandiran, Kumarasamy; Insisienmay, Lovella; Rice, Daren; Agbor, Valentine; Heckert, Leslie L

    2015-10-01

    The nuclear receptor steroidogenic factor 1 (SF-1, AD4BP, NR5A1) is a key regulator of the endocrine axes and is essential for adrenal and gonad development. Partial rescue of Nr5a1(-/-) mice with an SF-1-expressing transgene caused a hypomorphic phenotype that revealed its roles in Leydig cell development. In contrast to controls, all male rescue mice (Nr5a1(-/-);tg(+/0)) showed varying signs of androgen deficiency, including spermatogenic arrest, cryptorchidism, and poor virilization. Expression of various Leydig cell markers measured by immunohistochemistry, Western blot analysis, and RT-PCR indicated fetal and adult Leydig cell development were differentially impaired. Whereas fetal Leydig cell development was delayed in Nr5a1(-/-);tg(+/0) embryos, it recovered to control levels by birth. In contrast, Sult1e1, Vcam1, and Hsd3b6 transcript levels in adult rescue testes indicated complete blockage in adult Leydig cell development. In addition, between Postnatal Days 8 and 12, peritubular cells expressing PTCH1, SF-1, and CYP11A1 were observed in control testes but not in rescue testes, indicating SF-1 is needed for either survival or differentiation of adult Leydig cell progenitors. Cultured prepubertal rat peritubular cells also expressed SF-1 and PTCH1, but Cyp11a1 was expressed only after treatment with cAMP and retinoic acid. Together, data show SF-1 is needed for proper development of fetal and adult Leydig cells but with distinct primary functions; in fetal Leydig cells, it regulates differentiation, whereas in adult Leydig cells it regulates progenitor cell formation and/or survival. PMID:26269506

  9. Steroidogenic factor 1 differentially regulates fetal and adult leydig cell development in male mice.

    PubMed

    Karpova, Tatiana; Ravichandiran, Kumarasamy; Insisienmay, Lovella; Rice, Daren; Agbor, Valentine; Heckert, Leslie L

    2015-10-01

    The nuclear receptor steroidogenic factor 1 (SF-1, AD4BP, NR5A1) is a key regulator of the endocrine axes and is essential for adrenal and gonad development. Partial rescue of Nr5a1(-/-) mice with an SF-1-expressing transgene caused a hypomorphic phenotype that revealed its roles in Leydig cell development. In contrast to controls, all male rescue mice (Nr5a1(-/-);tg(+/0)) showed varying signs of androgen deficiency, including spermatogenic arrest, cryptorchidism, and poor virilization. Expression of various Leydig cell markers measured by immunohistochemistry, Western blot analysis, and RT-PCR indicated fetal and adult Leydig cell development were differentially impaired. Whereas fetal Leydig cell development was delayed in Nr5a1(-/-);tg(+/0) embryos, it recovered to control levels by birth. In contrast, Sult1e1, Vcam1, and Hsd3b6 transcript levels in adult rescue testes indicated complete blockage in adult Leydig cell development. In addition, between Postnatal Days 8 and 12, peritubular cells expressing PTCH1, SF-1, and CYP11A1 were observed in control testes but not in rescue testes, indicating SF-1 is needed for either survival or differentiation of adult Leydig cell progenitors. Cultured prepubertal rat peritubular cells also expressed SF-1 and PTCH1, but Cyp11a1 was expressed only after treatment with cAMP and retinoic acid. Together, data show SF-1 is needed for proper development of fetal and adult Leydig cells but with distinct primary functions; in fetal Leydig cells, it regulates differentiation, whereas in adult Leydig cells it regulates progenitor cell formation and/or survival.

  10. Signal integration by Ca2+ regulates intestinal stem cell activity

    PubMed Central

    Deng, Hansong; Gerencser, Akos A.; Jasper, Heinrich

    2015-01-01

    Summary Somatic stem cells (SCs) maintain tissue homeostasis by dynamically adjusting proliferation and differentiation in response to stress and metabolic cues. Here, we identify Ca2+ signaling as a central regulator of intestinal SC (ISC) activity in Drosophila. We find that dietary L-glutamate stimulates ISC division and gut growth. The metabotropic glutamate receptor (mGluR) is required in ISCs for this response and for an associated modulation of cytosolic Ca2+ oscillations that results in sustained high cytosolic Ca2+ concentrations. High cytosolic Ca2+ induces ISC proliferation by regulating Calcineurin and CREB - regulated transcriptional co-activator (CRTC). In response to a wide range of dietary and stress stimuli, ISCs reversibly transition between Ca2+ oscillation states that represent poised or activated modes of proliferation, respectively. We propose that the dynamic regulation of intracellular Ca2+ levels allows effective integration of diverse mitogenic signals in ISCs to tailor their proliferative activity to the needs of the tissue. PMID:26633624

  11. Circuit-level input integration in bacterial gene regulation.

    PubMed

    Espinar, Lorena; Dies, Marta; Cagatay, Tolga; Süel, Gürol M; Garcia-Ojalvo, Jordi

    2013-04-23

    Gene regulatory circuits can receive multiple simultaneous inputs, which can enter the system through different locations. It is thus necessary to establish how these genetic circuits integrate multiple inputs as a function of their relative entry points. Here, we use the dynamic circuit regulating competence for DNA uptake in Bacillus subtilis as a model system to investigate this issue. Specifically, we map the response of single cells in vivo to a combination of (i) a chemical signal controlling the constitutive expression of key competence genes, and (ii) a genetic perturbation in the form of copy number variation of one of these genes, which mimics the level of stress signals sensed by the bacteria. Quantitative time-lapse fluorescence microscopy shows that a variety of dynamical behaviors can be reached by the combination of the two inputs. Additionally, the integration depends strongly on the relative locations where the two perturbations enter the circuit. Specifically, when the two inputs act upon different circuit elements, their integration generates novel dynamical behavior, whereas inputs affecting the same element do not. An in silico bidimensional bifurcation analysis of a mathematical model of the circuit offers good quantitative agreement with the experimental observations, and sheds light on the dynamical mechanisms leading to the different integrated responses exhibited by the gene regulatory circuit.

  12. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes.

    PubMed

    Sinnesael, Mieke; Claessens, Frank; Laurent, Michaël; Dubois, Vanessa; Boonen, Steven; Deboel, Ludo; Vanderschueren, Dirk

    2012-12-01

    Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L(5) vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age-related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes.

  13. The Social and Ecological Integration of Captive-Raised Adolescent Male African Elephants (Loxodonta africana) into a Wild Population

    PubMed Central

    Evans, Kate; Moore, Randall; Harris, Stephen

    2013-01-01

    Background A rapid rise in the number of captive African elephants (Loxodonta africana) used in the tourism industry in southern Africa and orphaned elephants in human care has led to concerns about their long-term management, particularly males. One solution is to release them into the wild at adolescence, when young males naturally leave their herd. However, this raises significant welfare concerns: little is known about how well released elephants integrate into wild populations and whether they pose a greater threat to humans than wild elephants. We document the release of three captive-raised adolescent male African elephants in the Okavango Delta, Botswana. Methodology/Principal Findings Despite having been part of a herd of working elephants for at least eight years, the three males progressively integrated into the complex fission-fusion society of wild bull elephants. In the three years following release, they showed no tendency to be closer to human habitation, and there were no significant differences between wild and captive-raised adolescent males in the total number of social interactions, size of ranges and habitat use. However, the captive-raised elephants sparred less and vocalised more, and spent more time alone and in smaller social groups. Thereafter the released elephants continued to expand their ranges and interact with both mixed-sex herds and males. One male was shot by farmers 94 months after release, along with ten wild elephants, on a ranch outside the protected area. Conclusions/Significance We show that captive-raised adolescent male elephants can integrate into a wild population. Long-term studies are required to determine the longevity, breeding success, and eventual fate of released male elephants, but we identified no significant short-term welfare problems for the released elephants or recipient population. Release of captive-raised mammals with complex social systems is a husbandry option that should be explored further. PMID

  14. Whole-animal genome-wide RNAi screen identifies networks regulating male germline stem cells in Drosophila

    PubMed Central

    Liu, Ying; Ge, Qinglan; Chan, Brian; Liu, Hanhan; Singh, Shree Ram; Manley, Jacob; Lee, Jae; Weideman, Ann Marie; Hou, Gerald; Hou, Steven X.

    2016-01-01

    Stem cells are regulated both intrinsically and externally, including by signals from the local environment and distant organs. To identify genes and pathways that regulate stem-cell fates in the whole organism, we perform a genome-wide transgenic RNAi screen through ubiquitous gene knockdowns, focusing on regulators of adult Drosophila testis germline stem cells (GSCs). Here we identify 530 genes that regulate GSC maintenance and differentiation. Of these, we further knock down 113 selected genes using cell-type-specific Gal4s and find that more than half were external regulators, that is, from the local microenvironment or more distal sources. Some genes, for example, versatile (vers), encoding a heterochromatin protein, regulates GSC fates differentially in different cell types and through multiple pathways. We also find that mitosis/cytokinesis proteins are especially important for male GSC maintenance. Our findings provide valuable insights and resources for studying stem cell regulation at the organismal level. PMID:27484291

  15. The male fight-flight response: a result of SRY regulation of catecholamines?

    PubMed

    Lee, Joohyung; Harley, Vincent R

    2012-06-01

    The SRY gene, which is located on the Y chromosome and directs male development, may promote aggression and other traditionally male behavioural traits, resulting in the fight-or-flight reaction to stress.

  16. Integrating acute lung injury and regulation of alveolar fluid clearance.

    PubMed

    Guidot, David M; Folkesson, Hans G; Jain, Lucky; Sznajder, Jacob I; Pittet, Jean-François; Matthay, Michael A

    2006-09-01

    The acute respiratory distress syndrome (ARDS) is characterized by non-cardiogenic pulmonary edema and flooding of the alveolar air spaces with proteinaceous fluid. ARDS develops in response to inflammatory stresses including sepsis, trauma, and severe pneumonia, and despite aggressive critical care management, it still has a mortality of 30-50%. At the time of its original description in 1967, relatively little was known about the specific mechanisms by which the alveolar epithelium regulated lung fluid balance. Over the last 20 years, substantial advances in our understanding of the alveolar epithelium have provided major new insights into how molecular and cellular mechanisms regulate the active transport of solutes and fluid across the alveolar epithelium under both normal and pathological conditions. Beginning with the elucidation of active sodium transport as a major driving force for the transport of water from the air space to the interstitium, elegant work by multiple investigators has revealed a complex and integrated network of membrane channels and pumps that coordinately regulates sodium, chloride, and water flux in both a cell- and condition-specific manner. At the Experimental Biology Meeting in San Francisco on April 4, 2006, a symposium was held to discuss some of the most recent advances. Although there is still much to learn about the mechanisms that impair normal alveolar fluid clearance under pathological conditions, the compelling experimental findings presented in this symposium raise the prospect that we are now poised to test and develop therapeutic strategies to improve outcome in patients with acute lung injury. PMID:16698856

  17. Hormonal regulation of prolactin receptors in male rat target tissues: the effect of hypothyroidism and adrenalectomy.

    PubMed

    Kharroubi, A T; Slaunwhite, W R

    1984-10-01

    The effects of hypothyroidism and adrenalectomy (ADX) on PRL receptors as well as the subcellular distribution of PRL-binding sites in adult male rat target tissues were investigated. In ventral prostate, kidney, and adrenal, PRL-binding activity was enriched in the 15,000 X g pellet (mitochondrial/Golgi fraction). The zona fasiculata/reticularis plus medulla of the adrenal had higher PRL-binding activity than the zona glomerulosa (plus capsule). Propylthiouracil-induced hypothyroidism significantly decreased PRL binding to kidney (65%) and testis (50%), and 16-h replacement with T4 restored PRL binding to control levels. T4 was, however, without effect on renal PRL binding in hypothyroid castrated rats, indicating that androgen may be required for this response. The increase in PRL binding to ventral prostate and adrenal due to hypothyroidism was not reversed within 16 h of T4 injection, whereas T3 injection decreased PRL binding to ventral prostate within 12 h. ADX increased PRL binding to rat testis (38%) and kidney (18%), and 5-day replacement with dexamethasone decreased PRL binding to levels lower than those in control rats. ADX had no effect, and dexamethasone treatment decreased (16-20%) PRL binding to ventral prostate and hCG binding to rat testis. The modulation of PRL receptors by hypothyroidism and ADX suggests that thyroid and adrenal hormones play a role in the regulation of PRL receptors. PMID:6090097

  18. Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis

    PubMed Central

    Sheng, X. Rebecca; Posenau, Trevor; Gumulak-Smith, Juliann J.; Matunis, Erika; Van Doren, Mark; Wawersik, Matthew

    2009-01-01

    Summary Germline stem cells (GSCs) in Drosophila are descendants of primordial germ cells (PGCs) specified during embryogenesis. The precise timing of GSC establishment in the testis has not been determined, nor is it known whether mechanisms that control GSC maintenance in the adult are involved in GSC establishment. Here, we determine that PGCs in the developing male gonad first become GSCs at the embryo to larval transition. This coincides with formation of the embryonic hub; the critical signaling center that regulates adult GSC behavior within the stem cell microenvironment (niche). We find that the Jak-STAT signaling pathway is activated in a subset of PGCs that associate with the newly-formed embryonic hub. These PGCs express GSC markers and function like GSCs, while PGCs that do not associate with the hub begin to differentiate. In the absence of Jak-STAT activation, PGCs adjacent to the hub fail to exhibit the characteristics of GSCs, while ectopic activation of the Jak-STAT pathway prevents differentiation. These findings show that stem cell formation is closely linked to development of the stem cell niche, and suggest that Jak-STAT signaling is required for initial establishment of the GSC population in developing testes. PMID:19643104

  19. An integrative model of ion regulation in yeast.

    PubMed

    Ke, Ruian; Ingram, Piers J; Haynes, Ken

    2013-01-01

    Yeast cells are able to tolerate and adapt to a variety of environmental stresses. An essential aspect of stress adaptation is the regulation of monovalent ion concentrations. Ion regulation determines many fundamental physiological parameters, such as cell volume, membrane potential, and intracellular pH. It is achieved through the concerted activities of multiple cellular components, including ion transporters and signaling molecules, on both short and long time scales. Although each component has been studied in detail previously, it remains unclear how the physiological parameters are maintained and regulated by the concerted action of all components under a diverse range of stress conditions. In this study, we have constructed an integrated mathematical model of ion regulation in Saccharomyces cerevisiae to understand this coordinated adaptation process. Using this model, we first predict that the interaction between phosphorylated Hog1p and Tok1p at the plasma membrane inhibits Tok1p activity and consequently reduces Na(+) influx under NaCl stress. We further characterize the impacts of NaCl, sorbitol, KCl and alkaline pH stresses on the cellular physiology and the differences between the cellular responses to these stresses. We predict that the calcineurin pathway is essential for maintaining a non-toxic level of intracellular Na(+) in the long-term adaptation to NaCl stress, but that its activation is not required for maintaining a low level of Na(+) under other stresses investigated. We provide evidence that, in addition to extrusion of toxic ions, Ena1p plays an important role, in some cases alongside Nha1p, in re-establishing membrane potential after stress perturbation. To conclude, this model serves as a powerful tool for both understanding the complex system-level properties of the highly coordinated adaptation process and generating further hypotheses for experimental investigation.

  20. Photoperiod regulates growth of male accessory glands through juvenile hormone signaling in the linden bug, Pyrrhocoris apterus.

    PubMed

    Urbanová, Veronika; Bazalová, Olga; Vaněčková, Hanka; Dolezel, David

    2016-03-01

    Adult reproductive diapause is characterized by lower behavioral activity, ceased reproduction and absence of juvenile hormone (JH). The role of JH receptor Methoprene-tolerant (Met) in female reproduction is well established; however, its function in male reproductive development and behavior is unclear. In the bean bug, Riptortus pedestris, circadian genes are essential for mediating photoperiodically-dependent growth of the male accessory glands (MAGs). The present study explores the role of circadian genes and JH receptor in male diapause in the linden bug, Pyrrhocoris apterus. These data indicate that circadian factors Clock, Cycle and Cry2 are responsible for photoperiod measurement, whereas Met and its partner protein Taiman participate in JH reception. Surprisingly, knockdown of the JH receptor neither lowered locomotor activity nor reduced mating behavior of males. These data suggest existence of a parallel, JH-independent or JH-upstream photoperiodic regulation of reproductive behavior. PMID:26826599

  1. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

    PubMed Central

    Zhang, Qian; Dove, Christopher G.; Hor, Jyh Liang; Murdock, Heardley M.; Strauss-Albee, Dara M.; Garcia, Jordan A.; Mandl, Judith N.; Grodick, Rachael A.; Jing, Huie; Chandler-Brown, Devon B.; Lenardo, Timothy E.; Crawford, Greg; Matthews, Helen F.; Freeman, Alexandra F.; Cornall, Richard J.; Germain, Ronald N.

    2014-01-01

    DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin. PMID:25422492

  2. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity.

    PubMed

    Zhang, Qian; Dove, Christopher G; Hor, Jyh Liang; Murdock, Heardley M; Strauss-Albee, Dara M; Garcia, Jordan A; Mandl, Judith N; Grodick, Rachael A; Jing, Huie; Chandler-Brown, Devon B; Lenardo, Timothy E; Crawford, Greg; Matthews, Helen F; Freeman, Alexandra F; Cornall, Richard J; Germain, Ronald N; Mueller, Scott N; Su, Helen C

    2014-12-15

    DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin. PMID:25422492

  3. Dgcr8 and Dicer are essential for sex chromosome integrity during meiosis in males

    PubMed Central

    Modzelewski, Andrew J.; Hilz, Stephanie; Crate, Elizabeth A.; Schweidenback, Caterina T. H.; Fogarty, Elizabeth A.; Grenier, Jennifer K.; Freire, Raimundo; Cohen, Paula E.; Grimson, Andrew

    2015-01-01

    ABSTRACT Small RNAs play crucial roles in regulating gene expression during mammalian meiosis. To investigate the function of microRNAs (miRNAs) and small interfering RNAs (siRNAs) during meiosis in males, we generated germ-cell-specific conditional deletions of Dgcr8 and Dicer in mice. Analysis of spermatocytes from both conditional knockout lines revealed that there were frequent chromosomal fusions during meiosis, always involving one or both sex chromosomes. RNA sequencing indicates upregulation of Atm in spermatocytes from miRNA-deficient mice, and immunofluorescence imaging demonstrates an increased abundance of activated ATM kinase and mislocalization of phosphorylated MDC1, an ATM phosphorylation substrate. The Atm 3′UTR contains many potential microRNA target sites, and, notably, target sites for several miRNAs depleted in both conditional knockout mice were highly effective at promoting repression. RNF8, a telomere-associated protein whose localization is controlled by the MDC1–ATM kinase cascade, normally associates with the sex chromosomes during pachytene, but in both conditional knockouts redistributed to the autosomes. Taken together, these results suggest that Atm dysregulation in microRNA-deficient germ lines contributes to the redistribution of proteins involved in chromosomal stability from the sex chromosomes to the autosomes, resulting in sex chromosome fusions during meiotic prophase I. PMID:25934699

  4. Dgcr8 and Dicer are essential for sex chromosome integrity during meiosis in males.

    PubMed

    Modzelewski, Andrew J; Hilz, Stephanie; Crate, Elizabeth A; Schweidenback, Caterina T H; Fogarty, Elizabeth A; Grenier, Jennifer K; Freire, Raimundo; Cohen, Paula E; Grimson, Andrew

    2015-06-15

    Small RNAs play crucial roles in regulating gene expression during mammalian meiosis. To investigate the function of microRNAs (miRNAs) and small interfering RNAs (siRNAs) during meiosis in males, we generated germ-cell-specific conditional deletions of Dgcr8 and Dicer in mice. Analysis of spermatocytes from both conditional knockout lines revealed that there were frequent chromosomal fusions during meiosis, always involving one or both sex chromosomes. RNA sequencing indicates upregulation of Atm in spermatocytes from miRNA-deficient mice, and immunofluorescence imaging demonstrates an increased abundance of activated ATM kinase and mislocalization of phosphorylated MDC1, an ATM phosphorylation substrate. The Atm 3'UTR contains many potential microRNA target sites, and, notably, target sites for several miRNAs depleted in both conditional knockout mice were highly effective at promoting repression. RNF8, a telomere-associated protein whose localization is controlled by the MDC1-ATM kinase cascade, normally associates with the sex chromosomes during pachytene, but in both conditional knockouts redistributed to the autosomes. Taken together, these results suggest that Atm dysregulation in microRNA-deficient germ lines contributes to the redistribution of proteins involved in chromosomal stability from the sex chromosomes to the autosomes, resulting in sex chromosome fusions during meiotic prophase I.

  5. Integrated action of pheromone signals in promoting courtship behavior in male mice.

    PubMed

    Haga-Yamanaka, Sachiko; Ma, Limei; He, Jie; Qiu, Qiang; Lavis, Luke D; Looger, Loren L; Yu, C Ron

    2014-01-01

    The mammalian vomeronasal organ encodes pheromone information about gender, reproductive status, genetic background and individual differences. It remains unknown how pheromone information interacts to trigger innate behaviors. In this study, we identify vomeronasal receptors responsible for detecting female pheromones. A sub-group of V1re clade members recognizes gender-identifying cues in female urine. Multiple members of the V1rj clade are cognate receptors for urinary estrus signals, as well as for sulfated estrogen (SE) compounds. In both cases, the same cue activates multiple homologous receptors, suggesting redundancy in encoding female pheromone cues. Neither gender-specific cues nor SEs alone are sufficient to promote courtship behavior in male mice, whereas robust courtship behavior can be induced when the two cues are applied together. Thus, integrated action of different female cues is required in pheromone-triggered mating behavior. These results suggest a gating mechanism in the vomeronasal circuit in promoting specific innate behavior.DOI: http://dx.doi.org/10.7554/eLife.03025.001.

  6. Integrative network analysis reveals molecular mechanisms of blood pressure regulation.

    PubMed

    Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3(-/-) mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.

  7. Integrative network analysis reveals molecular mechanisms of blood pressure regulation.

    PubMed

    Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel

    2015-04-01

    Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.

  8. HABP2 is a Novel Regulator of Vascular Integrity

    PubMed Central

    Mambetsariev, N.; Mirzapoiazova, T.; Mambetsariev, B.; Sammani, S.; Lennon, F.E.; Garcia, J.G.N.; Singleton, P.A.

    2010-01-01

    Objective We evaluated the role of the extracellular serine protease, Hyaluronic Acid Binding Protein 2 (HABP2), in vascular barrier regulation. Methods and Results Using immunoblot and immunohistochemical analysis, we observed that lipopolysaccharide (LPS)-induces HABP2 expression in murine lung endothelium in vivo and in human pulmonary microvascular endothelial cell (HPMVEC) in vitro. High molecular weight hyaluronan (HMW-HA, ~1 million Da) decreased HABP2 protein expression in HPMVEC and decreased purified HABP2 enzymatic activity whereas low MW HA (LMW-HA, ~2,500 Da) increased these activities. The effects of LMW-HA on HABP2 activity, but not HMW-HA, were inhibited with a peptide of the polyanion binding domain (PABD) of HABP2. Silencing (siRNA) HABP2 expression augmented HMW-HA-induced EC barrier enhancement and inhibited LPS and LMW-HA-mediated EC barrier disruption, results which were reversed with overexpression of HABP2. Silencing PAR receptors 1 and 3, RhoA or ROCK expression attenuated LPS, LMW-HA and HABP2-mediated EC barrier disruption. Utilizing murine models of acute lung injury, we observed that LPS- and ventilator-induced pulmonary vascular hyper-permeability were significantly reduced with vascular silencing (siRNA) of HABP2. Conclusions HABP2 negatively regulates vascular integrity via activation of PAR receptor/RhoA/ROCK signaling and represents a potentially useful therapeutic target for syndromes of increased vascular permeability. PMID:20042707

  9. Sexual systems and dwarf males in barnacles: integrating life history and sex allocation theories.

    PubMed

    Yamaguchi, Sachi; Yusa, Yoichi; Sawada, Kota; Takahashi, Satoshi

    2013-03-01

    Barnacles, which are sedentary marine crustaceans, have diverse sexual systems that include simultaneous hermaphroditism, androdioecy (coexistence of hermaphrodites and males) and dioecy (females and males). In dioecious and androdioecious species, the males are very small and are thus called dwarf males. These sexual systems are defined by two factors: sex allocation of non-dwarf individuals and the presence or absence of dwarf males. We constructed an ESS model treating sex allocation and life history simultaneously to explain sexual systems in barnacles. We analyzed the evolutionarily stable size-dependent resource allocation strategy to male reproductive function, female reproductive function and growth in non-dwarf barnacles, and the ESS proportion of dwarf males, under conditions of varying mortality and food availability. Sex allocation in non-dwarf individuals (hermaphrodites or females) is affected by mate availability and the proportion of dwarf males. When hermaphrodites appear, all hermaphrodites become protandric simultaneous hermaphrodites. Furthermore, high mortality and poor resource availability favor dwarf males because of their early maturation and weakened sperm competition. In conclusion, we showed that combining sex allocation and life history theories is a useful way to understand various sexual systems in barnacles and perhaps in other organisms as well.

  10. Genetic mapping of male pheromone response in the European corn borer identifies candidate genes regulating neurogenesis

    PubMed Central

    Dekker, Teun; Heckel, David G.

    2016-01-01

    The sexual pheromone communication system of moths is a model system for studies of the evolution of reproductive isolation. Females emit a blend of volatile components that males detect at a distance. Species differences in female pheromone composition and male response directly reinforce reproductive isolation in nature, because even slight variations in the species-specific pheromone blend are usually rejected by the male. The mechanisms by which a new pheromone signal–response system could evolve are enigmatic, because any deviation from the optimally attractive blend should be selected against. Here we investigate the genetic mechanisms enabling a switch in male response. We used a quantitative trait locus-mapping approach to identify the genetic basis of male response in the two pheromone races of the European corn borer, Ostrinia nubilalis. Male response to a 99:1 vs. a 3:97 ratio of the E and Z isomers of the female pheromone is governed by a single, sex-linked locus. We found that the chromosomal region most tightly linked to this locus contains genes involved in neurogenesis but, in accordance with an earlier study, does not contain the odorant receptors expressed in the male antenna that detect the pheromone. This finding implies that differences in the development of neuronal pathways conveying information from the antenna, not differences in pheromone detection by the odorant receptors, are primarily responsible for the behavioral response differences among the males in this system. Comparison with other moth species reveals a previously unexplored mechanism by which male pheromone response can change in evolution. PMID:27698145

  11. Integrity of the permeability barrier regulates epidermal Langerhans cell density.

    PubMed

    Proksch, E; Brasch, J; Sterry, W

    1996-04-01

    Previous studies have shown that barrier requirements regulate epidermal liquid and DNA synthesis. In the present study, we examined the possibility that the integrity of the permeability barrier influences epidermal Langerhans cells involved with the immune response. Barrier disruption was achieved by treatment of human skin with acetone, sodium dodecylsulphate (SDS), or tape stripping, until a 10-20-fold increase in transepidermal water loss was achieved. Serial biopsies were performed 6-168 h after treatment, and Langerhans cells were complexed with anti-CD1a (Leu6) or S-100 antibodies, and visualized with an immunoperoxidase technique. Acetone treatment resulted in an increase in epidermal Langerhans cell density, reaching a maximum of 94% over control (P < 0.01) by 24 and 48 h post-treatment. Following SDS treatment or tape stripping, epidermal Langerhans cell density was increased by 100 and 175% (P < 0.01), respectively. There was a linear correlation between the degree of barrier disruption and the increase in epidermal Langerhans cell density. Studies with the Ki-S3 proliferation-associated nuclear antigen revealed a two- to threefold increase in epidermal proliferation after barrier disruption. The time curves of the increase in Langerhans cell density and the increase in epidermal proliferation were similar, suggesting that there was a coordinate regulation. In contrast with our previous studies employing patch test reactions to allergens or irritants, disruption of barrier function neither resulted in an increased dermal Langerhans cell density, nor influenced T lymphocytes (CD3+, Leu4+), macrophages (KiM8+), ICAM-1 or ELAM-1 expression in the skin. In addition, barrier disruption did not result in either dermal inflammation or epidermal spongiosis. In summary, these findings support our hypothesis that the permeability barrier influences epidermal Langerhans cell density, which is involved in maintaining an immunological barrier.

  12. Integrating membrane transport with male gametophyte development and function through transcriptomics(1)[W

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Male fertility depends on the proper development of the male gametophyte, successful pollen germination, tube growth, and delivery of the sperm cells to the ovule. Previous studies have shown that nutrients like boron, and ion gradients or currents of Ca(2+), H(+), and K(+) are critical for pollen ...

  13. Integration of human sleep-wake regulation and circadian rhythmicity

    NASA Technical Reports Server (NTRS)

    Dijk, Derk-Jan; Lockley, Steven W.

    2002-01-01

    The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.

  14. The role of growth hormone and insulin-like growth factor I in the regulation of male reproductive function.

    PubMed

    Spiteri-Grech, J; Nieschlag, E

    1992-01-01

    Animal experiments and clinical studies on the interactions between growth hormone (GH) and the male hypothalamic-pituitary-gonadal axis have predominantly concentrated on GH and sex steroid interactions in the regulation of growth and development, or on the metabolic effects of GH. In contrast, little attention has been paid to the possible effects of GH on spermatogenesis, although the first report dealing with this topic was published almost 30 years ago. The interactions of GH and its main mediator, insulin-like growth factor I (IGF-I), with the hypothalamic-pituitary-gonadal axis, and their role in spermatogenesis have recently been investigated using in vitro systems and different animal models (mice and rats). Using Leydig and Sertoli cell cultures, complex interactions between GH/IGF-I and the gonadotropins affecting differentiated cell functions, e.g. steroidogenesis and cell division, have been demonstrated at the cellular level. In vivo studies using immature and mature hypophysectomized rats and GH-deficient mutant male mice and rats indicate that IGF-I can play an important role in the regulation of steroidogenesis and spermatogenesis. Furthermore, although follicle-stimulating hormone and luteinizing hormone are the major regulators of testicular IGF-I production, GH may play an indirect role by potentiating the actions of the gonadotropins in regulating testicular IGF-I content. A large proportion of men presenting at male-infertility clinics are diagnosed as having idiopathic infertility. Further studies are necessary to investigate whether defects associated with GH and/or IGF-I effects in the testis are the cause of male infertility in a small group of these patients.

  15. Central oxytocin regulates social familiarity and scent marking behavior that involves amicable odor signals between male mice.

    PubMed

    Arakawa, Hiroyuki; Blanchard, D Caroline; Blanchard, Robert J

    2015-07-01

    The effect of oxytocin on social behavior and odor communication was investigated in male C57BL/6J mice. In three-male colonies, in visible burrow systems, icv oxytocin (OT) infusion before colony formation substantially increased huddling together over the initial 8 h of grouping, accompanied by decreased expression of a number of social approaches associated with conspecific aggression and defense. OT antagonist infusion had little impact on expression of social approaches but decreased time engaging in social components including huddle over the initial 8 h. These results demonstrate a linkage of social familiarity to OT availability in the brain. In a scent marking paradigm central infusion of OT reduced territorial marking towards male conspecifics, and this in turn reduced the scent marking of untreated stimulus males to OT-infused subjects. Infusion of an OT antagonist into stimulus mice who were confronted with OT-infused subjects prevented the reduction/suppression of scent marking that was normally seen following exposure of social odors released from OT-injected mice. Odor of pair-housed mice also induced a suppression of territorial scent marking in odor recipients, but OT antagonist administration into pair-housed mice blocked this suppressive effect of odor cue. These results indicate that central OT modulates release as well as detection of amicable signals facilitating/maintaining familiar relationships and suppressing territorial behavior between male mice. Overall, these findings suggest that OT plays a significant role in regulating social familiarity via changing qualities of conspecific odor cues.

  16. G9a-mediated histone methylation regulates cadmium-induced male fertility damage in pubertal mice.

    PubMed

    Li, Min; Liu, Chuan; Yang, Lingling; Zhang, Lei; Chen, Chunhai; He, Mindi; Lu, Yonghui; Feng, Wei; Pi, Huifeng; Zhang, Yanwen; Zhong, Min; Yu, Zhengping; Zhou, Zhou

    2016-06-11

    Increasing evidence suggests that cadmium (Cd) is associated with male fertility damage. However, the effects of histone modification on Cd-induced male fertility damage remain obscure. This study aims to evaluate the roles of histone methylation mediated by euchromatin histone methyltransferase (EHMT2/G9a) in regulating Cd-induced male fertility damage. We exposed 4-week-old male C57BL/6J mice to Cd by intraperitoneal injection at 2mg/kg for 1, 3 and 5days. Our data showed that Cd exposure decreased the numbers of impregnated females and litter sizes, which was concomitant with sperm count reduction, histological changes in the cauda epididymal ducts and seminiferous epithelium, and testicular cell apoptosis as evaluated by terminal dUTP nick-end labeling (TUNEL) assay and immunoblotting with increased levels of cleaved caspase 3, PARP and Bax and a decreased level of Bcl-2. Cd-induced male fertility damage was accompanied by enhanced G9a activity followed by increased histone H3 lysine 9 monomethylation (H3K9me1) and dimethylation (H3K9me2) in testes. Furthermore, inhibition of G9a by BIX-01294 normalized H3K9me1 and H3K9me2 to basal levels and prevented Cd-induced male fertility damage and testicular cell apoptosis. Our present study revealed that G9a-mediated histone methylation plays a critical role in Cd-induced male fertility damage and testicular cell apoptosis. PMID:27060504

  17. Development and psychometric properties of a self-regulation scale about leisure time physical activity in Iranian male adolescents

    PubMed Central

    Abasi, Mohammad Hadi; Eslami, Ahmad Ali; Rakhshani, Fatemeh; Shiri, Mansoor

    2016-01-01

    Background: Self-regulation is one of the current psychological concepts that have been known as a determinant of leisure time physical activity. Due to cultural and social diversity in different societies and age groups, application of specific questionnaires is essential to perform investigations about physical activities. The aim of this study is development and evaluation of psychometric properties of a self-regulation questionnaire about leisure time physical activity in Iranian male adolescents. Materials and Methods: This cross-sectional study was conducted in 2013, and data of 603 male students from 12 high schools in Isfahan were collected. A comprehensive literature review and similar questionnaire review were conducted and 25 items were selected or developed to measure self-regulation. Comprehensibility of items was evaluated in a pilot study and an expert panel evaluated face and content validity. Exploratory factors analysis (EFA) was used for evaluation of construct validity and extraction of sub-constructs of self-regulation. Leisure time physical activity was assessed using International Physical Activity Questionnaire (IPAQ). Results: The mean age of the participants was 16.3 years (SD =1.0) and the range was 15-19 years. Cronbach's α coefficient of the questionnaire in the pilot and main study was 0.84 and 0.90, respectively. EFA resulted in four sub-constructs including “enlistment of social support”, “goal setting”, “self-construction”, and “self-monitoring”, which explained 63.6% of the variance of self-regulation. Conclusions: Results of this investigation provide some support to the validity and reliability of the 16-item questionnaire of self-regulation abut leisure time physical activity in the target group. PMID:27095993

  18. Impact of Cystic Fibrosis Transmembrane Regulator (CFTR) gene mutations on male infertility.

    PubMed

    Elia, Jlenia; Mazzilli, Rossella; Delfino, Michele; Piane, Maria; Bozzao, Cristina; Spinosa, Vincenzo; Chessa, Luciana; Mazzilli, Fernando

    2014-09-01

    Objective. The aim of this study was to evaluate the prevalence of most common mutations and intron 8 5T (IVS8-5T) polymorphism of CFTR gene in Italian: a) azoospermic males; b) non azoospermic subjects, male partners of infertile couples enrolled in assisted reproductive technology (ART) programs. Material and methods. We studied 242 subjects attending our Andrology Unit (44 azoospermic subjects and 198 non azoospermic subjects, male partners of infertile couples enrolled in ART programs). Semen analysis, molecular analysis for CFTR gene mutations and genomic variant of IVS8-5T polymorphic tract, karyotype and chromosome Y microdeletions, hormonal profile (LH, FSH, Testosterone) and seminal biochemical markers (fructose, citric acid and L-carnitine) were carried out. Results. The prevalence of the common CFTR mutations and/or the IVS8-5T polymorphism was 12.9% (4/31 cases) in secretory azoospermia, while in obstructive azoospermia was 84.6% (11/13 cases; in these, the most frequent mutations were the F508del, R117H and W1282X). Regarding the non azoospermic subjects, the prevalence of the CFTR and/or the IVS8-5T polymorphism was 11.1% (11/99 cases) in severe dyspermia, 8.1% (6/74 cases) in moderate dyspermia and finally 4.0% (1/25 cases) in normospermic subjects. Conclusions. This study confirms the highly significant prevalence of CFTR mutations in males with bilateral absence of the vas deferens or ejaculatory ducts obstruction compared with subjects with secretory azoospermia. Moreover, the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of CFTR even in the spermatogenic process. This could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage. PMID:25308578

  19. 4-Nitrophenol isolated from diesel exhaust particles disrupts regulation of reproductive hormones in immature male rats.

    PubMed

    Li, Xuezheng; Li, Chunmei; Suzuki, Akira K; Taneda, Shinji; Watanabe, Gen; Taya, Kazuyoshi

    2009-08-01

    In previous studies, we found that 4-nitrophenol (PNP) isolated from diesel exhaust particles exhibited both estrogenic and anti-androgenic activities. This compound is also a degradation product of the insecticide parathion. Here, we investigated the in vivo effect of PNP on reproductive function in immature male rats. Twenty-eight-day-old rats were injected subcutaneously with PNP (0.01, 0.1, 1, or 10 mg/kg) daily for 14 days. Plasma concentrations of luteinizing hormone (LH) were significantly lower in all PNP dosage groups than in the control group, and follicle-stimulating hormone (FSH) was significantly decreased in rats treated with 0.1, 1, or 10 mg/kg PNP. However, plasma concentrations of testosterone were significantly increased by 10 mg/kg PNP, and plasma concentrations of immunoreactive (ir)-inhibin were also significantly increased in the 0.1, 1, and 10 mg/kg PNP groups. Plasma concentrations of prolactin were significantly increased by 10 mg/kg PNP, and plasma concentrations of corticosterone were significantly increased in all treatment groups. These findings clearly show that PNP influences the hypothalamic-pituitary-gonadal axis in immature male rats, with decreased secretion of LH and FSH and increased secretion of testosterone and inhibin. PNP, therefore, appears to disrupt endocrine activity in the immature male reproductive system.

  20. Opuntia humifusa supplementation increased bone density by regulating parathyroid hormone and osteocalcin in male growing rats.

    PubMed

    Kang, Junyong; Park, Jinho; Choi, Seong Hee; Igawa, Shoji; Song, Youngju

    2012-01-01

    We investigated the effect of Opuntia humifusa (O. humifusa) supplementation on bone density and related hormone secretion in growing male rats. Sixteen six-week-old male Sprague-Dawley rats were randomly divided into two groups; control diet group (CG, n = 8), and experimental diet group (EG, n = 8). The rats in the CG were given a control diet and those in the EG were given 5% O. humifusa added to the control diet for eight weeks. The serum OC level of the EG was significantly higher than that of the CG, and the serum parathyroid hormone (PTH) level of EG was significantly lower than that of the CG. In addition, the femoral and tibial BMD of the EG were significantly higher values than those of the CG, and the tibial BMC of the EG was significantly higher than that of the CG. These results suggest that O. humifusa supplementation has a positive effect on bone density by suppressing PTH and increasing the OC level in growing male rats.

  1. Opuntia humifusa Supplementation Increased Bone Density by Regulating Parathyroid Hormone and Osteocalcin in Male Growing Rats

    PubMed Central

    Kang, Junyong; Park, Jinho; Choi, Seong Hee; Igawa, Shoji; Song, Youngju

    2012-01-01

    We investigated the effect of Opuntia humifusa (O. humifusa) supplementation on bone density and related hormone secretion in growing male rats. Sixteen six-week-old male Sprague-Dawley rats were randomly divided into two groups; control diet group (CG, n = 8), and experimental diet group (EG, n = 8). The rats in the CG were given a control diet and those in the EG were given 5% O. humifusa added to the control diet for eight weeks. The serum OC level of the EG was significantly higher than that of the CG, and the serum parathyroid hormone (PTH) level of EG was significantly lower than that of the CG. In addition, the femoral and tibial BMD of the EG were significantly higher values than those of the CG, and the tibial BMC of the EG was significantly higher than that of the CG. These results suggest that O. humifusa supplementation has a positive effect on bone density by suppressing PTH and increasing the OC level in growing male rats. PMID:22837661

  2. Diversifying sunflower germplasm by integration and mapping of a novel male fertility restoration gene

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The combination of a single cytoplasmic male-sterile (CMS) PET-1, originating from wild Helianthus petiolaris subsp. petiolaris Nutt., and the corresponding fertility restoration gene Rf1, has been used for commercial sunflower hybrid seed production worldwide since the early 1970s. A new CMS line 5...

  3. Regulation of brain androgen receptor immunoreactivity by androgen in prepubertal male ferrets.

    PubMed

    Kashon, M L; Hayes, M J; Shek, P P; Sisk, C L

    1995-05-01

    During pubertal maturation, there is an increase in the number of androgen receptor-immunoreactive (AR-IR) cells in the preoptic area (POA), arcuate nucleus (ARC), medial amygdala (mAMY), and ventromedial hypothalamic nucleus (VMH) of the male ferret brain. In contrast, the number of AR-IR cells in the bed nucleus of the stria terminalis (BNST) or lateral septum (ISEP) does not change with pubertal development. This experiment tested the hypothesis that the pubertal increase in AR-IR cells in certain brain regions is the result of the pubertal increase in circulating androgens. Prepubertal male ferrets were left intact or were castrated and treated daily (10 days) with s.c. injections of either oil, testosterone (T; 5 mg/kg), dihydrotestosterone (DHT; 5 mg/kg), or estradiol (E; 10 micrograms/kg). Brains were processed for AR immunocytochemistry, and the number of immunopositive cells was quantified in POA, ARC, mAMY, VMH, BNST, and ISEP. Overall, castration reduced the number of AR-IR cells below that seen in intact animals, and E administration did not restore AR-IR cell number. Treatment of castrates with androgens restored numbers of AR-IR cells to those of intact animals in the BNST, ISEP, and VMH. However, AR-IR cell numbers were significantly greater in androgen-treated castrates than in intact animals in POA, mAMY, and ARC. These data show that AR-IR cells in prepubertal male ferrets are sensitive to circulating levels of androgens, supporting the hypothesis that the pubertal rise in T is responsible for the pubertal increase in the number of AR-IR cells in the POA, mAMY, and ARC. PMID:7626721

  4. A FEEDBACK MODEL FOR TESTICULAR-PITUITARY AXIS HORMONE KINETICS AND THEIR EFFECTS ON THE REGULATION OF THE PROSTATE IN ADULT MALE RATS

    EPA Science Inventory

    The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. A model describing the kinetics and dynamics of testosterone (T), dihydrotestosterone (DHT) and luteinizing hormone (LH) was developed based on a model by Barton and Anderson (1997). The mode...

  5. Long Hair and the Law: A Look at Constitutional and Title VII Challenges to Public and Private Regulation of Male Grooming

    ERIC Educational Resources Information Center

    Troup, David P.

    1975-01-01

    Arguments that have been advanced in court by both sides of the controversy are examined, and it is concluded that male grooming regulations may effectively exclude a significant proportion of males from job opportunities or require them to alter their personal appearance for reasons probably unrelated to job performance. (LBH)

  6. Photoperiodic regulation of hippocampal neurogenesis in adult male white-footed mice (Peromyscus leucopus).

    PubMed

    Walton, James C; Aubrecht, Taryn G; Weil, Zachary M; Leuner, Benedetta; Nelson, Randy J

    2014-08-01

    Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis, as males, in addition to having reduced hippocampal volume in short days (SD) with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog bromodeoxyuridine at multiple time points across 10 weeks of SD exposure. Compared with counterparts held in long day (LD) lengths, across the first 8 weeks of SD exposure hippocampal neurogenesis was reduced. However, at 10 weeks in SD lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in LD lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes and adaptive responses to changing day lengths affects brain structure, function and behavior at multiple levels. PMID:24893623

  7. The Magea gene cluster regulates male germ cell apoptosis without affecting the fertility in mice.

    PubMed

    Hou, Siyuan; Xian, Li; Shi, Peiliang; Li, Chaojun; Lin, Zhaoyu; Gao, Xiang

    2016-01-01

    While apoptosis is essential for male germ cell development, improper activation of apoptosis in the testis can affect spermatogenesis and cause reproduction defects. Members of the MAGE-A (melanoma antigen family A) gene family are frequently clustered in mammalian genomes and are exclusively expressed in the testes of normal animals but abnormally activated in a wide variety of cancers. We investigated the potential roles of these genes in spermatogenesis by generating a mouse model with a 210-kb genomic deletion encompassing six members of the Magea gene cluster (Magea1, Magea2, Magea3, Magea5, Magea6 and Magea8). Male mice carrying the deletion displayed smaller testes from 2 months old with a marked increase in apoptotic germ cells in the first wave of spermatogenesis. Furthermore, we found that Magea genes prevented stress-induced spermatogenic apoptosis after N-ethyl-N-nitrosourea (ENU) treatment during the adult stage. Mechanistically, deletion of the Magea gene cluster resulted in a dramatic increase in apoptotic germ cells, predominantly spermatocytes, with activation of p53 and induction of Bax in the testes. These observations demonstrate that the Magea genes are crucial in maintaining normal testicular size and protecting germ cells from excessive apoptosis under genotoxic stress. PMID:27226137

  8. Photoperiodic regulation of hippocampal neurogenesis in adult male white-footed mice (Peromyscus leucopus).

    PubMed

    Walton, James C; Aubrecht, Taryn G; Weil, Zachary M; Leuner, Benedetta; Nelson, Randy J

    2014-08-01

    Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis, as males, in addition to having reduced hippocampal volume in short days (SD) with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog bromodeoxyuridine at multiple time points across 10 weeks of SD exposure. Compared with counterparts held in long day (LD) lengths, across the first 8 weeks of SD exposure hippocampal neurogenesis was reduced. However, at 10 weeks in SD lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in LD lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes and adaptive responses to changing day lengths affects brain structure, function and behavior at multiple levels.

  9. Regulation of phase II enzymes by genistein and daidzein in male and female Swiss Webster mice.

    PubMed

    Froyen, Erik B; Reeves, Jaime L Rudolf; Mitchell, Alyson E; Steinberg, Francene M

    2009-12-01

    The consumption of soy and soy isoflavones has been associated with a decreased risk of certain cancers. A factor contributing to this dietary chemoprevention is the activity of phase I and II biotransformation enzymes. This study evaluated the hypothesis that dietary soy isoflavones will increase hepatic and extrahepatic quinone reductase (QR), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) phase II enzyme activities, under short-term feeding and basal (non-pharmacologic-induced) conditions. Male and female Swiss Webster mice were fed for 1, 3, 5, or 7 days of one of four treatments: control (casein AIN-93G) or control supplemented with flavone (positive control), genistein, or daidzein aglycones at 1,500 mg/kg of diet. QR activity was increased by daidzein in the liver, by both isoflavones in the kidney and small intestine, and by genistein in the heart. Genistein and daidzein slightly decreased UGT activities in some tissues. Liver GST activity was decreased by genistein in females. In contrast, genistein and daidzein increased kidney GST activity. In general, the greatest effects of isoflavones on phase II enzymes were observed in liver and kidney tissues, occurring at day 3, and peaking at day 5. Sex effects in the liver and kidney included females exhibiting higher QR activities and males exhibiting higher UGT and GST activities. In conclusion, individual soy isoflavones modulate phase II enzymes in mice under short-term feeding and basal conditions. This study provides insights into the actions of isolated isoflavones in mice.

  10. The Magea gene cluster regulates male germ cell apoptosis without affecting the fertility in mice

    PubMed Central

    Hou, Siyuan; Xian, Li; Shi, Peiliang; Li, Chaojun; Lin, Zhaoyu; Gao, Xiang

    2016-01-01

    While apoptosis is essential for male germ cell development, improper activation of apoptosis in the testis can affect spermatogenesis and cause reproduction defects. Members of the MAGE-A (melanoma antigen family A) gene family are frequently clustered in mammalian genomes and are exclusively expressed in the testes of normal animals but abnormally activated in a wide variety of cancers. We investigated the potential roles of these genes in spermatogenesis by generating a mouse model with a 210-kb genomic deletion encompassing six members of the Magea gene cluster (Magea1, Magea2, Magea3, Magea5, Magea6 and Magea8). Male mice carrying the deletion displayed smaller testes from 2 months old with a marked increase in apoptotic germ cells in the first wave of spermatogenesis. Furthermore, we found that Magea genes prevented stress-induced spermatogenic apoptosis after N-ethyl-N-nitrosourea (ENU) treatment during the adult stage. Mechanistically, deletion of the Magea gene cluster resulted in a dramatic increase in apoptotic germ cells, predominantly spermatocytes, with activation of p53 and induction of Bax in the testes. These observations demonstrate that the Magea genes are crucial in maintaining normal testicular size and protecting germ cells from excessive apoptosis under genotoxic stress. PMID:27226137

  11. GSK-3β Function in Bone Regulates Skeletal Development, Whole-Body Metabolism, and Male Life Span

    PubMed Central

    Gillespie, J. R.; Bush, J. R.; Bell, G. I.; Aubrey, L. A.; Dupuis, H.; Ferron, M.; Kream, B.; DiMattia, G.; Patel, S.; Woodgett, J. R.; Karsenty, G.; Hess, D. A.; Beier, F.

    2016-01-01

    Glycogen synthase kinase 3 β (GSK-3β) is an essential negative regulator or “brake” on many anabolic-signaling pathways including Wnt and insulin. Global deletion of GSK-3β results in peri-natal lethality and various skeletal defects. The goal of our research was to determine GSK-3β cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6-kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b knockout) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3β in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died after weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type 2 diabetes. Our data suggest that skeletal-specific deletion of GSK-3β affects global metabolism and sensitizes male mice to developing type 2 diabetes. PMID:23904355

  12. The Levels of Male Gametic Mitochondrial DNA Are Highly Regulated in Angiosperms with Regard to Mitochondrial Inheritance[W

    PubMed Central

    Wang, Dan-Yang; Zhang, Quan; Liu, Yang; Lin, Zhi-Fu; Zhang, Shao-Xiang; Sun, Meng-Xiang; Sodmergen

    2010-01-01

    The mechanisms that regulate mitochondrial inheritance are not yet clear, even though it is 100 years since the first description of non-Mendelian genetics. Here, we quantified the copy numbers of mitochondrial DNA (mtDNA) in the gametic cells of angiosperm species. We demonstrate that each egg cell from Arabidopsis thaliana, Antirrhinum majus, and Nicotiana tabacum possesses 59.0, 42.7, and 73.0 copies of mtDNA on average, respectively. These values are equivalent to those in Arabidopsis mesophyll cells, at 61.7 copies per cell. On the other hand, sperm or generative cells from Arabidopsis, A. majus, and N. tabacum possess minor amounts of mtDNA, at 0.083, 0.47, and 1 copy on average, respectively. We further reveal a 50-fold degradation of mtDNA during pollen development in A. majus. In contrast, markedly high levels of mtDNA are found in the male gametic cells of Cucumis melo and Pelargonium zonale (1296.3 and 256.7 copies, respectively). Our results provide direct evidence for mitochondrial genomic insufficiency in the eggs and somatic cells and indicate that a male gamete of an angiosperm may possess mtDNA at concentrations as high as 21-fold (C. melo) or as low as 0.1% (Arabidopsis) of the levels in somatic cells. These observations reveal the existence of a strong regulatory system for the male gametic mtDNA levels in angiosperms with regard to mitochondrial inheritance. PMID:20605854

  13. Role of the oxytocin system in amygdala subregions in the regulation of social interest in male and female rats.

    PubMed

    Dumais, Kelly M; Alonso, Andrea G; Bredewold, Remco; Veenema, Alexa H

    2016-08-25

    We previously found that oxytocin (OT) receptor (OTR) binding density in the medial amygdala (MeA) correlated positively with social interest (i.e., the motivation to investigate a conspecific) in male rats, while OTR binding density in the central amygdala (CeA) correlated negatively with social interest in female rats. Here, we determined the causal involvement of OTR in the MeA and CeA in the sex-specific regulation of social interest in adult rats by injecting an OTR antagonist (5ng/0.5μl/side) or OT (100pg/0.5μl/side) before the social interest test (4-min same-sex juvenile exposure). OTR blockade in the CeA decreased social interest in males but not females, while all other treatments had no behavioral effect. To further explore the sex-specific involvement of the OT system in the CeA in social interest, we used in vivo microdialysis to determine possible sex differences in endogenous OT release in the CeA during social interest. Interestingly, males and females showed similar levels of extracellular OT release at baseline and during social interest, suggesting that factors other than local OT release mediate the sex-specific role of CeA-OTR in social interest. Moreover, we found a positive correlation between CeA-OT release and social investigation time in females. This was further reflected by reduced CeA-OT release during social interest in females that expressed low compared to high social interest. We discuss the possibility that this reduction in OT release may be a consequence, rather than a cause, of exposure to a social stimulus. Overall, our findings show for the first time that extracellular OT release in the CeA is similar between males and females and that OTR in the CeA plays a causal role in the regulation of social interest toward juvenile conspecifics in males.

  14. Regulation of cell divisions and differentiation by MALE STERILITY32 is required for anther development in maize

    PubMed Central

    Moon, Jihyun; Skibbe, David; Timofejeva, Ljudmilla; Rachel Wang, Chung-Ju; Kelliher, Timothy; Kremling, Karl; Walbot, Virginia; Zacheus Cande, William

    2014-01-01

    Summary Male fertility in flowering plants relies on proper division and differentiation of cells in the anther, a process that gives rise to four somatic layers surrounding central germinal cells. The maize gene male sterility32 (ms32) encodes a basic helix–loop–helix (bHLH) transcription factor, which functions as an important regulator of both division and differentiation during anther development. After the four somatic cell layers are generated properly through successive periclinal divisions, in the ms32 mutant, tapetal precursor cells fail to differentiate, and, instead, undergo additional periclinal divisions to form extra layers of cells. These cells become vacuolated and expand, and lead to failure in pollen mother cell development. ms32 expression is specific to the pre-meiotic anthers and is distributed initially broadly in the four lobes, but as the anther develops, its expression becomes restricted to the innermost somatic layer, the tapetum. The ms32-ref mac1-1 double mutant is unable to form tapetal precursors and also exhibits excessive somatic proliferation leading to numerous, disorganized cell layers, suggesting a synergistic interaction between ms32 and mac1. Altogether, our results show that MS32 is a major regulator in maize anther development that promotes tapetum differentiation and inhibits periclinal division once a tapetal cell is specified. PMID:24033746

  15. Androgen receptor (AR) promotes male bladder cancer cell proliferation and migration via regulating CD24 and VEGF.

    PubMed

    Ding, Guoqing; Yu, Shicheng; Cheng, Sheng; Li, Gonghui; Yu, Yanlan

    2016-01-01

    Increasing evidence has proved the pivotal roles of androgen receptor in various diseases, including prostate cancer and bladder cancer. The CD24 has been proved to be correlated to bladder cancer metastasis and tumorigenesis in recent study. This study was aimed to investigate the roles of AR in bladder cell proliferation and metastasis and to explore its potential mechanism. Expressions of AR in two kinds of bladder tumor cells (T24 and UM-UC-3) were analyzed using the CRISPR Activation Plasmid transfection or siRNA-mediated gene. The effects of AR on tumor cell proliferation and migration were also analyzed. Moreover, the effects of CD24 and influence of AR on cell proliferation and metastasis-related protein were also analyzed. The results showed that AR was significantly down-regulated in T24 cells but was significantly overexpressed in UM-UC-3 cells. The up-regulated T24 promotes cell proliferation, but this enhance effect was blocked by silencing CD24. Additionally, the AR overexpression significantly increased the VEGF and CD24 expression. Besides, the migrated bladder cells was increased by the up-regulated AR, but was decreased by silencing CD24 or silencing VEGF. Taken together, our study suggested that the up-regulated AR enhances the male bladder tumor cell proliferation and metastasis via modulating the CD24 and VEGF. This study may provide theoretical basis for the possibility of AR to be a therapeutic target for bladder cancer.

  16. Falling apart: a process integral to the remodeling of male incest offenders.

    PubMed

    Scheela, R A; Stern, P N

    1994-04-01

    This article describes the falling apart component of a theoretical framework for incest offenders, the remodeling process. Methodology included 20 audiotaped interviews, 65 direct observations during group therapy, and record analysis of a theoretical sampling of adult male incest offenders currently in, graduates of, and dropouts from a community sexual abuse treatment program. Constant comparative analysis was used to collect and analyze data concurrently. Falling apart, a dynamic multifaceted process, occurs first when offenders are discovered, can be life-threatening, and few resources are presently available. Dimensions, properties, strategies, and contexts are discussed.

  17. Information Integration and Communication in Plant Growth Regulation.

    PubMed

    Chaiwanon, Juthamas; Wang, Wenfei; Zhu, Jia-Ying; Oh, Eunkyoo; Wang, Zhi-Yong

    2016-03-10

    Plants are equipped with the capacity to respond to a large number of diverse signals, both internal ones and those emanating from the environment, that are critical to their survival and adaption as sessile organisms. These signals need to be integrated through highly structured intracellular networks to ensure coherent cellular responses, and in addition, spatiotemporal actions of hormones and peptides both orchestrate local cell differentiation and coordinate growth and physiology over long distances. Further, signal interactions and signaling outputs vary significantly with developmental context. This review discusses our current understanding of the integrated intracellular and intercellular signaling networks that control plant growth.

  18. Information Integration and Communication in Plant Growth Regulation.

    PubMed

    Chaiwanon, Juthamas; Wang, Wenfei; Zhu, Jia-Ying; Oh, Eunkyoo; Wang, Zhi-Yong

    2016-03-10

    Plants are equipped with the capacity to respond to a large number of diverse signals, both internal ones and those emanating from the environment, that are critical to their survival and adaption as sessile organisms. These signals need to be integrated through highly structured intracellular networks to ensure coherent cellular responses, and in addition, spatiotemporal actions of hormones and peptides both orchestrate local cell differentiation and coordinate growth and physiology over long distances. Further, signal interactions and signaling outputs vary significantly with developmental context. This review discusses our current understanding of the integrated intracellular and intercellular signaling networks that control plant growth. PMID:26967291

  19. miR-544 Regulates Dairy Goat Male Germline Stem Cell Self-Renewal via Targeting PLZF.

    PubMed

    Song, Wencong; Mu, Hailong; Wu, Jiang; Liao, Mingzhi; Zhu, Haijing; Zheng, Liming; He, Xin; Niu, Bowen; Zhai, Yuanxin; Bai, Chunling; Lei, Anmin; Li, Guangpeng; Hua, Jinlian

    2015-10-01

    The balance between the self-renewal and differentiation of male germline stem cells (mGSCs) is critical for the initiation and maintenance of mammalian spermatogenesis. The promyelocytic leukemia zinc finger (PLZF), a zinc finger protein, is a critical factor for maintaining the self-renewal of mGSCs, so, evaluation of the PLZF pathway in mGSCs may provide a deeper insight into mammalian spermatogenesis. miRNA was also an important regulating factor for the self-renewal and differentiation of mGSCs; however, there is currently no data indicating that which miRNA regulate the self-renewal and differentiation of mGSCs via PLZF. Here, we predicted the prospective miRNA targeting to PLZF using the online Bioinformatics database-Targetscan, and performed an analysis of the dual-luciferase recombinant vector, psiCHCEKTM-2-PLZF-3'UTR. miR-544 mimics (miR-544m), miR-544 inhibitors (miR-544i), Control (NC, scrambled oligonucleotides transfection), pPLZF-IRES2-EGFP or PLZF siRNA were transfected into mGSCs; the cells proliferation was evaluated by BRDU incorporation assay and flow cytometry, and the mGSC marker, GFRa1, PLZF, KIT, DAZL, and VASA expression were analyzed by RT-qPCR, immunofluorescence and Western blot. The results showed that miR-544 regulates dairy goat male germline stem cell self-renewal via targeting PLZF. Our study identifies a new regulatory pathway for PLZF and expands upon the PLZF regulatory network in mGSCs.

  20. ROCK1 in AgRP neurons regulates energy expenditure and locomotor activity in male mice.

    PubMed

    Huang, Hu; Lee, Seung Hwan; Ye, Chianping; Lima, Ines S; Oh, Byung-Chul; Lowell, Bradford B; Zabolotny, Janice M; Kim, Young-Bum

    2013-10-01

    Normal leptin signaling is essential for the maintenance of body weight homeostasis. Proopiomelanocortin- and agouti-related peptide (AgRP)-producing neurons play critical roles in regulating energy metabolism. Our recent work demonstrates that deletion of Rho-kinase 1 (ROCK1) in the AgRP neurons of mice increased body weight and adiposity. Here, we report that selective loss of ROCK1 in AgRP neurons caused a significant decrease in energy expenditure and locomotor activity of mice. These effects were independent of any change in food intake. Furthermore, AgRP neuron-specific ROCK1-deficient mice displayed central leptin resistance, as evidenced by impaired Signal Transducer and Activator of Transcription 3 activation in response to leptin administration. Leptin's ability to hyperpolarize and decrease firing rate of AgRP neurons was also abolished in the absence of ROCK1. Moreover, diet-induced and genetic forms of obesity resulted in reduced ROCK1 activity in murine arcuate nucleus. Of note, high-fat diet also impaired leptin-stimulated ROCK1 activity in arcuate nucleus, suggesting that a defect in hypothalamic ROCK1 activity may contribute to the pathogenesis of central leptin resistance in obesity. Together, these data demonstrate that ROCK1 activation in hypothalamic AgRP neurons is required for the homeostatic regulation of energy expenditure and adiposity. These results further support previous work identifying ROCK1 as a key regulator of energy balance and suggest that targeting ROCK1 in the hypothalamus may lead to development of antiobesity therapeutics. PMID:23885017

  1. Androgens regulate sex differences in signaling but are not associated with male variation in morphology in the weakly electric fish Parapteronotus hasemani.

    PubMed

    Petzold, Jacquelyn M; Smith, G Troy

    2016-02-01

    Sexually dimorphic signaling is widespread among animals and can act as an honest indicator of mate quality. Additionally, differences in signaling and morphology within a sex can be associated with different strategies for acquiring mates. Weakly electric fish communicate via self-generated electrical fields that transmit information about sex, reproductive state, and social status. The weakly electric knifefish Parapteronotus hasemani exhibits sexual dimorphism in body size as well as substantial within-male variation in body size and jaw length. We asked whether P. hasemani exhibits hormonally mediated sexual dimorphism in electrocommunication behavior. We also asked whether males with short versus long jaws differed significantly from each other in morphology, behavior, hormone levels, or reproductive maturity. Males produced longer chirps than females, but other signal parameters (electric organ discharge frequency; chirp rate and frequency modulation) were sexually monomorphic. Pharmacologically blocking androgen receptors in males reduced chirp duration, suggesting that this sexually dimorphic trait is regulated at least in part by the activational effects of androgens. Males sorted into two distinct morphological categories but did not differ in circulating 11-ketotestosterone or testosterone. Short-jawed males and long-jawed males also did not differ in any aspects of signaling. Thus, chirping and high levels of 11-ketotestosterone were reliably associated with reproductively active males but do not necessarily indicate male type or quality. This contrasts with other alternative male morph systems in which males that differ in morphology also differ in androgen profiles and signaling behavior.

  2. Androgens regulate sex differences in signaling but are not associated with male variation in morphology in the weakly electric fish Parapteronotus hasemani.

    PubMed

    Petzold, Jacquelyn M; Smith, G Troy

    2016-02-01

    Sexually dimorphic signaling is widespread among animals and can act as an honest indicator of mate quality. Additionally, differences in signaling and morphology within a sex can be associated with different strategies for acquiring mates. Weakly electric fish communicate via self-generated electrical fields that transmit information about sex, reproductive state, and social status. The weakly electric knifefish Parapteronotus hasemani exhibits sexual dimorphism in body size as well as substantial within-male variation in body size and jaw length. We asked whether P. hasemani exhibits hormonally mediated sexual dimorphism in electrocommunication behavior. We also asked whether males with short versus long jaws differed significantly from each other in morphology, behavior, hormone levels, or reproductive maturity. Males produced longer chirps than females, but other signal parameters (electric organ discharge frequency; chirp rate and frequency modulation) were sexually monomorphic. Pharmacologically blocking androgen receptors in males reduced chirp duration, suggesting that this sexually dimorphic trait is regulated at least in part by the activational effects of androgens. Males sorted into two distinct morphological categories but did not differ in circulating 11-ketotestosterone or testosterone. Short-jawed males and long-jawed males also did not differ in any aspects of signaling. Thus, chirping and high levels of 11-ketotestosterone were reliably associated with reproductively active males but do not necessarily indicate male type or quality. This contrasts with other alternative male morph systems in which males that differ in morphology also differ in androgen profiles and signaling behavior. PMID:26518663

  3. Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice.

    PubMed

    Romero, Christopher J; Wolfe, Andrew; Law, Yi Ying; Costelloe, ChenChen Z; Miller, Ryan; Wondisford, Fredric; Radovick, Sally

    2016-04-01

    Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin-like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6-8week old male mice and again at 25weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model.

  4. Defective regulation of the ubiquitin/proteasome system in the hypothalamus of obese male mice.

    PubMed

    Ignacio-Souza, Leticia M; Bombassaro, Bruna; Pascoal, Livia B; Portovedo, Mariana A; Razolli, Daniela S; Coope, Andressa; Victorio, Sheila C; de Moura, Rodrigo F; Nascimento, Lucas F; Arruda, Ana P; Anhe, Gabriel F; Milanski, Marciane; Velloso, Licio A

    2014-08-01

    In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returning to normal weight becomes extremely difficult. Here we show that in prolonged but not in short-term obesity, the ubiquitin/proteasome system in the hypothalamus fails to maintain an adequate rate of protein recycling, leading to the accumulation of ubiquitinated proteins. This is accompanied by an increased colocalization of ubiquitin and p62 in the arcuate nucleus and reduced expression of autophagy markers in the hypothalamus. Genetic protection from obesity is accompanied by the normal regulation of the ubiquitin/proteasome system in the hypothalamus, whereas the inhibition of proteasome or p62 results in the acceleration of body mass gain in mice exposed for a short period to a high-fat diet. Thus, the defective regulation of the ubiquitin/proteasome system in the hypothalamus may be an important mechanism involved in the progression and autoperpetuation of obesity.

  5. Dynamics of the Transcriptome during Human Spermatogenesis: Predicting the Potential Key Genes Regulating Male Gametes Generation.

    PubMed

    Zhu, Zijue; Li, Chong; Yang, Shi; Tian, Ruhui; Wang, Junlong; Yuan, Qingqing; Dong, Hui; He, Zuping; Wang, Shengyue; Li, Zheng

    2016-01-01

    Many infertile men are the victims of spermatogenesis disorder. However, conventional clinical test could not provide efficient information on the causes of spermatogenesis disorder and guide the doctor how to treat it. More effective diagnosis and treating methods could be developed if the key genes that regulate spermatogenesis were determined. Many works have been done on animal models, while there are few works on human beings due to the limited sample resources. In current work, testis tissues were obtained from 27 patients with obstructive azoospermia via surgery. The combination of Fluorescence Activated Cell Sorting and Magnetic Activated Cell Sorting was chosen as the efficient method to sort typical germ cells during spermatogenesis. RNA Sequencing was carried out to screen the change of transcriptomic profile of the germ cells during spermatogenesis. Differential expressed genes were clustered according to their expression patterns. Gene Ontology annotation, pathway analysis, and Gene Set Enrichment Analysis were carried out on genes with specific expression patterns and the potential key genes such as HOXs, JUN, SP1, and TCF3 which were involved in the regulation of spermatogenesis, with the potential value serve as molecular tools for clinical purpose, were predicted. PMID:26753906

  6. Regulating bodily integrity: cosmetic surgery and voluntary limb amputation.

    PubMed

    Kennedy, Aileen

    2012-12-01

    Cosmetic surgery and voluntary limb amputation share a number of features. Both procedures are patient-driven forms of body shaping that can only be performed by surgeons, and therefore the procedures require the imprimatur of the medical profession to be lawful. Both invoke identity construction as a central legitimating factor that renders the procedures therapeutic. The legal regulation of surgery is subsumed within general principles regulating medical practice, where autonomy and consent are constituted as fundamental authorising principles. The legitimacy of consent to surgical intervention operates unevenly in relation to these two forms of surgery. Amputation of healthy limbs is presumed to be non-therapeutic. Capacity is closely interrogated and minutely scrutinised. Consent to cosmetic surgery, by contrast, is presumed to be a valid expression of autonomy and self-determination.

  7. Up-Regulation of microRNA-210 is Associated with Spermatogenesis by Targeting IGF2 in Male Infertility

    PubMed Central

    Tang, Dongdong; Huang, Yuanyuan; Liu, Weiqun; Zhang, Xiansheng

    2016-01-01

    Background MicroRNAs (miRNAs) play pivotal roles in spermatogenesis. MicroRNA-210 (miR-210) expression was up-regulated in the testes of sterile men with non-obstructive azoospermia (NOA). However, the underlying mechanisms of miR-210 involved in the spermatogenesis in patients with NOA are unknown. Material/Methods Expression of miR-210 and insulin-like growth factor II (IGF2) in the testes of NOA cases (only including maturation arrest and hypospermatogenesis) were detected in this study. We carried out in vitro experiments to determine if IGF2 was directly targeted by miR-210 in NT2 cells. Results Compared with obstructive azoospermia (OA) as normal control, our results suggest that miR-210 was significantly up-regulated in testis of patients with NOA (P<0.05), and IGF2 was down-regulated, but without a significant difference. The results also indicated that IGF2 was directly targeted by miR-210 in NT2 cells. Conclusions The results showed that miR-210 was involved in spermatogenesis by targeting IGF2 in male infertility. PMID:27535712

  8. Effects of aproteic diet on hypothalamic-pituitary- gonadal regulation in the male rat.

    PubMed

    Ponzo, Osvaldo J.; Rondina, Dora; Szwarcfarb, Berta; Carbone, Silvia; Moguilevsky, Jaime; Scacchi, Pablo

    1999-01-01

    The effect of an aproteic diet (Ap) on the reproductive axis in young male rats was studied. Also the refeeding effect at different times after the aproteic diet was studied. The Ap diet was given during 21 days. In refeeding groups, the control diet was given during 2, 4 and 6 weeks after the aproteic diet. We studied the plasmatic testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels. Also the hypothalamic GnRH concentration and in vitro hypothalamic GnRH secretion in basal and induced condition was studied. The total protein deficit produced significant reduction in body, testis, seminal vesicles and prostate weights. This was accompanied with decreased levels of plasmatic testosterone (P<0.02). In this aproteic group there was a significant reduction in LH (P<0.05) and FSH (P<0.05) plasmatic levels. Refeeding with control diet reversed this situation, producing significant increment in LH (P<0.05) and FSH levels (P<0.01) at the fourth and second weeks, respectively. The basal hypothalamic GnRH secretion did not differ from the control; nevertheless the induced secretion was significantly (P<0.05) greater in the aproteic group. Also the hypothalamic GnRH concentration was increased (P<0.05) in animals fed with the aproteic diet. The minor testis, prostate, and seminal vesicles" weight, and a decreased plasmatic testosterone in rats fed with an aproteic diet, are produced by a decrease in gonadotrophin secretion. This decrease in turn is caused by a reduction in GnRH secretion, since hypothalamic GnRH concentration is increased in rats fed with the aproteic group, and induced secretion is greater in this group. All these alterations produced by an aproteic diet are reversible, since-with contol diet refeeding-the gonadotrophin secretion returned at control levels.

  9. Weight loss by calorie restriction versus bariatric surgery differentially regulates the HPA axis in male rats

    PubMed Central

    Grayson, Bernadette E.; Hakala-Finch, Andrew P.; Kekulawala, Melani; Laub, Holly; Egan, Ann E.; Ressler, Ilana B.; Woods, Stephen C.; Herman, James P.; Seeley, Randy J.; Benoit, Stephen C.; Ulrich-Lai, Yvonne M.

    2015-01-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in 5 groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n=7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n=11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n=11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n=11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n=12). Compared to Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentrations and increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results suggest that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  10. 77 FR 52739 - Federal Acquisition Regulation; Information Collection; Integrity of Unit Prices

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-30

    ... Regulation; Information Collection; Integrity of Unit Prices AGENCY: Department of Defense (DOD), General... collection requirement concerning Integrity of Unit Prices. Public comments are particularly invited on... and methodology; ways to enhance the quality, utility, and clarity of the information to be...

  11. 77 FR 67804 - Federal Acquisition Regulation; Submission for OMB Review; Integrity of Unit Prices

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-14

    ... Regulation; Submission for OMB Review; Integrity of Unit Prices AGENCY: Department of Defense (DOD), General... collection requirement concerning Integrity of Unit Prices. A notice was published in the Federal Register at 77 FR 52739, on August 30, 2012. No comments were received. Public comments are particularly...

  12. 75 FR 41097 - Homeland Security Acquisition Regulation; Lead System Integrators [HSAR Case 2009-003

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-15

    ... Acquisition Regulation; Lead System Integrators AGENCY: Office of the Chief Procurement Officer, DHS. ACTION... lead system integrators in the acquisition of DHS major systems if they have direct financial interests... 6 U.S.C. 396; hereinafter ``Section 396''), limits firms that can serve as lead system...

  13. Fasting induced kisspeptin signaling suppression is regulated by glutamate mediated cues in adult male rhesus macaque (Macaca mulatta).

    PubMed

    Shamas, Shazia; Khan, Saeed-Ul-Hassan; Khan, Muhammad Yousaf; Shabbir, Nadia; Zubair, Hira; Shafqat, Saira; Wahab, Fazal; Shahab, Muhammad

    2015-08-01

    Kisspeptin signaling is suppressed by short term fasting. It has been reported that hypothalamic Kiss1 and Kiss1r mRNA expression decreased after 48h of fasting in male rhesus monkey. But the mechanism involved in the reduction of kisspeptin signaling after 48h of fasting is unknown. Recent studies have suggested the role of afferent excitatory and inhibitory pathways in the regulation of kisspeptin neurons. Therefore, this study was designed to observe the changes in the glutamate and GABA signaling during fed and 48h fasting states by performing immunofluorescence to examine the interaction of kisspeptin neurons with NR1 subunit of NMDA receptors and by performing SYBR green qRT-PCR to measure and quantify the levels of Kiss1, Kiss1r, NR1 and GAD67 mRNA in the POA and MBH of adult male rhesus macaque (Macaca mulatta) during 48h of fasting (n=2) and fed ad libitum (n=2). Plasma testosterone (p<0.05) and blood glucose levels were significantly (p<0.001) decreased after short term fasting. Our results clearly showed that expression of hypothalamic Kiss1, Kiss1r and NR1 mRNA was significantly (p<0.05) reduced in adult male rhesus monkeys which were fasted for 48h as compared to those which were fed ad libitum. There was no clear difference in the GAD67 mRNA contents between the two groups. Number of kisspeptin neurons and the interactions of kisspeptin neurons with NR1 were significantly (p<0.05) reduced after 48h fasting. These observations suggest that decreased kisspeptin signaling during fasting may occur due to reduction in glutamatergic inputs to kisspeptin neurons. Our results also suggest that fasting induced suppression of kisspeptin signaling is not mediated through GABAergic neurons.

  14. Fasting induced kisspeptin signaling suppression is regulated by glutamate mediated cues in adult male rhesus macaque (Macaca mulatta).

    PubMed

    Shamas, Shazia; Khan, Saeed-Ul-Hassan; Khan, Muhammad Yousaf; Shabbir, Nadia; Zubair, Hira; Shafqat, Saira; Wahab, Fazal; Shahab, Muhammad

    2015-08-01

    Kisspeptin signaling is suppressed by short term fasting. It has been reported that hypothalamic Kiss1 and Kiss1r mRNA expression decreased after 48h of fasting in male rhesus monkey. But the mechanism involved in the reduction of kisspeptin signaling after 48h of fasting is unknown. Recent studies have suggested the role of afferent excitatory and inhibitory pathways in the regulation of kisspeptin neurons. Therefore, this study was designed to observe the changes in the glutamate and GABA signaling during fed and 48h fasting states by performing immunofluorescence to examine the interaction of kisspeptin neurons with NR1 subunit of NMDA receptors and by performing SYBR green qRT-PCR to measure and quantify the levels of Kiss1, Kiss1r, NR1 and GAD67 mRNA in the POA and MBH of adult male rhesus macaque (Macaca mulatta) during 48h of fasting (n=2) and fed ad libitum (n=2). Plasma testosterone (p<0.05) and blood glucose levels were significantly (p<0.001) decreased after short term fasting. Our results clearly showed that expression of hypothalamic Kiss1, Kiss1r and NR1 mRNA was significantly (p<0.05) reduced in adult male rhesus monkeys which were fasted for 48h as compared to those which were fed ad libitum. There was no clear difference in the GAD67 mRNA contents between the two groups. Number of kisspeptin neurons and the interactions of kisspeptin neurons with NR1 were significantly (p<0.05) reduced after 48h fasting. These observations suggest that decreased kisspeptin signaling during fasting may occur due to reduction in glutamatergic inputs to kisspeptin neurons. Our results also suggest that fasting induced suppression of kisspeptin signaling is not mediated through GABAergic neurons. PMID:26138506

  15. Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism.

    PubMed

    Andreoli, María Florencia; Stoker, Cora; Rossetti, María Florencia; Alzamendi, Ana; Castrogiovanni, Daniel; Luque, Enrique H; Ramos, Jorge Guillermo

    2015-02-01

    The absence of phytoestrogens in the diet during pregnancy has been reported to result in obesity later in adulthood. We investigated whether phytoestrogen withdrawal in adult life could alter the hypothalamic signals that regulate food intake and affect body weight and glucose homeostasis. Male Wistar rats fed from conception to adulthood with a high phytoestrogen diet were submitted to phytoestrogen withdrawal by feeding a low phytoestrogen diet, or a high phytoestrogen-high fat diet. Withdrawal of dietary phytoestrogens increased body weight, adiposity and energy intake through an orexigenic hypothalamic response characterized by upregulation of AGRP and downregulation of POMC. This was associated with elevated leptin and T4, reduced TSH, testosterone and estradiol, and diminished hypothalamic ERα expression, concomitant with alterations in glucose tolerance. Removing dietary phytoestrogens caused manifestations of obesity and diabetes that were more pronounced than those induced by the high phytoestrogen-high fat diet intake.

  16. Long-term methylphenidate treatment down-regulates c-fos in the striatum of male CD-1 mice.

    PubMed

    Hawken, Christianne M; Brown, Richard E; Carrey, Normand; Wilkinson, Michael

    2004-04-29

    Methylphenidate (Ritalin) is routinely prescribed to children with attention deficit hyperactivity disorder, but little is known about its long-term consequences on brain development. We treated pre- and peri-pubertal male CD-1 mice with repeated injections of methylphenidate hydrochloride (MPH) and quantified the expression of the immediate early gene c-fos in the striatum. A single injection of MPH (5 or 40 mg/kg) significantly elevated FOS immunoreactivity in the striatum in a dose-dependent manner, compared with saline. Repeated MPH treatment attenuated the effect of a single challenge dose of MPH on striatal c-fos expression. These results replicate those observed with rats and indicate that long-term use of MPH may alter neural activity by down-regulation of gene expression in the striatum.

  17. Effects of age on plasma levels of calcium-regulating hormones and bone status in male SAMP8 mice.

    PubMed

    Chen, Chun-Chi; Wang, Ming-Fu; Liu, Mei-Hui; Lin, Wu-Ting; Yang, Shyi-Kuen

    2004-03-31

    This study was undertaken to examine whether the plasma levels of calcium-regulating hormones and bone status alter with age in male senescence accelerated mice (SAM), SAMP8. Age-matched senescence-resistant mice, SAMR1, were used as controls. The blood and femur samples were collected at 2.5 months of age (M) and then monthly from 3 to 12 M for physicochemical analyses, biochemical analyses, and the determination of hormones by radioimmunoassay. With advancing age, the plasma calcitonin (CT) levels decreased progressively, and the plasma parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3) levels increased in both SAMR1 and SAMP8. The plasma calcium concentrations were maintained within a narrow range throughout the experimental period, while the plasma phosphorus (P) concentrations decreased with age in both strains. In contrast to SAMR1, the curves of age-related changes in the plasma CT levels and P concentrations were lower, and those in the plasma PTH levels were higher in SAMP8. The femoral bone densities and calcium contents increased gradually with age from the beginning of the experiment and peaked at 6 M in both strains, then declined. Those peaks were lower in SAMP8 than in SAMR1. These results indicate that the male SAMP8 develops osteoporotic signs earlier than SAMR1, and is proved to be a satisfactory animal model for longitudinal studies related to osteoporosis for men. PMID:15239589

  18. Adaptive regulation of testis gene expression and control of male fertility by the Drosophila hairpin RNA pathway. [Corrected].

    PubMed

    Wen, Jiayu; Duan, Hong; Bejarano, Fernando; Okamura, Katsutomo; Fabian, Lacramioara; Brill, Julie A; Bortolamiol-Becet, Diane; Martin, Raquel; Ruby, J Graham; Lai, Eric C

    2015-01-01

    Although endogenous siRNAs (endo-siRNAs) have been described in many species, still little is known about their endogenous utility. Here, we show that Drosophila hairpin RNAs (hpRNAs) generate an endo-siRNA class with predominant expression in testes. Although hpRNAs are universally recently evolved, we identify highly complementary protein-coding targets for all hpRNAs. Importantly, we find broad evidence for evolutionary divergences that preferentially maintain compensatory pairing between hpRNAs and targets, serving as first evidence for adaptive selection for siRNA-mediated target regulation in metazoans. We demonstrate organismal impact of hpRNA activity, since knockout of hpRNA1 derepresses its target ATP synthase-β in testes and compromises spermatogenesis and male fertility. Moreover, we reveal surprising male-specific impact of RNAi factors on germ cell development and fertility, consistent with testis-directed function of the hpRNA pathway. Finally, the collected hpRNA loci chronicle an evolutionary timeline that reflects their origins from prospective target genes, mirroring a strategy described for plant miRNAs.

  19. Bile acid-FXRα pathways regulate male sexual maturation in mice

    PubMed Central

    Vega, Aurélie; Sédes, Lauriane; Rouaisnel, Betty; de Haze, Angélique; Baron, Silvère; Schoonjans, Kristina; Caira, Françoise; Volle, David H.

    2016-01-01

    The bile acid receptor Farnesol-X-Receptor alpha (FRXα) is a member of the nuclear receptor superfamily. FRXα is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. In adult, short term treatment (12 hours) with FRXα agonist inhibits the expression of steroidogenic genes via the induction of the Small heterodimer partner (SHP). However the consequences of FRXα activation on testicular pathophysiology have never been evaluated. We demonstrate here that mice fed a diet supplemented with bile acid during pubertal age show increased incidence of infertility. This is associated with altered differentiation and increase apoptosis of germ cells due to lower testosterone levels. At the molecular level, next to the repression of basal steroidogenesis via the induction expression of Shp and Dax-1, two repressors of steroidogenesis, the main action of the BA-FRXα signaling is through lowering the Leydig cell sensitivity to the hypothalamo-pituitary axis, the main regulator of testicular endocrine function. In conclusion, BA-FRXα signaling is a critical actor during sexual maturation. PMID:26848619

  20. Estriol blunts postprandial blood glucose rise in male rats through regulating intestinal glucose transporters.

    PubMed

    Yamabe, Noriko; Kang, Ki Sung; Lee, Woojung; Kim, Su-Nam; Zhu, Bao Ting

    2015-03-01

    Despite increased total food intake in healthy, late-stage pregnant women, their peak postprandial blood sugar levels are normally much lower than the levels seen in healthy nonpregnant women. In this study, we sought to determine whether estriol (E3), an endogenous estrogen predominantly produced during human pregnancy, contributes to the regulation of the postprandial blood glucose level in healthy normal rats. In vivo studies using rats showed that E3 blunted the speed and magnitude of the blood glucose rise following oral glucose administration, but it did not appear to affect the total amount of glucose absorbed. E3 also did not affect insulin secretion, but it significantly reduced the rate of intestinal glucose transport compared with vehicle-treated animals. Consistent with this finding, expression of the sodium-dependent glucose transporter 1 and 2 was significantly downregulated by E3 treatment in the brush-border membrane and basolateral membrane, respectively, of enterocytes. Most of the observed in vivo effects were noticeably stronger with E3 than with 17β-estradiol. Using differentiated human Caco-2 enterocyte monolayer culture as an in vitro model, we confirmed that E3 at physiologically relevant concentrations could directly inhibit glucose uptake via suppression of glucose transporter 2 expression, whereas 17β-estradiol did not have a similar effect. Collectively, these data showed that E3 can blunt the postprandial glycemic surge in rats through modulating the level of intestinal glucose transporters.

  1. Bile acid-FXRα pathways regulate male sexual maturation in mice.

    PubMed

    Baptissart, Marine; Martinot, Emmanuelle; Vega, Aurélie; Sédes, Lauriane; Rouaisnel, Betty; de Haze, Angélique; Baron, Silvère; Schoonjans, Kristina; Caira, Françoise; Volle, David H

    2016-04-12

    The bile acid receptor Farnesol-X-Receptor alpha (FRXα) is a member of the nuclear receptor superfamily. FRXα is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. In adult, short term treatment (12 hours) with FRXα agonist inhibits the expression of steroidogenic genes via the induction of the Small heterodimer partner (SHP). However the consequences of FRXα activation on testicular pathophysiology have never been evaluated. We demonstrate here that mice fed a diet supplemented with bile acid during pubertal age show increased incidence of infertility. This is associated with altered differentiation and increase apoptosis of germ cells due to lower testosterone levels. At the molecular level, next to the repression of basal steroidogenesis via the induction expression of Shp and Dax-1, two repressors of steroidogenesis, the main action of the BA-FRXα signaling is through lowering the Leydig cell sensitivity to the hypothalamo-pituitary axis, the main regulator of testicular endocrine function. In conclusion, BA-FRXα signaling is a critical actor during sexual maturation. PMID:26848619

  2. Regulation of mitotic spindle orientation: an integrated view.

    PubMed

    di Pietro, Florencia; Echard, Arnaud; Morin, Xavier

    2016-08-01

    Mitotic spindle orientation is essential for cell fate decisions, epithelial maintenance, and tissue morphogenesis. In most animal cell types, the dynein motor complex is anchored at the cell cortex and exerts pulling forces on astral microtubules to position the spindle. Early studies identified the evolutionarily conserved Gαi/LGN/NuMA complex as a key regulator that polarizes cortical force generators. In recent years, a combination of genetics, biochemistry, modeling, and live imaging has contributed to decipher the mechanisms of spindle orientation. Here, we highlight the dynamic nature of the assembly of this complex and discuss the molecular regulation of its localization. Remarkably, a number of LGN-independent mechanisms were described recently, whereas NuMA remains central in most pathways involved in recruiting force generators at the cell cortex. We also describe the emerging role of the actin cortex in spindle orientation and discuss how dynamic astral microtubule formation is involved. We further give an overview on instructive external signals that control spindle orientation in tissues. Finally, we discuss the influence of cell geometry and mechanical forces on spindle orientation. PMID:27432284

  3. Concepts for regulation of axon integrity by enwrapping glia

    PubMed Central

    Beirowski, Bogdan

    2013-01-01

    Long axons and their enwrapping glia (EG; Schwann cells (SCs) and oligodendrocytes (OLGs)) form a unique compound structure that serves as conduit for transport of electric and chemical information in the nervous system. The peculiar cytoarchitecture over an enormous length as well as its substantial energetic requirements make this conduit particularly susceptible to detrimental alterations. Degeneration of long axons independent of neuronal cell bodies is observed comparatively early in a range of neurodegenerative conditions as a consequence of abnormalities in SCs and OLGs . This leads to the most relevant disease symptoms and highlights the critical role that these glia have for axon integrity, but the underlying mechanisms remain elusive. The quest to understand why and how axons degenerate is now a crucial frontier in disease-oriented research. This challenge is most likely to lead to significant progress if the inextricable link between axons and their flanking glia in pathological situations is recognized. In this review I compile recent advances in our understanding of the molecular programs governing axon degeneration, and mechanisms of EG’s non-cell autonomous impact on axon-integrity. A particular focus is placed on emerging evidence suggesting that EG nurture long axons by virtue of their intimate association, release of trophic substances, and neurometabolic coupling. The correction of defects in these functions has the potential to stabilize axons in a variety of neuronal diseases in the peripheral nervous system and central nervous system (PNS and CNS). PMID:24391540

  4. The "omics" of human male infertility: integrating big data in a systems biology approach.

    PubMed

    Carrell, D T; Aston, K I; Oliva, R; Emery, B R; De Jonge, C J

    2016-01-01

    Spermatogenesis is a complex process in which >2300 genes are temporally and spatially regulated to form a terminally differentiated sperm cell that must maintain the ability to contribute to a totipotent embryo which can successfully differentiate into a healthy individual. This process is dependent on fidelity of the genome, epigenome, transcriptome, and proteome of the spermatogonia, supporting cells, and the resulting sperm cell. Infertility and/or disease risk may increase in the offspring if abnormalities are present. This review highlights the recent advances in our understanding of these processes in light of the "omics revolution". We briefly review each of these areas, as well as highlight areas of future study and needs to advance further.

  5. Cystic fibrosis transmembrane conductance regulator (CFTR) gene abnormalities in Indian males with congenital bilateral absence of vas deferens & renal anomalies

    PubMed Central

    Gajbhiye, Rahul; Kadam, Kaushiki; Khole, Aalok; Gaikwad, Avinash; Kadam, Seema; Shah, Rupin; Kumaraswamy, Rangaswamy; Khole, Vrinda

    2016-01-01

    Background & objectives: The role of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in congenital bilateral absence of vas deferens and unilateral renal agenesis (CBAVD-URA) has been controversial. Here, we report the cases of five Indian males with CBAVD-URA. The objective was to evaluate the presence or absence of CFTR gene mutations and variants in CBAVD-URA. The female partners of these males were also screened for cystic fibrosis (CF) carrier status. Methods: Direct DNA sequencing of CFTR gene was carried out in five Indian infertile males having CBAVD-URA. Female partners (n=5) and healthy controls (n=32) were also screened. Results: Three potential regulatory CFTR gene variants (c.1540A>G, c.2694T>G and c.4521G>A) were detected along with IVS8-5T mutation in three infertile males with CBAVD-URA. Five novel CFTR gene variants (c.621+91A>G, c.2752+106A>T, c.2751+85_88delTA, c.3120+529InsC and c.4375-69C>T), four potential regulatory CFTR gene variants (M470V, T854T, P1290P, Q1463Q) and seven previously reported CFTR gene variants (c.196+12T>C, c.875+40A>G, c.3041-71G>C, c.3271+42A>T, c.3272-93T>C, c.3500-140A>C and c.3601-65C>A) were detected in infertile men having CBAVD and renal anomalies Interpretation & conclusions: Based on our findings, we speculate that CBAVD-URA may also be attributed to CFTR gene mutations and can be considered as CFTR-related disorder (CFTR-RD). The CFTR gene mutation screening may be offered to CBAVD-URA men and their female partners undergoing ICSI. Further studies need to be done in a large sample to confirm the findings. PMID:27488005

  6. Integration of detailed modules in a core model of body fluid homeostasis and blood pressure regulation.

    PubMed

    Hernández, Alfredo I; Le Rolle, Virginie; Ojeda, David; Baconnier, Pierre; Fontecave-Jallon, Julie; Guillaud, François; Grosse, Thibault; Moss, Robert G; Hannaert, Patrick; Thomas, S Randall

    2011-10-01

    This paper presents a contribution to the definition of the interfaces required to perform heterogeneous model integration in the context of integrative physiology. A formalization of the model integration problem is proposed and a coupling method is presented. The extension of the classic Guyton model, a multi-organ, integrated systems model of blood pressure regulation, is used as an example of the application of the proposed method. To this end, the Guyton model has been restructured, extensive sensitivity analyses have been performed, and appropriate transformations have been applied to replace a subset of its constituting modules by integrating a pulsatile heart and an updated representation of the renin-angiotensin system. Simulation results of the extended integrated model are presented and the impacts of their integration within the original model are evaluated.

  7. TAK1 regulates Paneth cell integrity partly through blocking necroptosis

    PubMed Central

    Simmons, A N; Kajino-Sakamoto, R; Ninomiya-Tsuji, J

    2016-01-01

    Paneth cells reside at the base of crypts of the small intestine and secrete antimicrobial factors to control gut microbiota. Paneth cell loss is observed in the chronically inflamed intestine, which is often associated with increased reactive oxygen species (ROS). However, the relationship between Paneth cell loss and ROS is not yet clear. Intestinal epithelial-specific deletion of a protein kinase Tak1 depletes Paneth cells and highly upregulates ROS in the mouse model. We found that depletion of gut bacteria or myeloid differentiation factor 88 (Myd88), a mediator of bacteria-derived cell signaling, reduced ROS but did not block Paneth cell loss, suggesting that gut bacteria are the cause of ROS accumulation but bacteria-induced ROS are not the cause of Paneth cell loss. In contrast, deletion of the necroptotic cell death signaling intermediate, receptor-interacting protein kinase 3 (Ripk3), partially blocked Paneth cell loss. Thus, Tak1 deletion causes Paneth cell loss in part through necroptotic cell death. These results suggest that TAK1 participates in intestinal integrity through separately modulating bacteria-derived ROS and RIPK3-dependent Paneth cell loss. PMID:27077812

  8. Specific down-regulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-Chromosome introgression.

    PubMed

    Li, Runsheng; Ren, Xiaoliang; Bi, Yu; Ho, Vincy Wing Sze; Hsieh, Chia-Ling; Young, Amanda; Zhang, Zhihong; Lin, Tingting; Zhao, Yanmei; Miao, Long; Sarkies, Peter; Zhao, Zhongying

    2016-09-01

    Hybrid incompatibility (HI) prevents gene flow between species, thus lying at the heart of speciation genetics. One of the most common HIs is male sterility. Two superficially contradictory observations exist for hybrid male sterility. First, an introgression on the X Chromosome is more likely to produce male sterility than on autosome (so-called large-X theory); second, spermatogenesis genes are enriched on the autosomes but depleted on the X Chromosome (demasculinization of X Chromosome). Analysis of gene expression in Drosophila hybrids suggests a genetic interaction between the X Chromosome and autosomes that is essential for male fertility. However, the prevalence of such an interaction and its underlying mechanism remain largely unknown. Here we examine the interaction in nematode species by contrasting the expression of both coding genes and transposable elements (TEs) between hybrid sterile males and its parental nematode males. We use two lines of hybrid sterile males, each carrying an independent introgression fragment from Caenorhabditis briggsae X Chromosome in an otherwise Caenorhabditis nigoni background, which demonstrate similar defects in spermatogenesis. We observe a similar pattern of down-regulated genes that are specific for spermatogenesis between the two hybrids. Importantly, the down-regulated genes caused by the X Chromosome introgressions show a significant enrichment on the autosomes, supporting an epistatic interaction between the X Chromosome and autosomes. We investigate the underlying mechanism of the interaction by measuring small RNAs and find that a subset of 22G RNAs specifically targeting the down-regulated spermatogenesis genes is significantly up-regulated in hybrids, suggesting that perturbation of small RNA-mediated regulation may contribute to the X-autosome interaction.

  9. Specific down-regulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-Chromosome introgression.

    PubMed

    Li, Runsheng; Ren, Xiaoliang; Bi, Yu; Ho, Vincy Wing Sze; Hsieh, Chia-Ling; Young, Amanda; Zhang, Zhihong; Lin, Tingting; Zhao, Yanmei; Miao, Long; Sarkies, Peter; Zhao, Zhongying

    2016-09-01

    Hybrid incompatibility (HI) prevents gene flow between species, thus lying at the heart of speciation genetics. One of the most common HIs is male sterility. Two superficially contradictory observations exist for hybrid male sterility. First, an introgression on the X Chromosome is more likely to produce male sterility than on autosome (so-called large-X theory); second, spermatogenesis genes are enriched on the autosomes but depleted on the X Chromosome (demasculinization of X Chromosome). Analysis of gene expression in Drosophila hybrids suggests a genetic interaction between the X Chromosome and autosomes that is essential for male fertility. However, the prevalence of such an interaction and its underlying mechanism remain largely unknown. Here we examine the interaction in nematode species by contrasting the expression of both coding genes and transposable elements (TEs) between hybrid sterile males and its parental nematode males. We use two lines of hybrid sterile males, each carrying an independent introgression fragment from Caenorhabditis briggsae X Chromosome in an otherwise Caenorhabditis nigoni background, which demonstrate similar defects in spermatogenesis. We observe a similar pattern of down-regulated genes that are specific for spermatogenesis between the two hybrids. Importantly, the down-regulated genes caused by the X Chromosome introgressions show a significant enrichment on the autosomes, supporting an epistatic interaction between the X Chromosome and autosomes. We investigate the underlying mechanism of the interaction by measuring small RNAs and find that a subset of 22G RNAs specifically targeting the down-regulated spermatogenesis genes is significantly up-regulated in hybrids, suggesting that perturbation of small RNA-mediated regulation may contribute to the X-autosome interaction. PMID:27197225

  10. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; Ramírez-Expósito, María Jesús

    2003-06-20

    Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.

  11. Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant-path long-term potentiation in adult male rats.

    PubMed

    Anagnostaras, S G; Maren, S; DeCola, J P; Lane, N I; Gale, G D; Schlinger, B A; Fanselow, M S

    1998-04-01

    We recently reported that Pavlovian fear conditioning and hippocampal perforant-path long-term potentiation (LTP) are sexually dimorphic in rats. Males show greater contextual fear conditioning, which depends on the hippocampus, as well as greater hippocampal LTP. In order to examine the role of circulating gonadal hormones in adult male rats, animals were castrated in two experiments, and Pavlovian fear conditioning and in vivo perforant-path LTP were examined. It was found that sexually-dimorphic LTP and fear conditioning are not regulated by the activational effects of testicular hormones in adult male rats. That is, in every respect, castrated male rats were similar to intact male rats in Pavlovian fear conditioning and hippocampal LTP. It is likely that sexual dimorphism in this system is established earlier in development by the organizational effects of gonadal hormones.

  12. Integrin β1 regulates leiomyoma cytoskeletal integrity and growth

    PubMed Central

    Malik, Minnie; Segars, James; Catherino, William H.

    2014-01-01

    Uterine leiomyomas are characterized by an excessive extracellular matrix, increased mechanical stress, and increased active RhoA. Previously, we observed that mechanical signaling was attenuated in leiomyoma, but the mechanisms responsible remain unclear. Integrins, especially integrin β1, are transmembrane adhesion receptors that couple extracellular matrix stresses to the intracellular cytoskeleton to influence cell proliferation and differentiation. Here we characterized integrin and laminin to signaling in leiomyoma cells. We observed a 2.25 ± 0.32 fold increased expression of integrin β1 in leiomyoma cells, compared to myometrial cells. Antibody-mediated inhibition of integrin β1 led to significant growth inhibition in leiomyoma cells and a loss of cytoskeletal integrity. Specifically, polymerization of actin filaments and formation of focal adhesions were reduced by inhibition of integrin p1. Inhibition of integrin β1 in leiomyoma cells led to 0.81 ± 0.02 fold decrease in active RhoA, and resembled levels found in serum-starved cells. Likewise, inhibition of integrin β1 was accompanied by a decrease in phospho-ERK. Compared to myometrial cells, leiomyoma cells demonstrated increased expression of integrin α6 subunit to laminin receptor (1.91 ± 0.11 fold), and increased expression of laminin 5α (1.52±0.02), laminin 5β (3.06±0.92), and laminin 5γ (1.66 ± 0.06). Of note, leiomyoma cells grown on laminin matrix appear to realign themselves. Taken together, the findings reveal that the attenuated mechanical signaling in leiomyoma cells is accompanied by an increased expression and a dependence on integrin β1 signaling in leiomyoma cells, compared to myometrial cells. PMID:23023061

  13. Mutations in Transcriptional Regulators Allow Selective Engineering of Signal Integration Logic

    PubMed Central

    2014-01-01

    ABSTRACT Bacterial cells monitor their environment by sensing a set of signals. Typically, these environmental signals affect promoter activities by altering the activity of transcription regulatory proteins. Promoters are often regulated by more than one regulatory protein, and in these cases the relevant signals are integrated by certain logic. In this work, we study how single amino acid substitutions in a regulatory protein (GalR) affect transcriptional regulation and signal integration logic at a set of engineered promoters. Our results suggest that point mutations in regulatory genes allow independent evolution of regulatory logic at different promoters. PMID:24961691

  14. A guide to integrating transcriptional regulatory and metabolic networks using PROM (probabilistic regulation of metabolism).

    PubMed

    Simeonidis, Evangelos; Chandrasekaran, Sriram; Price, Nathan D

    2013-01-01

    The integration of transcriptional regulatory and metabolic networks is a crucial step in the process of predicting metabolic behaviors that emerge from either genetic or environmental changes. Here, we present a guide to PROM (probabilistic regulation of metabolism), an automated method for the construction and simulation of integrated metabolic and transcriptional regulatory networks that enables large-scale phenotypic predictions for a wide range of model organisms.

  15. Testicular Steroidogenesis and Locomotor Activity Are Regulated by Gonadotropin-Inhibitory Hormone in Male European Sea Bass

    PubMed Central

    Paullada-Salmerón, José A.; Cowan, Mairi; Aliaga-Guerrero, María; López-Olmeda, José F.; Mañanós, Evaristo L.; Zanuy, Silvia

    2016-01-01

    Gonadotropin-inhibitory hormone (GnIH) is a neurohormone that suppresses reproduction by acting at both the brain and pituitary levels. In addition to the brain, GnIH may also be produced in gonads and can regulate steroidogenesis and gametogenesis. However, the function of GnIH in gonadal physiology has received little attention in fish. The main objective of this study was to evaluate the effects of peripheral sbGnih-1 and sbGnih-2 implants on gonadal development and steroidogenesis during the reproductive cycle of male sea bass (Dicentrarchus labrax). Both Gnihs decreased testosterone (T) and 11-ketotestosterone (11-KT) plasma levels in November and December (early- and mid-spermatogenesis) but did not affect plasma levels of the progestin 17,20β-dihydroxy-4-pregnen-3-one (DHP). In February (spermiation), fish treated with sbGnih-1 and sbGnih-2 exhibited testicles with abundant type A spermatogonia and partial spermatogenesis. In addition, we determined the effects of peripheral Gnih implants on plasma follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) levels, as well as on brain and pituitary expression of the main reproductive hormone genes and their receptors during the spermiation period (February). Treatment with sbGnih-2 increased brain gnrh2, gnih, kiss1r and gnihr transcript levels. Whereas, both Gnihs decreased lhbeta expression and plasma Lh levels, and sbGnih-1 reduced plasmatic Fsh. Finally, through behavioral recording we showed that Gnih implanted animals exhibited a significant increase in diurnal activity from late spermatogenic to early spermiogenic stages. Our results indicate that Gnih may regulate the reproductive axis of sea bass acting not only on brain and pituitary hormones but also on gonadal physiology and behavior. PMID:27788270

  16. Regulation of testicular insulin-like growth factor-I in pubertal growth hormone-deficient male rats.

    PubMed

    Spiteri-Grech, J; Bartlett, J M; Nieschlag, E

    1991-11-01

    GH plays a major role in pubertal growth, effects mainly mediated by stimulation of insulin-like growth factor-I (IGF-I) production by the liver. However, the role of GH in the regulation of pubertal onset, spermatogenesis and fertility is still under debate. GH and FSH have, in addition, been implicated in the regulation of IGF-I production by Sertoli cells in a number of studies, although conflicting results have been reported. The interpretation of studies using GH-deficient mutant mice has been complicated by the presence of additional defects in the hypothalamic-pituitary-gonadal axis of these animals. We have therefore used GH-deficient mutant male rats with no other documented hormonal deficiencies to study the effect of GH administration on somatic and testicular development, circulating and testicular IGF-I concentrations and testicular histology. Body weights in GH-deficient rats substituted with GH were not significantly different from untreated or GH-treated normal rats and were significantly higher than body weights in untreated dwarf rats. Similarly, circulating IGF-I concentrations in GH-treated GH-deficient rats were not significantly different from those in untreated or GH-treated normal rats but were significantly higher than circulating IGF-I concentrations in untreated dwarf rats. No differences in testicular IGF-I concentrations were observed in any of the groups studied. Testicular weights remained low in both untreated and GH-treated GH-deficient animals compared with control animals but spermatogenesis was qualitatively and quantitatively normal in all groups at the end of the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis

    PubMed Central

    Choi, Hyunmo; Oh, Eunkyoo

    2016-01-01

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  18. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis.

    PubMed

    Choi, Hyunmo; Oh, Eunkyoo

    2016-08-31

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  19. Integrating the Regulation of Affect, Behavior, and Cognition into Self-Regulated Learning Paradigms among Secondary and Post-Secondary Students

    ERIC Educational Resources Information Center

    Ben-Eliyahu, Adar; Linnenbrink-Garcia, Lisa

    2015-01-01

    An integrative framework for investigating self-regulated learning situated in students' favorite and least favorite courses was empirically tested in a sample of 178 high school and 280 college students. Building on cognitive, clinical, social, and educational conceptions of self-regulation, the current paper integrated affective (e.g.,…

  20. High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring.

    PubMed

    Kruse, Michael; Keyhani-Nejad, Farnaz; Isken, Frank; Nitz, Barbara; Kretschmer, Anja; Reischl, Eva; de las Heras Gala, Tonia; Osterhoff, Martin A; Grallert, Harald; Pfeiffer, Andreas F H

    2016-03-01

    Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming.

  1. VITELLOGENIN MRNA REGULATION AND PLASMA CLEARANCE IN MALE SHEEPSHEAD MINNOWS, CYPRINODON VARIEGATUS AFTER CESSATION OF EXPOSURE TO 17B-ESTRADIOL AND P-NONYLPHENOL

    EPA Science Inventory

    Research was conducted to determine the kinetics of hepatic vitellogenin (VTG) mRNA regulation and plasma VTG accumulation and clearance in male sheepshead minnows (Cyprinodon variegatus) during and after cessation of exposure to either 17b-estradiol (E2) or para-nonylphenol (NP)...

  2. Combined melatonin and exendin-4 therapy preserves renal ultrastructural integrity after ischemia-reperfusion injury in the male rat.

    PubMed

    Yip, Hon-Kan; Yang, Chih-Chao; Chen, Kuan-Hung; Huang, Tien-Hung; Chen, Yi-Ling; Zhen, Yen-Yi; Sung, Pei-Hsun; Chiang, Hsin-Ju; Sheu, Jiunn-Jye; Chang, Chia-Lo; Chen, Chih-Hung; Chang, Hsueh-Wen; Chen, Yen-Ta

    2015-11-01

    We tested whether combined melatonin (Mel) and exendin-4 (Ex4) treatment can better preserve glomerular structural integrity after ischemia-reperfusion (IR) injury compared with either alone. Adult male Sprague Dawley rats (n = 50) were equally divided into sham control (SC), IR, IR-Ex4 (10 μg/kg subcutaneously 30 min after reperfusion and daily for 5 days), IR-Mel (20 mg/kg intraperitoneally at 30 min postreperfusion and 50 mg/kg at 6 and 18 hr), and IR-Ex4-Mel were euthanized at day 14. Serum creatinine level and urine protein-to-creatinine ratio at days 3 and 14 were highest in IR group and lowest in SC, significantly higher in IR-Ex4 and IR-Mel groups than in IR-Ex4-Mel group (all P < 0.001) without significant difference between IR-Ex4 and IR-Mel groups. Changes in podocyte injury score (PIS) and kidney injury score were highest in IR group and lowest in SC, significantly higher in IR-Ex4 and IR-Mel groups than in IR-Ex4-Mel, and significantly higher in IR-Mel group than in IR-Ex4 group (all P < 0.001). Immunohistochemical microscopic findings of the expressions of FSP-1 and WT-1 (two glomerular damage indicators) and KIM-1 and snail (two renal tubular-damaged indicators) showed an identical pattern, whereas the expressions of ZO-1, p-cadherin, podocin, dystroglycan, fibronectin, and synaptopodin (six indices of glomerular integrity) demonstrated an opposite pattern compared to that of PIS among five groups (all P < 0.001). Protein expressions of inflammatory (TNF-α/NF-κB/MMP-9) and oxidative stress (NOX-1, NOX-2, oxidized protein) biomarkers exhibited an identical pattern to that of PIS among five groups (all P < 0.001). Combined melatonin-exednin-4 therapy further protected glomerulus from IR injury.

  3. 75 FR 3178 - Defense Federal Acquisition Regulation Supplement; Lead System Integrators

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-20

    ... an interim rule at 73 FR 1823 on January 10, 2008, to implement Section 807 of the National ] Defense... 74 FR 34268 on July 15, 2009, is adopted as a final rule without change. BILLING CODE 5001-08-P ... Acquisition Regulation Supplement; Lead System Integrators AGENCY: Department of Defense (DoD). ACTION:...

  4. Thyrotropin regulates the levels of free ubiquitin and ubiquitin-protein conjugates in the male mouse thyroid.

    PubMed

    Keegan, B P; Sheflin, L G; Spaulding, S W

    1997-12-01

    The conjugation of ubiquitin to proteins can be a signal for their degradation, but can also be involved in regulatory processes not directly involved in protein degradation. Because thyrotropin (TSH) is the major physiological regulator of the thyroid, we have investigated whether changes in the circulating level of TSH influence the level of immunoreactive ubiquitin in the thyroid, as assessed by dot-blot assays. Putting male Balb/c mice on a low iodine diet with methimazole (MMI) in their drinking water for 14 days raised the level of ubiquitin by 425 % (p < 0.001) per microgram nonthyroglobulin protein (the mean thyroglobulin level dropped by 35% (p < 0.05)). Western blots similarly indicated that immunoreactivity migrating in the region of monoubiquitin, ubiquitin oligomers, and ubiquitinated thyroid proteins increased on the low iodine/MMI diet. Injecting 1 microg triiodothyronine (T3) 6 hours prior to sacrifice appeared to reduce the ubiquitin levels by 31% when compared with mice only on the low iodine/MMI (p < 0.07), but injection of T3 had no effect on ubiquitin levels in mice on the control diet. Injecting male ICR mice with a large dose of TSH (200 mU) increased immunoreactive ubiquitin levels by 50% (p < 0.05) 2 hours later. After a second dose of TSH was injected 12 hours later, the level of immunoreactive thyroglobulin fell by 17% (p < 0.05). With further 12 hourly injections, thyroglobulin levels then began to reaccumulate, and they had returned to the level of saline-injected controls after 50 hours (five TSH injections), while ubiquitin levels fell, but remained significantly elevated above the saline-injected controls (36%, p < 0.01). When ICR mice were given perchlorate in their drinking water to block the iodide pump, thus preserving thyroidal responsiveness to repeated TSH injections, the responses to the initial two TSH injections were similar to mice who received ordinary tap water. However, with further TSH injections, the reaccumulation of

  5. Multiple-Family Group Intervention for Incarcerated Male Adolescents Who Sexually Offend and Their Families: Change in Maladaptive Emotion Regulation Predicts Adaptive Change in Adolescent Behaviors.

    PubMed

    Keiley, Margaret K; Zaremba-Morgan, Ali; Datubo-Brown, Christiana; Pyle, Raven; Cox, Milira

    2015-07-01

    The multiple-family group intervention is an effective, yet affordable, 8-week treatment that is conducted in a juvenile correctional institution in Alabama with adolescents who sexually offend and their families. Data from 115 incarcerated male adolescents and their male and female caregivers collected at pre-, post-, and 1-year follow-up were used to determine that problem behaviors (internalizing, externalizing) decreased over pre- and posttest and the significant decreases in maladaptive emotion regulation predicted those changes. Adolescent-reported anxiety over abandonment and attachment dependence on parents increased significantly; these changes were predicted by decreases in maladaptive emotion regulation. Linear growth models were also fit over the 3 time points and indicate decreases in adolescent problem behavior and maladaptive emotion regulation. PMID:24809985

  6. Intergenerational Transmission of Self-Regulation: A Multidisciplinary Review and Integrative Conceptual Framework

    PubMed Central

    Bridgett, David J.; Burt, Nicole M.; Edwards, Erin S.; Deater-Deckard, Kirby

    2014-01-01

    This review examines mechanisms contributing to the intergenerational transmission of self-regulation. To provide an integrated account of how self-regulation is transmitted across generations, we draw from over 75 years of accumulated evidence, spanning case studies to experimental approaches, in literatures covering developmental, social, and clinical psychology, and criminology, physiology, genetics, and human and animal neuroscience (among others). First, we present a taxonomy of what self-regulation is and then examine how it develops – overviews that guide the main foci of the review. Next, studies supporting an association between parent and child self-regulation are reviewed. Subsequently, literature that considers potential social mechanisms of transmission, specifically parenting behavior, inter-parental (i.e., marital) relationship behaviors, and broader rearing influences (e.g., household chaos) are considered. Finally, literature providing evidence that prenatal programming may be the starting point of the intergenerational transmission of self-regulation is covered, along with key findings from the behavioral and molecular genetics literatures. To integrate these literatures, we introduce the Self-Regulation Intergenerational Transmission Model, a framework that brings together prenatal, social, and neurobiological mechanisms (spanning endocrine, neural, and genetic levels, including gene-environment interplay and epigenetic processes) to explain the intergenerational transmission of self-regulation. This model also incorporates potential transactional processes between generations (e.g., children’s self-regulation and parent-child interaction dynamics that may affect parents’ self-regulation) that further influence intergenerational processes. In pointing the way forward, we note key future directions and ways to address limitations in existing work throughout the review and in closing. We also conclude by noting several implications for

  7. Mechanisms regulating male sexual behavior in the rat: role of 3 alpha- and 3 beta-androstanediols.

    PubMed

    Morali, G; Oropeza, M V; Lemus, A E; Perez-Palacios, G

    1994-09-01

    To assess whether naturally occurring 5 alpha-androstanediols (5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol) play a role in the regulation of male sexual behavior in the rat, their capability to restore copulatory behavior in castrated animals was evaluated. Androstanediols were chronically administered either alone or in combination with 5 alpha-dihydrotestosterone (DHT) or with estradiol-17 beta (E2). Animals treated with testosterone (T), DHT, E2, and vehicle, either alone or in different combinations, served as controls. The occurrence of mounting, intromission, and ejaculation as well as detailed parameters of copulatory behavior were recorded twice per week for 3 weeks. At the end of treatments, the weights of sex accessory organs were also recorded. When 3 beta, 5 alpha-androstanediol (3 beta-diol; 500 micrograms/day) was administered in combination with DHT (300 micrograms/day), full copulatory behavior was restored in all subjects in a manner similar to that obtained with E2 plus DHT or T plus DHT combinations, thus indicating an estrogen-like behavioral effect of 3 beta-diol. Administration of 3 alpha, 5 alpha-androstanediol (3 alpha-diol; 500 micrograms/day) combined with DHT also restored sexual behavior, though to a lesser extent. When 3 alpha-diol (500 micrograms/day) was simultaneously administered with E2 (5 micrograms/day), the copulatory behavior of castrated animals was fully restored in a fashion similar to that observed after administration of DHT plus E2 and T plus E2 combinations, indicating a potent androgen-like effect of 3 alpha-diol.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7803627

  8. Effects of alpha1-adrenergic receptor blockade by doxazosin on renin-angiotensin system-regulating aminopeptidase and vasopressin-degrading activities in male and female rat thalamus.

    PubMed

    de la Chica-Rodríguez, S; Cortés-Denia, P; Ramírez-Expósito, M J; Martínez-Martos, J M

    2007-11-01

    The thalamus has connections with central autonomic centers involved in cardiovascular control and is enervated by noradrenergic fibers. The excitability of thalamic neurons is due to a reduction of ionic currents mediated by alpha(1)-adrenoceptors. The brain renin- angiotensin system (RAS) and the peptide hormone arginine-vasopressin (AVP) are also involved in the central control of blood pressure, and fluid and electrolyte homeostasis. It has been extensively reported that aminopeptidase A (APA), aminopeptidase B (APB), aminopeptidase N (APN), and vasopressin-degrading cystyl aminopeptidase activity (AVP-DA) play an important role in the regulation of the activity of angiotensins and AVP. We have analyzed the effect of alpha(1)-adrenoceptor blockade by doxazosin on RAS-regulating aminopeptidase activities and AVP-DA in soluble and membrane-bound fractions of male and female rat thalamus. Our results show that alpha(1)-adrenoceptors blockade by doxazosin does not modify the RAS through its degrading peptidases at thalamic level either in male or female rats. However, alpha(1)-adrenoceptors blockade shows gender differences in AVP-DA, increasing in males but not in females, supporting an increased capacity of males against females to degrade AVP and, therefore, to regulate cardiovascular homeostasis, under this pharmacological manipulation.

  9. A multi-process model of self-regulation: influences of mindfulness, integrative self-knowledge and self-control in Iran.

    PubMed

    Ghorbani, Nima; Watson, P J; Farhadi, Mehran; Chen, Zhuo

    2014-04-01

    Self-regulation presumably rests upon multiple processes that include an awareness of ongoing self-experience, enduring self-knowledge and self-control. The present investigation tested this multi-process model using the Five-Facet Mindfulness Questionnaire (FFMQ) and the Integrative Self-Knowledge and Brief Self-Control Scales. Using a sample of 1162 Iranian university students, we confirmed the five-factor structure of the FFMQ in Iran and documented its factorial invariance across males and females. Self-regulatory variables correlated negatively with Perceived Stress, Depression, and Anxiety and positively with Self-Esteem and Satisfaction with Life. Partial mediation effects confirmed that self-regulatory measures ameliorated the disturbing effects of Perceived Stress. Integrative Self-Knowledge and Self-Control interacted to partially mediate the association of Perceived Stress with lower levels of Satisfaction with Life. Integrative Self-Knowledge, alone or in interaction with Self-Control, was the only self-regulation variable to display the expected mediation of Perceived Stress associations with all other measures. Self-Control failed to be implicated in self-regulation only in the mediation of Anxiety. These data confirmed the need to further examine this multi-process model of self-regulation.

  10. Signal integration by Ca(2+) regulates intestinal stem-cell activity.

    PubMed

    Deng, Hansong; Gerencser, Akos A; Jasper, Heinrich

    2015-12-10

    Somatic stem cells maintain tissue homeostasis by dynamically adjusting proliferation and differentiation in response to stress and metabolic cues. Here we identify Ca(2+) signalling as a central regulator of intestinal stem cell (ISC) activity in Drosophila. We show that dietary L-glutamate stimulates ISC division and gut growth. The metabotropic glutamate receptor (mGluR) is required in ISCs for this response, and for an associated modulation of cytosolic Ca(2+) oscillations that results in sustained high cytosolic Ca(2+) concentrations. High cytosolic Ca(2+) concentrations induce ISC proliferation by regulating Calcineurin and CREB-regulated transcriptional co-activator (Crtc). In response to a wide range of dietary and stress stimuli, ISCs reversibly transition between Ca(2+) oscillation states that represent poised or activated modes of proliferation, respectively. We propose that the dynamic regulation of intracellular Ca(2+) levels allows effective integration of diverse mitogenic signals in ISCs to adapt their proliferative activity to the needs of the tissue.

  11. Central dopamine D2 receptors regulate growth-hormone-dependent body growth and pheromone signaling to conspecific males.

    PubMed

    Noaín, Daniela; Pérez-Millán, M Inés; Bello, Estefanía P; Luque, Guillermina M; Casas Cordero, Rodrigo; Gelman, Diego M; Peper, Marcela; Tornadu, Isabel García; Low, Malcolm J; Becú-Villalobos, Damasia; Rubinstein, Marcelo

    2013-03-27

    Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males. PMID:23536095

  12. Central dopamine D2 receptors regulate growth-hormone-dependent body growth and pheromone signaling to conspecific males.

    PubMed

    Noaín, Daniela; Pérez-Millán, M Inés; Bello, Estefanía P; Luque, Guillermina M; Casas Cordero, Rodrigo; Gelman, Diego M; Peper, Marcela; Tornadu, Isabel García; Low, Malcolm J; Becú-Villalobos, Damasia; Rubinstein, Marcelo

    2013-03-27

    Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.

  13. An integrated network of Arabidopsis growth regulators and its use for gene prioritization

    PubMed Central

    Sabaghian, Ehsan; Drebert, Zuzanna; Inzé, Dirk; Saeys, Yvan

    2015-01-01

    Elucidating the molecular mechanisms that govern plant growth has been an important topic in plant research, and current advances in large-scale data generation call for computational tools that efficiently combine these different data sources to generate novel hypotheses. In this work, we present a novel, integrated network that combines multiple large-scale data sources to characterize growth regulatory genes in Arabidopsis, one of the main plant model organisms. The contributions of this work are twofold: first, we characterized a set of carefully selected growth regulators with respect to their connectivity patterns in the integrated network, and, subsequently, we explored to which extent these connectivity patterns can be used to suggest new growth regulators. Using a large-scale comparative study, we designed new supervised machine learning methods to prioritize growth regulators. Our results show that these methods significantly improve current state-of-the-art prioritization techniques, and are able to suggest meaningful new growth regulators. In addition, the integrated network is made available to the scientific community, providing a rich data source that will be useful for many biological processes, not necessarily restricted to plant growth. PMID:26620795

  14. 10 CFR 905.10 - Who must comply with the integrated resource planning and reporting regulations in this subpart?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Who must comply with the integrated resource planning and reporting regulations in this subpart? 905.10 Section 905.10 Energy DEPARTMENT OF ENERGY ENERGY PLANNING AND... planning and reporting regulations in this subpart? (a) Integrated resource plans (IRP) and...

  15. Cocaine-and-Amphetamine-Regulated-Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: lack of sex differences

    PubMed Central

    Job, Martin O.; Perry, JoAnna; Shen, Li L.; Kuhar, Michael J.

    2014-01-01

    Cocaine-and-Amphetamine Regulated Transcript peptide (CART peptide) is known for having an inhibitory effect on dopamine (DA)- and cocaine-mediated actions and is postulated to be a homeostatic, regulatory factor in the nucleus accumbens (NAc). Some sex differences in cocaine-mediated LMA and in the expression and function of CART peptide have been reported. However, it is not known if the inhibitory effect of CART peptide on cocaine-mediated locomotor activity (LMA) is sexually dimorphic. In this study, the effect of CART 55-102 on LMA due to intra-NAc DA and i.p. cocaine were determined in male and female Sprague-Dawley rats. The results show that CART 55-102 blunted or reduced both the DA- and cocaine-induced LMA in both males and females. In conclusion, CART peptide is effective in blunting DA- and cocaine-mediated LMA in both males and females. PMID:24630272

  16. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity

    NASA Astrophysics Data System (ADS)

    Yao, Yao; Chen, Zu-Lin; Norris, Erin H.; Strickland, Sidney

    2014-03-01

    Blood brain barrier (BBB) breakdown is not only a consequence of but also contributes to many neurological disorders, including stroke and Alzheimer’s disease. How the basement membrane (BM) contributes to the normal functioning of the BBB remains elusive. Here we use conditional knockout mice and an acute adenovirus-mediated knockdown model to show that lack of astrocytic laminin, a brain-specific BM component, induces BBB breakdown. Using functional blocking antibody and RNAi, we further demonstrate that astrocytic laminin, by binding to integrin α2 receptor, prevents pericyte differentiation from the BBB-stabilizing resting stage to the BBB-disrupting contractile stage, and thus maintains the integrity of BBB. Additionally, loss of astrocytic laminin decreases aquaporin-4 (AQP4) and tight junction protein expression. Altogether, we report a critical role for astrocytic laminin in BBB regulation and pericyte differentiation. These results indicate that astrocytic laminin maintains the integrity of BBB through, at least in part, regulation of pericyte differentiation.

  17. Integrating emotion regulation and emotional intelligence traditions: a meta-analysis

    PubMed Central

    Peña-Sarrionandia, Ainize; Mikolajczak, Moïra; Gross, James J.

    2015-01-01

    Two relatively independent research traditions have developed that address emotion management. The first is the emotion regulation (ER) tradition, which focuses on the processes which permit individuals to influence which emotions they have, when they have them, and how they experience and express these emotions. The second is the emotional intelligence (EI) tradition, which focuses—among other things—on individual differences in ER. To integrate these two traditions, we employed the process model of ER (Gross, 1998b) to review the literature on EI. Two key findings emerged. First, high EI individuals shape their emotions from the earliest possible point in the emotion trajectory and have many strategies at their disposal. Second, high EI individuals regulate their emotions successfully when necessary but they do so flexibly, thereby leaving room for emotions to emerge. We argue that ER and EI traditions stand to benefit substantially from greater integration. PMID:25759676

  18. Molecular regulation of the hypothalamic-pituitary-adrenal axis in adult male guinea pigs after prenatal stress at different stages of gestation

    PubMed Central

    Kapoor, Amita; Leen, Jason; Matthews, Stephen G

    2008-01-01

    Studies in humans and animals have demonstrated that maternal stress during fetal development can lead to altered hypothalamic-pituitary-adrenal (HPA) axis function and behaviour postnatally. We have previously shown adult male guinea pigs that were born to mothers exposed to a stressor during the phase of rapid fetal brain growth (gestational days (GD) 50, 51 and 52; prenatal stress (PS)50) exhibit significantly increased basal plasma cortisol levels. In contrast, male guinea pig offspring whose mothers were exposed to stress later in gestation (GD60, 61 and 62; PS60) exhibited a significantly higher plasma cortisol response to activation of the HPA axis. In the present study, we hypothesized that the endocrine changes in HPA axis function observed in male guinea pig offspring would be reflected by altered molecular regulation of the HPA axis. Corticosteroid receptors in the hippocampus, hypothalamus and pituitary were measured, as well as corticotropin-releasing hormone (CRH), pro-opiomelanocortin (POMC) and adrenal enzymes in the paraventricular nucleus, pituitary and adrenal cortex, respectively, by in situ hybridization and Western blot. PS50 male offspring exhibited a significant reduction in glucocorticoid receptor (GR) mRNA (P <0.01) in the CA3 region of the hippocampus and significantly increased POMC mRNA (P <0.05) in the pituitary, consistent with the increase in basal HPA axis activity observed. In line with elevated activity of the HPA axis, both PS50 and PS60 male offspring exhibited significantly higher steroidogenic factor (SF)-1 (P <0.001) and melanocortin 2 receptor (MC2-R) mRNA (P <0.001) in the adrenal cortex. This study demonstrates that short periods of prenatal stress during critical windows of neuroendocrine development affect the expression of key regulators of HPA axis activity leading to the changes in endocrine function observed in prenatally stressed male offspring. Further, these changes are dependent on the timing of the maternal

  19. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain

    PubMed Central

    Duan, Xin; Chang, Jay H.; Ge, Shaoyu; Faulkner, Regina L.; Kim, Ju Young; Kitabatake, Yasuji; Liu, Xiao-bo; Yang, Chih-Hao; Jordan, J. Dedrick; Ma, Dengke K.; Liu, Cindy Y.; Ganesan, Sundar; Cheng, Hwai-Jong; Ming, Guo-li; Lu, Bai; Song, Hongjun

    2007-01-01

    Summary Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, down regulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mis-positioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner Ndel1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis. PMID:17825401

  20. GABA regulates synaptic integration of newly generated neurons in the adult brain

    NASA Astrophysics Data System (ADS)

    Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

    2006-02-01

    Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

  1. 10 CFR 905.10 - Who must comply with the integrated resource planning and reporting regulations in this subpart?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Who must comply with the integrated resource planning and reporting regulations in this subpart? 905.10 Section 905.10 Energy DEPARTMENT OF ENERGY ENERGY PLANNING AND MANAGEMENT PROGRAM Integrated Resource Planning § 905.10 Who must comply with the integrated...

  2. Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation

    PubMed Central

    Wang, Yongbo; Gogol-Döring, Andreas; Hu, Hao; Fröhler, Sebastian; Ma, Yunxia; Jens, Marvin; Maaskola, Jonas; Murakawa, Yasuhiro; Quedenau, Claudia; Landthaler, Markus; Kalscheuer, Vera; Wieczorek, Dagmar; Wang, Yang; Hu, Yuhui; Chen, Wei

    2013-01-01

    RBM10 encodes an RNA binding protein. Mutations in RBM10 are known to cause multiple congenital anomaly syndrome in male humans, the TARP syndrome. However, the molecular function of RBM10 is unknown. Here we used PAR-CLIP to identify thousands of binding sites of RBM10 and observed significant RBM10–RNA interactions in the vicinity of splice sites. Computational analyses of binding sites as well as loss-of-function and gain-of-function experiments provided evidence for the function of RBM10 in regulating exon skipping and suggested an underlying mechanistic model, which could be subsequently validated by minigene experiments. Furthermore, we demonstrated the splicing defects in a patient carrying an RBM10 mutation, which could be explained by disrupted function of RBM10 in splicing regulation. Overall, our study established RBM10 as an important regulator of alternative splicing, presented a mechanistic model for RBM10-mediated splicing regulation and provided a molecular link to understanding a human congenital disorder. PMID:24000153

  3. Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels.

    PubMed

    Sladek, Celia D; Johnson, Alan Kim

    2013-10-01

    Maintenance of body water homeostasis is critical for preventing hyperthermia, because evaporative cooling is the most efficient means of dissipating excess body heat. Water homeostasis is achieved by regulation of water intake and water loss by the kidneys. The former is achieved by sensations of thirst that motivate water acquisition, whereas the latter is regulated by the antidiuretic action of vasopressin. Vasopressin secretion and thirst are stimulated by increases in the osmolality of the extracellular fluid as well as decreases in blood pressure and/or blood volume, signals that are precipitated by water depletion associated with the excess evaporative water loss required to prevent hyperthermia. In addition, they are stimulated by increases in body temperature. The sites and molecular mechanisms involved in integrating thermal and osmotic regulation of thirst and vasopressin secretion are reviewed here with a focus on the role of the thermal and mechanosensitive transient receptor potential-vanilloid (TRPV) family of ion channels.

  4. The adaptor protein Cindr regulates JNK activity to maintain epithelial sheet integrity.

    PubMed

    Yasin, Hannah W R; van Rensburg, Samuel H; Feiler, Christina E; Johnson, Ruth I

    2016-02-15

    Epithelia are essential barrier tissues that must be appropriately maintained for their correct function. To achieve this a plethora of protein interactions regulate epithelial cell number, structure and adhesion, and differentiation. Here we show that Cindr (the Drosophila Cin85 and Cd2ap ortholog) is required to maintain epithelial integrity. Reducing Cindr triggered cell delamination and movement. Most delaminating cells died. These behaviors were consistent with JNK activation previously associated with loss of epithelial integrity in response to ectopic oncogene activity. We confirmed a novel interaction between Cindr and Drosophila JNK (dJNK), which when perturbed caused inappropriate JNK signaling. Genetically reducing JNK signaling activity suppressed the effects of reducing Cindr. Furthermore, ectopic JNK signaling phenocopied loss of Cindr and was partially rescued by concomitant cindr over-expression. Thus, correct Cindr-dJNK stoichiometry is essential to maintain epithelial integrity and disturbing this balance may contribute to the pathogenesis of disease states, including cancer. PMID:26772997

  5. A novel function for the Hox gene Abd-B in the male accessory gland regulates the long-term female post-mating response in Drosophila.

    PubMed

    Gligorov, Dragan; Sitnik, Jessica L; Maeda, Robert K; Wolfner, Mariana F; Karch, François

    2013-03-01

    In insects, products of the male reproductive tract are essential for initiating and maintaining the female post-mating response (PMR). The PMR includes changes in egg laying, receptivity to courting males, and sperm storage. In Drosophila, previous studies have determined that the main cells of the male accessory gland produce some of the products required for these processes. However, nothing was known about the contribution of the gland's other secretory cell type, the secondary cells. In the course of investigating the late functions of the homeotic gene, Abdominal-B (Abd-B), we discovered that Abd-B is specifically expressed in the secondary cells of the Drosophila male accessory gland. Using an Abd-B BAC reporter coupled with a collection of genetic deletions, we discovered an enhancer from the iab-6 regulatory domain that is responsible for Abd-B expression in these cells and that apparently works independently from the segmentally regulated chromatin domains of the bithorax complex. Removal of this enhancer results in visible morphological defects in the secondary cells. We determined that mates of iab-6 mutant males show defects in long-term egg laying and suppression of receptivity, and that products of the secondary cells are influential during sperm competition. Many of these phenotypes seem to be caused by a defect in the storage and gradual release of sex peptide in female mates of iab-6 mutant males. We also found that Abd-B expression in the secondary cells contributes to glycosylation of at least three accessory gland proteins: ovulin (Acp26Aa), CG1656, and CG1652. Our results demonstrate that long-term post-mating changes observed in mated females are not solely induced by main cell secretions, as previously believed, but that secondary cells also play an important role in male fertility by extending the female PMR. Overall, these discoveries provide new insights into how these two cell types cooperate to produce and maintain a robust female PMR.

  6. Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

    PubMed Central

    Kim, Jaekyoon; Tuscher, Jennifer J.; Fortress, Ashley M.

    2015-01-01

    Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17β-estradiol (E2), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes the effects of E2 on hippocampal spinogenesis, neurogenesis, physiology, and memory, with particular attention paid to the effects of E2 in male rodents. The estrogen receptors, cell-signaling pathways, and epigenetic processes necessary for E2 to enhance memory in female rodents are also discussed in detail. Finally, practical considerations for working with female rodents are described for those investigators thinking of adding females to their experimental designs. PMID:26286657

  7. Male-female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.

    PubMed

    Schoenhard, J A; Asselbergs, F W; Poku, K A; Stocki, S A; Gordon, S; Vaughan, D E; Brown, N J; Moore, J H; Williams, Scott M

    2008-12-01

    Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) directly influence thrombus formation and degradation, and have been identified as risk factors for thromboembolic disease. Prior studies investigated determinants of t-PA and PAI-1 expression, but mainly in Caucasian subjects. The aim of this study was to identify the contributions of genetic and other factors to inter-individual variation in plasma levels of t-PA and PAI-1 in a large-scale population-based sample from urban West Africa. t-PA, PAI-1 and several demographic, anthropometric, and metabolic parameters were measured in 992 residents of Sunyani, the capital of the Brong-Ahafo region of Ghana. In addition, nine gene polymorphisms associated with components of the renin-angiotensin and fibrinolytic systems were determined. We found that BMI, systolic and diastolic blood pressure, total cholesterol, glucose, and triglycerides were all significant predictors of t-PA and PAI-1 in both females and males. In addition, a significant relationship was found between the PAI-1 4G/5G (rs1799768) polymorphism on PAI-1 levels in females, the TPA I/D (rs4646972) polymorphism on t-PA and PAI-1 in males, the renin (rs3730103) polymorphism on t-PA and PAI-1 in males, the ethanolamine kinase 2 (rs1917542) polymorphism on PAI-1 in males, and the renin (rs1464816) polymorphism on t-PA in females and on PAI-1 in males. This study of urban West Africans shows that t-PA and PAI-1 levels are determined by both genetic loci of the fibrinolytic and renin-angiotensin systems and other factors often associated with cardiovascular disease, and that genetic factors differ between males and females.

  8. NODAL secreted by male germ cells regulates the proliferation and function of human Sertoli cells from obstructive azoospermia and nonobstructive azoospermia patients

    PubMed Central

    Tian, Ru-Hui; Yang, Shi; Zhu, Zi-Jue; Wang, Jun-Long; Liu, Yun; Yao, Chencheng; Ma, Meng; Guo, Ying; Yuan, Qingqing; Hai, Yanan; Huang, Yi-Ran; He, Zuping; Li, Zheng

    2015-01-01

    This study was designed to explore the regulatory effects of male germ cell secreting factor NODAL on Sertoli cell fate decisions from obstructive azoospermia (OA) and nonobstructive azoospermia (NOA) patients. Human Sertoli cells and male germ cells were isolated using two-step enzymatic digestion and SATPUT from testes of azoospermia patients. Expression of NODAL and its multiple receptors in human Sertoli cells and male germ cells were characterized by reverse transcription-polymerase chain reaction (RT-PCR) and immunochemistry. Human recombinant NODAL and its receptor inhibitor SB431542 were employed to probe their effect on the proliferation of Sertoli cells using the CCK-8 assay. Quantitative PCR and Western blots were utilized to assess the expression of Sertoli cell functional genes and proteins. NODAL was found to be expressed in male germ cells but not in Sertoli cells, whereas its receptors ALK4, ALK7, and ACTR-IIB were detected in Sertoli cells and germ cells, suggesting that NODAL plays a regulatory role in Sertoli cells and germ cells via a paracrine and autocrine pathway, respectively. Human recombinant NODAL could promote the proliferation of human Sertoli cells. The expression of cell cycle regulators, including CYCLIN A, CYCLIN D1 and CYCLIN E, was not remarkably affected by NODAL signaling. NODAL enhanced the expression of essential growth factors, including GDNF, SCF, and BMP4, whereas SB431542 decreased their levels. There was not homogeneity of genes changes by NODAL treatment in Sertoli cells from OA and Sertoli cell-only syndrome (SCO) patients. Collectively, this study demonstrates that NODAL produced by human male germ cells regulates proliferation and numerous gene expression of Sertoli cells. PMID:26289399

  9. Ghrelin and GHS-R1A signaling within the ventral and laterodorsal tegmental area regulate sexual behavior in sexually naïve male mice.

    PubMed

    Prieto-Garcia, Luna; Egecioglu, Emil; Studer, Erik; Westberg, Lars; Jerlhag, Elisabet

    2015-12-01

    In addition to food intake and energy balance regulation, ghrelin mediate the rewarding and motivational properties of palatable food as well as addictive drugs. The ability of ghrelin to regulate reinforcement involves the cholinergic-dopaminergic reward link, which encompasses a cholinergic projection from the laterodorsal tegmental area (LDTg) to the ventral tegmental area (VTA) together with mesolimbic dopaminergic projections from the VTA to the nucleus accumbens (NAc). Recently, systemic ghrelin was shown to regulate sexual behavior and motivation in male mice via dopamine neurotransmission. The present study therefore elucidates the role of ghrelin and ghrelin receptor (GHS-R1A) antagonist treatment within NAc, VTA or LDTg for sexual behavior in sexually naïve male mice. Local administration of the GHSR-1A antagonist, JMV2959, into the VTA or LDTg was found to reduce the preference for female mice, the number of mounts and the duration of mounting as well as to prolong the latency to mount. This was further substantiated by the findings that ghrelin administration into the VTA or LDTg increased the number of mounts and the duration of mounting and decreased the latency to mount. Moreover, ghrelin administered into the LDTg increased the preference for female mice. Accumbal administration of ghrelin increased whereas GHS-R1A antagonist decreased the intake of palatable food, but did not alter sexual behavior. In males exposed to sexual interaction, systemic administration of ghrelin increases whereas JMV2959 decreases the turnover of dopamine in the VTA. These data suggest that ghrelin signaling within the tegmental areas is required for sexual behavior in sexually naïve male mice.

  10. A MATHEMATICAL MODEL FOR THE ANDROGENIC REGULATION OF THE PROSTATE IN INTACT AND CASTRATE ADULT MALE RATS

    EPA Science Inventory

    An abstract that provides understanding for a mathematical model by Barton and Anderson, for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the rodent ventral prostate.

  11. Receptor-Like Kinase RUPO Interacts with Potassium Transporters to Regulate Pollen Tube Growth and Integrity in Rice

    PubMed Central

    Liu, Lingtong; Zheng, Canhui; Kuang, Baijan; Wei, Liqin; Yan, Longfeng; Wang, Tai

    2016-01-01

    During sexual reproduction of flowering plants, the pollen tube grows fast and over a long distance within the pistil to deliver two sperms for double fertilization. Growing plant cells need to communicate constantly with external stimuli as well as monitor changes in surface tension of the cell wall and plasma membrane to coordinate these signals and internal growth machinery; however, the underlying mechanisms remain largely unknown. Here we show that the rice member of plant-specific receptor-like kinase CrRLK1Ls subfamily, Ruptured Pollen tube (RUPO), is specifically expressed in rice pollen. RUPO localizes to the apical plasma membrane and vesicle of pollen tubes and is required for male gamete transmission. K+ levels were greater in pollen of homozygous CRISPR-knockout lines than wild-type plants, and pollen tubes burst shortly after germination. We reveal the interaction of RUPO with high-affinity potassium transporters. Phosphorylation of RUPO established and dephosphorylation abolished the interaction. These results have revealed the receptor-like kinase as a regulator of high-affinity potassium transporters via phosphorylation-dependent interaction, and demonstrated a novel receptor-like kinase signaling pathway that mediates K+ homeostasis required for pollen tube growth and integrity. PMID:27447945

  12. Receptor-Like Kinase RUPO Interacts with Potassium Transporters to Regulate Pollen Tube Growth and Integrity in Rice.

    PubMed

    Liu, Lingtong; Zheng, Canhui; Kuang, Baijan; Wei, Liqin; Yan, Longfeng; Wang, Tai

    2016-07-01

    During sexual reproduction of flowering plants, the pollen tube grows fast and over a long distance within the pistil to deliver two sperms for double fertilization. Growing plant cells need to communicate constantly with external stimuli as well as monitor changes in surface tension of the cell wall and plasma membrane to coordinate these signals and internal growth machinery; however, the underlying mechanisms remain largely unknown. Here we show that the rice member of plant-specific receptor-like kinase CrRLK1Ls subfamily, Ruptured Pollen tube (RUPO), is specifically expressed in rice pollen. RUPO localizes to the apical plasma membrane and vesicle of pollen tubes and is required for male gamete transmission. K+ levels were greater in pollen of homozygous CRISPR-knockout lines than wild-type plants, and pollen tubes burst shortly after germination. We reveal the interaction of RUPO with high-affinity potassium transporters. Phosphorylation of RUPO established and dephosphorylation abolished the interaction. These results have revealed the receptor-like kinase as a regulator of high-affinity potassium transporters via phosphorylation-dependent interaction, and demonstrated a novel receptor-like kinase signaling pathway that mediates K+ homeostasis required for pollen tube growth and integrity. PMID:27447945

  13. Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23*

    PubMed Central

    Han, Xiaobin; Xiao, Zhousheng; Quarles, L. Darryl

    2015-01-01

    Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions. PMID:25752607

  14. Research on regulating technique of material flow for 2-person and 30-day integrated CELSS test

    NASA Astrophysics Data System (ADS)

    Guo, Shuangsheng; Dong, Wenping; Ai, Weidang; Feng, Hongqi; Tang, Yongkang; Huang, Zhide; Shen, Yunze; Ren, Jin; Qin, Lifeng; Zeng, Gu; Zhang, Lihong; Zhu, Jingtao; Fei, Jinxue; Xu, Guoxin

    2014-07-01

    A man-plant integration test was processed using the CELSS integration experiment platform in which 4 kinds of plants were grown (Lactuca sativa L var. Dasusheng, L. sativa L var. Youmaicai, Gynura bicolor and Cichorium endivia L) to exchange material with 2 persons in order to research the dynamic changing laws and balanced regulation of air and water between man and plant in an inclosed system. In the test the material flow was measured so that the dynamically changing laws and balanced regulation of air and water between man and plant in the closed system were mostly mastered. The material closure degree of air, water and food reached 100%, 90% and 13.9% respectively with the whole system closure degree up to 95.1%. Meanwhile, it was proved that a 13.5 m2 planting area could meet the demand of one person for O2 in the system, and the energy efficiency ratio of which reached 59.56 g/(kW m2 day). The material flow dynamic balance-regulating technology was initially mastered between man and plant through the test. The interaction was realized among man, plant and environment in the closed system, which is of great significance to the advancement of long-term manned environment control and life support technology for China.

  15. Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

    PubMed Central

    Beck, Halfdan; Nähse, Viola; Larsen, Marie Sofie Yoo; Groth, Petra; Clancy, Trevor; Lees, Michael; Jørgensen, Mette; Helleday, Thomas; Syljuåsen, Randi G.

    2010-01-01

    Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication. PMID:20194642

  16. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response

    PubMed Central

    van der Lee, Robin; ter Horst, Rob; Szklarczyk, Radek; Netea, Mihai G.; Andeweg, Arno C.; van Kuppeveld, Frank J. M.; Huynen, Martijn A.

    2015-01-01

    The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50%) that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research. PMID:26485378

  17. Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex

    PubMed Central

    Peyre, Elise; Silva, Carla G.; Nguyen, Laurent

    2015-01-01

    During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: (1) Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; (2) Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; (3) Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex. PMID:25926769

  18. Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

    PubMed Central

    Levin, David E.

    2011-01-01

    The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to the Rho1 GTPase, which mobilizes a physiologic response through a variety of effectors. Activation of CWI signaling regulates the production of various carbohydrate polymers of the cell wall, as well as their polarized delivery to the site of cell wall remodeling. This review article centers on CWI signaling in Saccharomyces cerevisiae through the cell cycle and in response to cell wall stress. The interface of this signaling pathway with other pathways that contribute to the maintenance of cell wall integrity is also discussed. PMID:22174182

  19. Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking

    PubMed Central

    Daniel, Anna E.; Timmerman, Ilse; Kovacevic, Igor; Hordijk, Peter L.; Adriaanse, Luc; Paatero, Ilkka; Belting, Heinz-Georg; van Buul, Jaap D.

    2015-01-01

    Background Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact. Methodology/Principal Findings We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC) monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus. Conclusions/Significance Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall. PMID:26714278

  20. Soy Isoflavones Regulate Lipid Metabolism through an AKT/mTORC1 Pathway in Diet-Induced Obesity (DIO) Male Rats.

    PubMed

    Huang, Chao; Pang, Dejiang; Luo, Qihui; Chen, Xiaolin; Gao, Qi; Shi, Liangqin; Liu, Wentao; Zou, Yuanfeng; Li, Lixia; Chen, Zhengli

    2016-05-03

    The pandemic tendency of obesity and its strong association with serious co-morbidities have elicited interest in the underlying mechanisms of these pathologies. Lipid homeostasis, closely involved in obesity, has been reported to be regulated by multiple pathways. mTORC1 is emerging as a critical regulator of lipid metabolism. Here, we describe that the consumption of soy isoflavones, with a structural similarity to that of estradiol, could mitigate obesity through an AKT/mTORC1 pathway. Fed with soy isoflavones, the diet-induced obesity (DIO) male rats exhibited decreased body weight, accompanied with suppressed lipogenesis and adipogenesis, as well as enhanced lipolysis and β‑oxidation. The phosphorylation of AKT and S6 were decreased after soy isoflavone treatment in vivo and in vitro, suggesting an inhibition effect of soy isoflavones on mTORC1 activity. Our study reveals a potential mechanism of soy isoflavones regulating lipid homeostasis, which will be important for obesity treatment.

  1. The lonely mouse - single housing affects serotonergic signaling integrity measured by 8-OH-DPAT-induced hypothermia in male mice.

    PubMed

    Kalliokoski, Otto; Teilmann, A Charlotte; Jacobsen, Kirsten R; Abelson, Klas S P; Hau, Jann

    2014-01-01

    Male BALB/c mice single-housed for a period of three weeks were found to respond with a more marked hypothermia to a challenge with a selective serotonergic agonist (8-OH-DPAT) than their group-housed counterparts. This effect of single housing was verified by screening a genetically heterogeneous population of male mice on a C57BL/6 background from a breeding colony. Enhanced activity of the implicated receptor (5-HT1A) leading to an amplified hypothermic effect is strongly associated with depressive states. We therefore suggest that the 8-OH-DPAT challenge can be used to demonstrate a negative emotional state brought on by e.g. long-term single housing in male laboratory mice. The study emphasizes the importance of social housing, and demonstrates that male mice deprived of social contact respond with altered serotonergic signaling activity. Male mice not only choose social contact when given the option, as has previously been shown, but will also, when it is deprived, be negatively affected by its absence. We propose that the 8-OH-DPAT challenge constitutes a simple, but powerful, tool capable of manifesting the effect of social deprivation in laboratory mice. It potentially allows not only for an unbiased, biochemical evaluation of psychological stressors, but may also allow for determining whether the effect of these can be counteracted.

  2. Regulation of active genome integrity and expression by Rad26p

    PubMed Central

    Malik, Shivani; Bhaumik, Sukesh R

    2014-01-01

    Rad26p is a SWI/SNF-like ATPase in yeast, and is conserved among eukaryotes. Both Rad26p and its human homolog CSB (Cockayne syndrome group B) are involved in regulation of chromatin structure, transcription and DNA repair.  Thus, mutations or malfunctions of these proteins have significant effects on cellular functions. Mutations in CSB are associated with Cockayne syndrome (CS) that is characterized by heterogeneous pathologies such as mental and physical retardation, sun sensitivity, premature aging, muscular and skeletal abnormalities, and progressive decline in neurological and cognitive functions. Therefore, many research groups focused their studies to understand the mechanisms of Rad26p/CSB functions to illuminate the molecular bases of CS. These studies have provided significant functional and mechanistic insights of Rad26p/CSB in regulation of gene expression and genome integrity as described here. PMID:25484185

  3. Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration.

    PubMed

    Higley, Michael J; Soler-Llavina, Gilberto J; Sabatini, Bernardo L

    2009-09-01

    The pleiotropic actions of neuromodulators on pre- and postsynaptic targets make disentangling the mechanisms underlying regulation of synaptic transmission challenging. In the striatum, acetylcholine modulates glutamate release via activation of muscarinic receptors (mAchRs), although the consequences for postsynaptic signaling are unclear. Using two-photon microscopy and glutamate uncaging to examine individual synapses in the rat striatum, we found that glutamatergic afferents have a high degree of multivesicular release (MVR) in the absence of postsynaptic receptor saturation. We found that mAchR activation decreased both the probability of release and the concentration of glutamate in the synaptic cleft. The corresponding decrease in synaptic potency reduced the duration of synaptic potentials and limited temporal summation of afferent inputs. These findings reveal a mechanism by which a combination of basal MVR and low receptor saturation allow the presynaptic actions of a neuromodulator to control the engagement of postsynaptic nonlinearities and regulate synaptic integration.

  4. Evaluation of phase change materials for thermal regulation enhancement of building integrated photovoltaics

    SciTech Connect

    Hasan, A.; Norton, B.; McCormack, S.J.; Huang, M.J.

    2010-09-15

    Regulating the temperature of building integrated photovoltaics (BIPV) using phase change materials (PCMs) reduces the loss of temperature dependent photovoltaic (PV) efficiency. Five PCMs were selected for evaluation all with melting temperatures {proportional_to}25 {+-} 4 C and heat of fusion between 140 and 213 kJ/kg. Experiments were conducted at three insolation intensities to evaluate the performance of each PCM in four different PV/PCM systems. The effect on thermal regulation of PV was determined by changing the (i) mass of PCM and (ii) thermal conductivities of the PCM and PV/PCM system. A maximum temperature reduction of 18 C was achieved for 30 min while 10 C temperature reduction was maintained for 5 h at -1000 W/m{sup 2} insolation. (author)

  5. Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation.

    PubMed

    Waites, Clarissa L; Leal-Ortiz, Sergio A; Okerlund, Nathan; Dalke, Hannah; Fejtova, Anna; Altrock, Wilko D; Gundelfinger, Eckart D; Garner, Craig C

    2013-04-01

    The presynaptic active zone (AZ) is a specialized microdomain designed for the efficient and repetitive release of neurotransmitter. Bassoon and Piccolo are two high molecular weight components of the AZ, with hypothesized roles in its assembly and structural maintenance. However, glutamatergic synapses lacking either protein exhibit relatively minor defects, presumably due to their significant functional redundancy. In the present study, we have used interference RNAs to eliminate both proteins from glutamatergic synapses, and find that they are essential for maintaining synaptic integrity. Loss of Bassoon and Piccolo leads to the aberrant degradation of multiple presynaptic proteins, culminating in synapse degeneration. This phenotype is mediated in part by the E3 ubiquitin ligase Siah1, an interacting partner of Bassoon and Piccolo whose activity is negatively regulated by their conserved zinc finger domains. Our findings demonstrate a novel role for Bassoon and Piccolo as critical regulators of presynaptic ubiquitination and proteostasis.

  6. Integral control of plant gravitropism through the interplay of hormone signaling and gene regulation.

    PubMed

    Rodrigo, Guillermo; Jaramillo, Alfonso; Blázquez, Miguel A

    2011-08-17

    The interplay between hormone signaling and gene regulatory networks is instrumental in promoting the development of living organisms. In particular, plants have evolved mechanisms to sense gravity and orient themselves accordingly. Here, we present a mathematical model that reproduces plant gravitropic responses based on known molecular genetic interactions for auxin signaling coupled with a physical description of plant reorientation. The model allows one to analyze the spatiotemporal dynamics of the system, triggered by an auxin gradient that induces differential growth of the plant with respect to the gravity vector. Our model predicts two important features with strong biological implications: 1), robustness of the regulatory circuit as a consequence of integral control; and 2), a higher degree of plasticity generated by the molecular interplay between two classes of hormones. Our model also predicts the ability of gibberellins to modulate the tropic response and supports the integration of the hormonal role at the level of gene regulation.

  7. Integrative modeling of small artery structure and function uncovers critical parameters for diameter regulation.

    PubMed

    VanBavel, Ed; Tuna, Bilge Guvenc

    2014-01-01

    Organ perfusion is regulated by vasoactivity and structural adaptation of small arteries and arterioles. These resistance vessels are sensitive to pressure, flow and a range of vasoactive stimuli. Several strongly interacting control loops exist. As an example, the myogenic response to a change of pressure influences the endothelial shear stress, thereby altering the contribution of shear-dependent dilation to the vascular tone. In addition, acute responses change the stimulus for structural adaptation and vice versa. Such control loops are able to maintain resistance vessels in a functional and stable state, characterized by regulated wall stress, shear stress, matched active and passive biomechanics and presence of vascular reserve. In this modeling study, four adaptation processes are identified that together with biomechanical properties effectuate such integrated regulation: control of tone, smooth muscle cell length adaptation, eutrophic matrix rearrangement and trophic responses. Their combined action maintains arteries in their optimal state, ready to cope with new challenges, allowing continuous long-term vasoregulation. The exclusion of any of these processes results in a poorly regulated state and in some cases instability of vascular structure.

  8. Integrating the immune system with the regulation of growth and efficiency.

    PubMed

    Gabler, N K; Spurlock, M E

    2008-04-01

    Muscle growth in meat animals is a complex process governed by integrated signals emanating from multiple endocrine and immune cells. A generalized phenomenon among meat animal industries is that animals commonly fail to meet their genetic potential for growth in commercial production settings. Recent evidence indicates that adipocytes and myofibers are equipped with functional pattern recognition receptors and are capable of responding directly to the corresponding pathogens and other receptor ligands. Thus, these cells are active participants in the innate immune response and, as such, produce a number of immune and metabolic regulators, including proinflammatory cytokines and adiponectin. Specifically, the transcription factor, nuclear factor kappa B, is activated in adipocytes and muscle cells by bacterial lipopolysaccharide and certain saturated fatty acids, which are potent agonists for the Toll-like receptor-4 pattern recognition receptor. Receptor activation results in the local production of interleukin-6 and tumor necrosis factor-alpha, and creates a local environment by which these cytokines regulate both metabolic and immunological pathways. However, adipocytes are also the predominant source of the antiinflammatory hormone, adiponectin, which suppresses the activation of nuclear factor kappa B and the production of proinflammatory cytokines. The molecular ability to recognize antigens and produce regulatory molecules strategically positions adipocytes and myofibers to regulate growth locally and to reciprocally regulate metabolism in peripheral tissues.

  9. Signal integration by Ca(2+) regulates intestinal stem-cell activity.

    PubMed

    Deng, Hansong; Gerencser, Akos A; Jasper, Heinrich

    2015-12-10

    Somatic stem cells maintain tissue homeostasis by dynamically adjusting proliferation and differentiation in response to stress and metabolic cues. Here we identify Ca(2+) signalling as a central regulator of intestinal stem cell (ISC) activity in Drosophila. We show that dietary L-glutamate stimulates ISC division and gut growth. The metabotropic glutamate receptor (mGluR) is required in ISCs for this response, and for an associated modulation of cytosolic Ca(2+) oscillations that results in sustained high cytosolic Ca(2+) concentrations. High cytosolic Ca(2+) concentrations induce ISC proliferation by regulating Calcineurin and CREB-regulated transcriptional co-activator (Crtc). In response to a wide range of dietary and stress stimuli, ISCs reversibly transition between Ca(2+) oscillation states that represent poised or activated modes of proliferation, respectively. We propose that the dynamic regulation of intracellular Ca(2+) levels allows effective integration of diverse mitogenic signals in ISCs to adapt their proliferative activity to the needs of the tissue. PMID:26633624

  10. Integrative Analysis of Transcriptomic and Epigenomic Data to Reveal Regulation Patterns for BMD Variation

    PubMed Central

    Zhang, Ji-Gang; Tan, Li-Jun; Xu, Chao; He, Hao; Tian, Qing; Zhou, Yu; Qiu, Chuan; Chen, Xiang-Ding; Deng, Hong-Wen

    2015-01-01

    Integration of multiple profiling data and construction of functional gene networks may provide additional insights into the molecular mechanisms of complex diseases. Osteoporosis is a worldwide public health problem, but the complex gene-gene interactions, post-transcriptional modifications and regulation of functional networks are still unclear. To gain a comprehensive understanding of osteoporosis etiology, transcriptome gene expression microarray, epigenomic miRNA microarray and methylome sequencing were performed simultaneously in 5 high hip BMD (Bone Mineral Density) subjects and 5 low hip BMD subjects. SPIA (Signaling Pathway Impact Analysis) and PCST (Prize Collecting Steiner Tree) algorithm were used to perform pathway-enrichment analysis and construct the interaction networks. Through integrating the transcriptomic and epigenomic data, firstly we identified 3 genes (FAM50A, ZNF473 and TMEM55B) and one miRNA (hsa-mir-4291) which showed the consistent association evidence from both gene expression and methylation data; secondly in network analysis we identified an interaction network module with 12 genes and 11 miRNAs including AKT1, STAT3, STAT5A, FLT3, hsa-mir-141 and hsa-mir-34a which have been associated with BMD in previous studies. This module revealed the crosstalk among miRNAs, mRNAs and DNA methylation and showed four potential regulatory patterns of gene expression to influence the BMD status. In conclusion, the integration of multiple layers of omics can yield in-depth results than analysis of individual omics data respectively. Integrative analysis from transcriptomics and epigenomic data improves our ability to identify causal genetic factors, and more importantly uncover functional regulation pattern of multi-omics for osteoporosis etiology. PMID:26390436

  11. Integrative Analysis of Transcriptomic and Epigenomic Data to Reveal Regulation Patterns for BMD Variation.

    PubMed

    Zhang, Ji-Gang; Tan, Li-Jun; Xu, Chao; He, Hao; Tian, Qing; Zhou, Yu; Qiu, Chuan; Chen, Xiang-Ding; Deng, Hong-Wen

    2015-01-01

    Integration of multiple profiling data and construction of functional gene networks may provide additional insights into the molecular mechanisms of complex diseases. Osteoporosis is a worldwide public health problem, but the complex gene-gene interactions, post-transcriptional modifications and regulation of functional networks are still unclear. To gain a comprehensive understanding of osteoporosis etiology, transcriptome gene expression microarray, epigenomic miRNA microarray and methylome sequencing were performed simultaneously in 5 high hip BMD (Bone Mineral Density) subjects and 5 low hip BMD subjects. SPIA (Signaling Pathway Impact Analysis) and PCST (Prize Collecting Steiner Tree) algorithm were used to perform pathway-enrichment analysis and construct the interaction networks. Through integrating the transcriptomic and epigenomic data, firstly we identified 3 genes (FAM50A, ZNF473 and TMEM55B) and one miRNA (hsa-mir-4291) which showed the consistent association evidence from both gene expression and methylation data; secondly in network analysis we identified an interaction network module with 12 genes and 11 miRNAs including AKT1, STAT3, STAT5A, FLT3, hsa-mir-141 and hsa-mir-34a which have been associated with BMD in previous studies. This module revealed the crosstalk among miRNAs, mRNAs and DNA methylation and showed four potential regulatory patterns of gene expression to influence the BMD status. In conclusion, the integration of multiple layers of omics can yield in-depth results than analysis of individual omics data respectively. Integrative analysis from transcriptomics and epigenomic data improves our ability to identify causal genetic factors, and more importantly uncover functional regulation pattern of multi-omics for osteoporosis etiology.

  12. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice.

    PubMed

    Scheving, Lawrence A; Zhang, Xiuqi; Garcia, Oscar A; Wang, Rebecca F; Stevenson, Mary C; Threadgill, David W; Russell, William E

    2014-03-01

    Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.

  13. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice.

    PubMed

    Scheving, Lawrence A; Zhang, Xiuqi; Garcia, Oscar A; Wang, Rebecca F; Stevenson, Mary C; Threadgill, David W; Russell, William E

    2014-03-01

    Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies. PMID:24407590

  14. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice

    PubMed Central

    Zhang, Xiuqi; Garcia, Oscar A.; Wang, Rebecca F.; Stevenson, Mary C.; Threadgill, David W.; Russell, William E.

    2014-01-01

    Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies. PMID:24407590

  15. The Integration of Genetic Propensities into Social-Control Models of Delinquency and Violence among Male Youths

    ERIC Educational Resources Information Center

    Guo, Guang; Roettger, Michael E.; Cai, Tianji

    2008-01-01

    This study, drawing on approximately 1,100 males from the National Longitudinal Study of Adolescent Health, demonstrates the importance of genetics, and genetic-environmental interactions, for understanding adolescent delinquency and violence. Our analyses show that three genetic polymorphisms--specifically, the 30-bp promoter-region variable…

  16. Integrating family planning and HIV services in western Kenya: the impact on HIV-infected patients' knowledge of family planning and male attitudes toward family planning.

    PubMed

    Onono, Maricianah; Guzé, Mary A; Grossman, Daniel; Steinfeld, Rachel; Bukusi, Elizabeth A; Shade, Starley; Cohen, Craig R; Newmann, Sara J

    2015-01-01

    Little information exists on the impact of integrating family planning (FP) services into HIV care and treatment on patients' familiarity with and attitudes toward FP. We conducted a cluster-randomized trial in 18 public HIV clinics with 12 randomized to integrated FP and HIV services and 6 to the standard referral-based system where patients are referred to an FP clinic. Serial cross-sectional surveys were done before (n = 488 women, 486 men) and after (n = 479 women, 481 men) the intervention to compare changes in familiarity with FP methods and attitudes toward FP between integrated and nonintegrated (NI) sites. We created an FP familiarity score based on the number of more effective FP methods patients could identify (score range: 0-6). Generalized estimating equations were used to control for clustering within sites. An increase in mean familiarity score between baseline (mean = 5.16) and post-intervention (mean = 5.46) occurred with an overall mean change of 0.26 (95% confidence intervals [CI] = 0.09, 0.45; p = 0.003) across all sites. At end line, there was no difference in increase of mean FP familiarity scores at intervention versus control sites (mean = 5.41 vs. 5.49, p = 0.94). We observed a relative decrease in the proportion of males agreeing that FP was "women's business" at integrated sites (baseline 42% to end line 30%; reduction of 12%) compared to males at NI sites (baseline 35% to end line 42%; increase of 7%; adjusted odds ration [aOR] = 0.43; 95% CI = 0.22, 0.85). Following FP-HIV integration, familiarity with FP methods increased but did not differ by study arm. Integration was associated with a decrease in negative attitudes toward FP among men.

  17. Extracting regulator activity profiles by integration of de novo motifs and expression data: characterizing key regulators of nutrient depletion responses in Streptomyces coelicolor

    PubMed Central

    Iqbal, Mudassar; Mast, Yvonne; Amin, Rafat; Hodgson, David A.; Wohlleben, Wolfgang; Burroughs, Nigel J.

    2012-01-01

    Determining transcriptional regulator activities is a major focus of systems biology, providing key insight into regulatory mechanisms and co-regulators. For organisms such as Escherichia coli, transcriptional regulator binding site data can be integrated with expression data to infer transcriptional regulator activities. However, for most organisms there is only sparse data on their transcriptional regulators, while their associated binding motifs are largely unknown. Here, we address the challenge of inferring activities of unknown regulators by generating de novo (binding) motifs and integrating with expression data. We identify a number of key regulators active in the metabolic switch, including PhoP with its associated directed repeat PHO box, candidate motifs for two SARPs, a CRP family regulator, an iron response regulator and that for LexA. Experimental validation for some of our predictions was obtained using gel-shift assays. Our analysis is applicable to any organism for which there is a reasonable amount of complementary expression data and for which motifs (either over represented or evolutionary conserved) can be identified in the genome. PMID:22406834

  18. Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress

    PubMed Central

    Uban, Kristina A.; Comeau, Wendy; Ellis, Linda A.; Galea, Liisa A. M.; Weinberg, Joanne

    2013-01-01

    Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of mental health problems, including substance use disorders (SUD). The hypothalamic-pituitary-adrenal (HPA) and dopamine systems have overlapping neurocircuitries and are both implicated in SUD. PAE alters both HPA and dopaminergic activity and regulation, resulting in increased HPA tone and an overall reduction in tonic dopamine activity. However, effects of PAE on the interaction between HPA and dopamine (DA) systems have not been investigated. The present study examined PAE effects on basal regulation of central stress and dopamine systems in key brain regions where these systems intersect. Adult Sprague-Dawley male and female offspring from prenatal alcohol-exposed (PAE), pairfed (PF), and ad libitum-fed control (C) groups were subjected to chronic variable stress (CVS) or remained as a no stress (non-CVS) control group. Corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and DA receptor (DA-R) expression were measured under basal conditions 24 hours following the end of CVS. We show, for the first time, that regulation of basal HPA and DA systems, and likely, HPA-DA interactions, are altered differentially in males and females by PAE and CVS. PAE augmented the typical attenuation in weight gain during CVS in males and caused increased weight loss in females. Increased basal corticosterone levels in control, but not PAE, females suggest that PAE alters the profile of basal hormone secretion throughout CVS. CVS downregulated basal CRH mRNA in the prefrontal cortex and throughout the bed nucleus of the stria terminalis (BNST) in PAE females but only in the posterior BNST of control females. PAE males and females exposed to CVS exhibited more widespread upregulation of basal mineralocorticoid receptor (MR) mRNA throughout the hippocampus, and an attenuated decrease in DA-R expression throughout the nucleus accumbens and striatum compared

  19. The involvement of the olfactory bulbs in the regulation of gonadal and thyroidal activities of male red-winged blackbirds, exposed to short-day light regime.

    PubMed

    Robinzon, B; Katz, Y; Rogers, J G

    1979-01-01

    Surgical removal of the olfactory bulbs (OB) was performed in mature male red-winged blackbirds, maintained under a short-day light regime. Bulbectomy caused hyperphagia, which was not accompanied by obesity. Bulbectomized (OBX) birds had incresaed thyroid follicular activity and had greater developed testes than sham-operated controls. In the adenohypophyses of the OB-removed birds there was an increase in the populations of 4 types of chromophils: alcianophils, PAS-positive basophils, orangeophils and PAS-positive acidophils. The possibility that the OB are involved in the photoperiodic regulation of the activity of the gonads and thyroids is discussed.

  20. Building-to-Grid Integration through Commercial Building Portfolios Participating in Energy and Frequency Regulation Markets

    NASA Astrophysics Data System (ADS)

    Pavlak, Gregory S.

    Building energy use is a significant contributing factor to growing worldwide energy demands. In pursuit of a sustainable energy future, commercial building operations must be intelligently integrated with the electric system to increase efficiency and enable renewable generation. Toward this end, a model-based methodology was developed to estimate the capability of commercial buildings to participate in frequency regulation ancillary service markets. This methodology was integrated into a supervisory model predictive controller to optimize building operation in consideration of energy prices, demand charges, and ancillary service revenue. The supervisory control problem was extended to building portfolios to evaluate opportunities for synergistic effect among multiple, centrally-optimized buildings. Simulation studies performed showed that the multi-market optimization was able to determine appropriate opportunities for buildings to provide frequency regulation. Total savings were increased by up to thirteen percentage points, depending on the simulation case. Furthermore, optimizing buildings as a portfolio achieved up to seven additional percentage points of savings, depending on the case. Enhanced energy and cost savings opportunities were observed by taking the novel perspective of optimizing building portfolios in multiple grid markets, motivating future pursuits of advanced control paradigms that enable a more intelligent electric grid.

  1. Hemorrhagic shock impairs myocardial cell volume regulation and membrane integrity in dogs

    SciTech Connect

    Horton, J.W.

    1987-06-01

    An in vitro myocardial slice technique was used to quantitate alterations in cell volume regulation and membrane integrity after 2 h or hemorrhagic shock. After in vitro incubation in Krebs-Ringer-phosphate medium containing trace (/sup 14/C)inulin, values (ml H/sub 2/O/g dry wt) for control nonshocked myocardial slices were 4.03 /plus minus/ 0.11 (SE) for total water, 2.16 /plus minus/ 0.07 for inulin impermeable space, and 1.76 /plus minus/ 0.15 for inulin diffusible space. Shocked myocardial slices showed impaired response to cold incubation. After 2 h of in vivo shock, total tissue water, inulin diffusible space, and inulin impermeable space increased significantly for subendocardium, whereas changes in subepicardium parameters were minimal. Shock-induced cellular swelling was accompanied by an increased total tissue sodium, but no change in tissue potassium. Calcium entry blockade in vivo significantly reduced subendocardial total tissue water as compared with shock-untreated dogs. In addition, calcium entry blockade reduced shock-induced increases in inulin diffusible space. In vitro myocardial slice studies confirm alterations in subendocardial membrane integrity after 2 h of in vivo hemorrhagic shock. Shock-induced abnormalities in myocardial cell volume regulation are reduced by calcium entry blockade in vivo.

  2. Environmental conditions and transcriptional regulation in Escherichia coli: a physiological integrative approach.

    PubMed

    Martínez-Antonio, Agustino; Salgado, Heladia; Gama-Castro, Socorro; Gutiérrez-Ríos, Rosa María; Jiménez-Jacinto, Verónica; Collado-Vides, Julio

    2003-12-30

    Bacteria develop a number of devices for sensing, responding, and adapting to different environmental conditions. Understanding within a genomic perspective how the transcriptional machinery of bacteria is modulated, as a response for changing conditions, is a major challenge for biologists. Knowledge of which genes are turned on or turned off under specific conditions is essential for our understanding of cell behavior. In this study we describe how the information pertaining to gene expression and associated growth conditions (even with very little knowledge of the associated regulatory mechanisms) is gathered from the literature and incorporated into RegulonDB, a database on transcriptional regulation and operon organization in E. coli. The link between growth conditions, signal transduction, and transcriptional regulation is modeled in the database in a simple format that highlights biological relevant information. As far as we know, there is no other database that explicitly clarifies the effect of environmental conditions on gene transcription. We discuss how this knowledge constitutes a benchmark that will impact future research aimed at integration of regulatory responses in the cell; for instance, analysis of microarrays, predicting culture behavior in biotechnological processes, and comprehension of dynamics of regulatory networks. This integrated knowledge will contribute to the future goal of modeling the behavior of E. coli as an entire cell. The RegulonDB database can be accessed on the web at the URL: http://www.cifn.unam.mx/Computational_Biology/regulondb/. PMID:14708114

  3. Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity

    PubMed Central

    Mirzapoiazova, Tamara; Lennon, Frances E.; Mambetsariev, Bolot; Allen, Michael; Riehm, Jacob; Poroyko, Valeriy A.; Singleton, Patrick A.

    2015-01-01

    Defects in vascular integrity are an initiating factor in several disease processes. We have previously reported that high molecular weight hyaluronan (HMW-HA), a major glycosaminoglycan in the body, promotes rapid signal transduction in human pulmonary microvascular endothelial cells (HPMVEC) leading to barrier enhancement. In contrast, low molecular weight hyaluronan (LMW-HA), produced in disease states by hyaluronidases and reactive oxygen species (ROS), induces HPMVEC barrier disruption. However, the mechanism(s) of sustained barrier regulation by HA are poorly defined. Our results indicate that long-term (6–24 hours) exposure of HMW-HA induced release of a novel type of extracellular vesicle from HLMVEC called enlargeosomes (characterized by AHNAK expression) while LMW-HA long-term exposure promoted release of exosomes (characterized by CD9, CD63, and CD81 expression). These effects were blocked by inhibiting caveolin-enriched microdomain (CEM) formation. Further, inhibiting enlargeosome release by annexin II siRNA attenuated the sustained barrier enhancing effects of HMW-HA. Finally, exposure of isolated enlargeosomes to HPMVEC monolayers generated barrier enhancement while exosomes led to barrier disruption. Taken together, these results suggest that differential release of extracellular vesicles from CEM modulate the sustained HPMVEC barrier regulation by HMW-HA and LMW-HA. HMW-HA-induced specialized enlargeosomes can be a potential therapeutic strategy for diseases involving impaired vascular integrity. PMID:26447809

  4. Integrating Emotion Regulation Strategies and Religiosity/Spirituality in Counseling Sessions: Perceptions of Counselors in Christian School Settings

    ERIC Educational Resources Information Center

    Karigan, Kathleen J.

    2015-01-01

    Counselors working in religious schools have a unique opportunity to help students integrate religious/spiritual (R/S) practices, teachings, or beliefs and emotion regulation (ER) strategies to control intense emotions. The primary research question guiding this study was to explore how school counselors integrate ER strategies with R/S practices,…

  5. Integrating Content Knowledge-Building and Student-Regulated Comprehension Practices in Secondary English Language Arts Classes

    ERIC Educational Resources Information Center

    Simmons, Deborah; Fogarty, Melissa; Oslund, Eric L.; Simmons, Leslie; Hairrell, Angela; Davis, John; Anderson, Leah; Clemens, Nathan; Vaughn, Sharon; Roberts, Greg; Stillman, Stephanie; Fall, Anna-Maria

    2014-01-01

    In this experimental study we examined the effects of integrating teacher-directed knowledge-building and student-regulated comprehension practices in 7th- to 10th-grade English language arts classes. We also investigated the effect of instructional quality and whether integrating practices differentially benefitted students with lower entry-level…

  6. Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

    PubMed

    Stark, Romana; Reichenbach, Alex; Andrews, Zane B

    2015-12-15

    The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

  7. Joint-linkage mapping and GWAS reveal extensive genetic loci that regulate male inflorescence size in maize.

    PubMed

    Wu, Xun; Li, Yongxiang; Shi, Yunsu; Song, Yanchun; Zhang, Dengfeng; Li, Chunhui; Buckler, Edward S; Li, Yu; Zhang, Zhiwu; Wang, Tianyu

    2016-07-01

    Both insufficient and excessive male inflorescence size leads to a reduction in maize yield. Knowledge of the genetic architecture of male inflorescence is essential to achieve the optimum inflorescence size for maize breeding. In this study, we used approximately eight thousand inbreds, including both linkage populations and association populations, to dissect the genetic architecture of male inflorescence. The linkage populations include 25 families developed in the U.S. and 11 families developed in China. Each family contains approximately 200 recombinant inbred lines (RILs). The association populations include approximately 1000 diverse lines from the U.S. and China. All inbreds were genotyped by either sequencing or microarray. Inflorescence size was measured as the tassel primary branch number (TBN) and tassel length (TL). A total of 125 quantitative trait loci (QTLs) were identified (63 for TBN, 62 for TL) through linkage analyses. In addition, 965 quantitative trait nucleotides (QTNs) were identified through genomewide study (GWAS) at a bootstrap posterior probability (BPP) above a 5% threshold. These QTLs/QTNs include 24 known genes that were cloned using mutants, for example Ramosa3 (ra3), Thick tassel dwarf1 (td1), tasselseed2 (ts2), liguleless2 (lg2), ramosa1 (ra1), barren stalk1 (ba1), branch silkless1 (bd1) and tasselseed6 (ts6). The newly identified genes encode a zinc transporter (e.g. GRMZM5G838098 and GRMZM2G047762), the adapt in terminal region protein (e.g. GRMZM5G885628), O-methyl-transferase (e.g. GRMZM2G147491), helix-loop-helix (HLH) DNA-binding proteins (e.g. GRMZM2G414252 and GRMZM2G042895) and an SBP-box protein (e.g. GRMZM2G058588). These results provide extensive genetic information to dissect the genetic architecture of inflorescence size for the improvement of maize yield.

  8. Restoring ecological integrity in highly regulated rivers: the role of baseline data and analytical references.

    PubMed

    Downs, Peter W; Singer, Maia S; Orr, Bruce K; Diggory, Zooey E; Church, Tamara C; Stella, J C

    2011-10-01

    The goal of restoring ecological integrity in rivers is frequently accompanied by an assumption that a comparative reference reach can be identified to represent minimally impaired conditions. However, in many regulated rivers, no credible historical, morphological or process-based reference reach exists. Resilient restoration designs should instead be framed around naturalization, using multiple analytical references derived from empirically-calibrated field- and model-based techniques to develop an integrated ecological reference condition. This requires baseline data which are rarely collected despite increasing evidence for systematic deficiencies in restoration practice. We illustrate the utility of baseline data collection in restoration planning for the highly fragmented and regulated lower Merced River, California, USA. The restoration design was developed using various baseline data surveys, monitoring, and modeling within an adaptive management framework. Baseline data assisted in transforming conceptual models of ecosystem function into specific restoration challenges, defining analytical references of the expected relationships among ecological parameters required for restoration, and specifying performance criteria for post-project monitoring and evaluation. In this way the study is an example of process-based morphological restoration designed to prompt recovery of ecosystem processes and resilience. For the Merced River, we illustrate that project-specific baseline data collection is a necessary precursor in developing performance-based restoration designs and addressing scale-related uncertainties, such as whether periodic gravel augmentation will sustain bed recovery and whether piecemeal efforts will improve ecological integrity. Given the numerous impediments to full, historical, restoration in many river systems, it seems apparent that projects of naturalization are a critical step in reducing the deleterious impacts of fragmented rivers

  9. Restoring Ecological Integrity in Highly Regulated Rivers: The Role of Baseline Data and Analytical References

    NASA Astrophysics Data System (ADS)

    Downs, Peter W.; Singer, Maia S.; Orr, Bruce K.; Diggory, Zooey E.; Church, Tamara C.

    2011-10-01

    The goal of restoring ecological integrity in rivers is frequently accompanied by an assumption that a comparative reference reach can be identified to represent minimally impaired conditions. However, in many regulated rivers, no credible historical, morphological or process-based reference reach exists. Resilient restoration designs should instead be framed around naturalization, using multiple analytical references derived from empirically-calibrated field- and model-based techniques to develop an integrated ecological reference condition. This requires baseline data which are rarely collected despite increasing evidence for systematic deficiencies in restoration practice. We illustrate the utility of baseline data collection in restoration planning for the highly fragmented and regulated lower Merced River, California, USA. The restoration design was developed using various baseline data surveys, monitoring, and modeling within an adaptive management framework. Baseline data assisted in transforming conceptual models of ecosystem function into specific restoration challenges, defining analytical references of the expected relationships among ecological parameters required for restoration, and specifying performance criteria for post-project monitoring and evaluation. In this way the study is an example of process-based morphological restoration designed to prompt recovery of ecosystem processes and resilience. For the Merced River, we illustrate that project-specific baseline data collection is a necessary precursor in developing performance-based restoration designs and addressing scale-related uncertainties, such as whether periodic gravel augmentation will sustain bed recovery and whether piecemeal efforts will improve ecological integrity. Given the numerous impediments to full, historical, restoration in many river systems, it seems apparent that projects of naturalization are a critical step in reducing the deleterious impacts of fragmented rivers

  10. Infant, Control Thyself: Infants’ Integration of Multiple Social Cues to Regulate Their Imitative Behavior

    PubMed Central

    Repacholi, Betty M.; Meltzoff, Andrew N.; Rowe, Hillary; Toub, Tamara Spiewak

    2016-01-01

    This study investigated 15-month-old infants’ (N = 150) ability to self-regulate based on observing a social interaction between two adults. Infants were bystanders to a social exchange in which an Experimenter performed actions on objects and an Emoter expressed anger, as if they were forbidden acts. Next, the Emoter became neutral and her visual access to the infant was experimentally manipulated. The Emoter either: (a) left the room, (b) turned her back, (c) faced the infant but looked down at a magazine, or (d) faced and looked toward the infant. Infants were then presented with the test objects. When the previously angry Emoter was facing them, infants were hesitant to imitate the demonstrated acts in comparison to the other conditions. We hypothesize that infants integrated the emotional and visual-perceptual cues to determine whether the Emoter would get angry at them, and then regulated their behavior accordingly. Temperament was related to infants’ self-regulation –infants with higher impulsivity scores were more likely to perform the forbidden acts. Taken together, these findings provide insight into the roots of executive functions in late infancy.

  11. Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction

    NASA Astrophysics Data System (ADS)

    Yeger-Lotem, Esti; Sattath, Shmuel; Kashtan, Nadav; Itzkovitz, Shalev; Milo, Ron; Pinter, Ron Y.; Alon, Uri; Margalit, Hanah

    2004-04-01

    Genes and proteins generate molecular circuitry that enables the cell to process information and respond to stimuli. A major challenge is to identify characteristic patterns in this network of interactions that may shed light on basic cellular mechanisms. Previous studies have analyzed aspects of this network, concentrating on either transcription-regulation or protein-protein interactions. Here we search for composite network motifs: characteristic network patterns consisting of both transcription-regulation and protein-protein interactions that recur significantly more often than in random networks. To this end we developed algorithms for detecting motifs in networks with two or more types of interactions and applied them to an integrated data set of protein-protein interactions and transcription regulation in Saccharomyces cerevisiae. We found a two-protein mixed-feedback loop motif, five types of three-protein motifs exhibiting coregulation and complex formation, and many motifs involving four proteins. Virtually all four-protein motifs consisted of combinations of smaller motifs. This study presents a basic framework for detecting the building blocks of networks with multiple types of interactions.

  12. Uncovering Hidden Layers of Cell Cycle Regulation through Integrative Multi-omic Analysis

    PubMed Central

    Aviner, Ranen; Shenoy, Anjana; Elroy-Stein, Orna; Geiger, Tamar

    2015-01-01

    Studying the complex relationship between transcription, translation and protein degradation is essential to our understanding of biological processes in health and disease. The limited correlations observed between mRNA and protein abundance suggest pervasive regulation of post-transcriptional steps and support the importance of profiling mRNA levels in parallel to protein synthesis and degradation rates. In this work, we applied an integrative multi-omic approach to study gene expression along the mammalian cell cycle through side-by-side analysis of mRNA, translation and protein levels. Our analysis sheds new light on the significant contribution of both protein synthesis and degradation to the variance in protein expression. Furthermore, we find that translation regulation plays an important role at S-phase, while progression through mitosis is predominantly controlled by changes in either mRNA levels or protein stability. Specific molecular functions are found to be co-regulated and share similar patterns of mRNA, translation and protein expression along the cell cycle. Notably, these include genes and entire pathways not previously implicated in cell cycle progression, demonstrating the potential of this approach to identify novel regulatory mechanisms beyond those revealed by traditional expression profiling. Through this three-level analysis, we characterize different mechanisms of gene expression, discover new cycling gene products and highlight the importance and utility of combining datasets generated using different techniques that monitor distinct steps of gene expression. PMID:26439921

  13. An Integrated Cell Purification and Genomics Strategy Reveals Multiple Regulators of Pancreas Development

    PubMed Central

    Benitez, Cecil M.; Qu, Kun; Sugiyama, Takuya; Pauerstein, Philip T.; Liu, Yinghua; Tsai, Jennifer; Gu, Xueying; Ghodasara, Amar; Arda, H. Efsun; Zhang, Jiajing; Dekker, Joseph D.; Tucker, Haley O.; Chang, Howard Y.; Kim, Seung K.

    2014-01-01

    The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus. PMID:25330008

  14. Extension of IMC tuning correlations for non-self regulating (integrating) processes.

    PubMed

    Arbogast, Jeffrey E; Cooper, Douglas J

    2007-06-01

    The filter term of a PID with Filter controller reduces the impact of measurement noise on the derivative action of the controller. This impact is quantified by the controller output travel defined as the total movement of the controller output per unit time. Decreasing controller output travel is important to reduce wear in the final control element. Internal Model Control (IMC) tuning correlations are widely published for PI, PID, and PID with Filter controllers for self regulating processes. For non-self regulating (or integrating) processes, IMC tuning correlations are published for PI and PID controllers but not for PID with Filter controllers. The important contribution of this work is that it completes the set of IMC tuning correlations with an extension to the PID with Filter controller for non-self regulating processes. Other published correlations (not based upon the IMC framework) for PID with Filter controllers fix the filter time constant at one-tenth the derivative time regardless of the model of the process. In contrast, the novel IMC correlations presented in this paper calculate a filter time constant based upon the model of the process and the user's choice for the closed-loop time constant. The set point tracking and disturbance rejection performance of the proposed IMC tunings is demonstrated using simulation studies and a bench-scale experimental system. The proposed IMC tunings are shown to perform as well as various PID correlations (with and without a filter term) while requiring considerably less controller action.

  15. Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice.

    PubMed

    Fritz, Brandon M; Boehm, Stephen L

    2015-08-01

    We recently observed that the addition of caffeine (a nonselective adenosine receptor antagonist) to a 20% ethanol solution significantly altered the intoxication profile of male C57BL/6J (B6) mice induced by voluntary binge-like consumption in the 'Drinking-in-the-Dark' (DID) paradigm. In the current study, the roles of A1 and A2A adenosine receptor subtypes, specifically, in binge-like ethanol consumption and associated locomotor effects were explored. Adult male B6 mice (PND 60-70) were allowed to consume 20% ethanol (v/v) or 2% sucrose (w/v) for 6days via DID. On day 7, mice received a systemic administration (i.p.) of the A1 antagonist DPCPX (1, 3, 6mg/kg), the A2A antagonist MSX-3 (1, 2, 4mg/kg), or vehicle immediately prior to fluid access in DID. Antagonism of the A1 receptor via DPCPX was found to dose-dependently decrease binge-like ethanol intake and associated blood ethanol concentrations (p's<0.05), although no effect was observed on sucrose intake. Antagonism of A2A had no effect on ethanol or sucrose consumption, however, MSX-3 elicited robust locomotor stimulation in mice consuming either solution (p's<0.05). Together, these findings suggest unique roles for the A1 and A2A adenosine receptor subtypes in binge-like ethanol intake and its associated locomotor effects. PMID:26033424

  16. Cloning and characterisation of two CTR1-like genes in Cucurbita pepo: regulation of their expression during male and female flower development.

    PubMed

    Manzano, Susana; Martínez, Cecilia; Gómez, Pedro; Garrido, Dolores; Jamilena, Manuel

    2010-12-01

    Ethylene is an essential regulator of flower development in Cucurbita pepo, controlling the sexual expression, and the differentiation and maturation of floral organs. To study the action mechanism of ethylene during the male and female flower development, we have identified two CTR1 homologues from C. pepo, CpCTR1 and CpCTR2, and analysed their expressions during female and male flower development and in response to external treatments with ethylene. CpCTR1 and CpCTR2 share a high homology with plant CTR1-like kinases, but differ from other related kinases such as the Arabidopsis EDR1 and the tomato LeCTR2. The C-terminal ends of both CpCTR1 and CpCTR2 have all the conserved motifs of Ser/Thr kinase domains, including the ATP-binding signature and the protein kinase active site consensus sequence, which suggests that CpCTR1 and CpCTR2 could have the same function as CTR1 in ethylene signalling. The transcripts of both genes were detected in different organs of the plant, including roots, leaves and shoots, but were mostly accumulated in mature flowers. During the development of male and female flowers, CpCTR1 and CpCTR2 expressions were concomitant with ethylene production, which indicates that both genes could be upregulated by ethylene, at least in flowers. Moreover, external treatments with ethylene, although did not alter the expression of these two genes in seedlings and leaves, were able to upregulate their expression in flowers. In the earlier stages of flower development, when ethylene production is very low, the expression of CpCTR1 and CpCTR2 is higher in male floral organs, which agrees with the role of these genes as negative regulators of ethylene signalling, and explain the lower ethylene sensitivity of male flowers in comparison with female flowers. The function of the upregulation of these two genes in later stages of female flower development, when the production of ethylene is also increased, is discussed.

  17. Male hypogonadism.

    PubMed

    Isidori, Andrea M; Giannetta, Elisa; Lenzi, Andrea

    2008-01-01

    The hypothalamic-pituitary-gonadal (HPG) axis regulates the development, endocrine and reproductive function of the gonads throughout all phases of life. Male hypogonadism is defined an inadequate gonadal function, as manifested by deficiency in gametogenesis and/or secretion of gonadal hormones. In most cases, male hypogonadism is diagnosed through detailed history, physical examination and a few basic hormonal evaluations. In selected cases, however, additional tests are needed to define the aetiology and the extent of HPG axis dysfunction. These include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography, testicular biopsy and hormonal dynamic testing. The stimulation tests of the HPG are of particular importance in the differential diagnosis of congenital delayed puberty versus pre-pubertal hypogonadism in children. This review will focus on the methods, indications and limitations of endocrine testing in the characterisation and differential diagnosis of male hypogonadism at various ages. A practical hands-on guide on how to perform these tests is also provided.

  18. Investigation of the malE Promoter and MalR, a Positive Regulator of the Maltose Regulon, for an Improved Expression System in Sulfolobus acidocaldarius

    PubMed Central

    Wagner, Michaela; Wagner, Alexander; Ma, Xiaoqing; Kort, Julia Christin; Ghosh, Abhrajyoti; Rauch, Bernadette; Siebers, Bettina

    2014-01-01

    In this study, the regulator MalR (Saci_1161) of the TrmB family from Sulfolobus acidocaldarius was identified and was shown to be involved in transcriptional control of the maltose regulon (Saci_1660 to Saci_1666), including the ABC transporter (malEFGK), α-amylase (amyA), and α-glycosidase (malA). The ΔmalR deletion mutant exhibited a significantly decreased growth rate on maltose and dextrin but not on sucrose. The expression of the genes organized in the maltose regulon was induced only in the presence of MalR and maltose in the growth medium, indicating that MalR, in contrast to its TrmB and TrmB-like homologues, is an activator of the maltose gene cluster. Electrophoretic mobility shift assays revealed that the binding of MalR to malE was independent of sugars. Here we report the identification of the archaeal maltose regulator protein MalR, which acts as an activator and controls the expression of genes involved in maltose transport and metabolic conversion in S. acidocaldarius, and its use for improvement of the S. acidocaldarius expression system under the control of an optimized maltose binding protein (malE) promoter by promoter mutagenesis. PMID:24271181

  19. Investigation of the malE promoter and MalR, a positive regulator of the maltose regulon, for an improved expression system in Sulfolobus acidocaldarius.

    PubMed

    Wagner, Michaela; Wagner, Alexander; Ma, Xiaoqing; Kort, Julia Christin; Ghosh, Abhrajyoti; Rauch, Bernadette; Siebers, Bettina; Albers, Sonja-Verena

    2014-02-01

    In this study, the regulator MalR (Saci_1161) of the TrmB family from Sulfolobus acidocaldarius was identified and was shown to be involved in transcriptional control of the maltose regulon (Saci_1660 to Saci_1666), including the ABC transporter (malEFGK), α-amylase (amyA), and α-glycosidase (malA). The ΔmalR deletion mutant exhibited a significantly decreased growth rate on maltose and dextrin but not on sucrose. The expression of the genes organized in the maltose regulon was induced only in the presence of MalR and maltose in the growth medium, indicating that MalR, in contrast to its TrmB and TrmB-like homologues, is an activator of the maltose gene cluster. Electrophoretic mobility shift assays revealed that the binding of MalR to malE was independent of sugars. Here we report the identification of the archaeal maltose regulator protein MalR, which acts as an activator and controls the expression of genes involved in maltose transport and metabolic conversion in S. acidocaldarius, and its use for improvement of the S. acidocaldarius expression system under the control of an optimized maltose binding protein (malE) promoter by promoter mutagenesis.

  20. Two ATP Binding Cassette G Transporters, Rice ATP Binding Cassette G26 and ATP Binding Cassette G15, Collaboratively Regulate Rice Male Reproduction1[OPEN

    PubMed Central

    Zhao, Guochao; Shi, Jianxin; Liang, Wanqi; Xue, Feiyang; Luo, Qian; Zhu, Lu; Qu, Guorun; Chen, Mingjiao; Schreiber, Lukas; Zhang, Dabing

    2015-01-01

    Male reproduction in higher plants requires the support of various metabolites, including lipid molecules produced in the innermost anther wall layer (the tapetum), but how the molecules are allocated among different anther tissues remains largely unknown. Previously, rice (Oryza sativa) ATP binding cassette G15 (ABCG15) and its Arabidopsis (Arabidopsis thaliana) ortholog were shown to be required for pollen exine formation. Here, we report the significant role of OsABCG26 in regulating the development of anther cuticle and pollen exine together with OsABCG15 in rice. Cytological and chemical analyses indicate that osabcg26 shows reduced transport of lipidic molecules from tapetal cells for anther cuticle development. Supportively, the localization of OsABCG26 is on the plasma membrane of the anther wall layers. By contrast, OsABCG15 is polarly localized in tapetal plasma membrane facing anther locules. osabcg26 osabcg15 double mutant displays an almost complete absence of anther cuticle and pollen exine, similar to that of osabcg15 single mutant. Taken together, we propose that OsABCG26 and OsABCG15 collaboratively regulate rice male reproduction: OsABCG26 is mainly responsible for the transport of lipidic molecules from tapetal cells to anther wall layers, whereas OsABCG15 mainly is responsible for the export of lipidic molecules from the tapetal cells to anther locules for pollen exine development. PMID:26392263

  1. An integrative model of control: implications for understanding emotion regulation and dysregulation in childhood anxiety.

    PubMed

    Weems, Carl F; Silverman, Wendy K

    2006-04-01

    Theorists and investigators have emphasized an important role for control in emotional problems such as anxiety and anxiety disorders in youth. However, the term "control" is subject to theoretical ambiguities because of the broad conceptual bases for the term. In this article, we examine the concepts of locus of control, learned helplessness/attributional style, self-efficacy, and perceived control to develop an integrative model of control based on research and theory. The review emphasizes each of the theories distinguishing features in order to show how these distinctive features relate to real versus perceived control and how they may be differentially associated with childhood anxiety. We attempt to clarify the various definitions of control and the implications of these various definitions with respect to childhood anxiety, its disorders and their treatment and present a model of control that is integrative but also addresses the complexities of the different definitions of control (i.e., is multifaceted). The model developed from our review of the literature postulates that individuals differ in the extent to which they actually have control and differ, also on a continuum, in their perceptions of control. The need for this integrative model is highlighted by methodological, developmental, and clinical considerations. In particular, research has operationalized control and related constructs such as emotion regulation in ways that may be confounding actual control and perceived control. The need for an integrative but also multifaceted conceptualization of the role of control in childhood anxiety is also highlighted by clinical and developmental considerations. For instance, different facets of control may have differential relevance to clinical anxiety and at different points in childhood.

  2. An integrative model of control: implications for understanding emotion regulation and dysregulation in childhood anxiety.

    PubMed

    Weems, Carl F; Silverman, Wendy K

    2006-04-01

    Theorists and investigators have emphasized an important role for control in emotional problems such as anxiety and anxiety disorders in youth. However, the term "control" is subject to theoretical ambiguities because of the broad conceptual bases for the term. In this article, we examine the concepts of locus of control, learned helplessness/attributional style, self-efficacy, and perceived control to develop an integrative model of control based on research and theory. The review emphasizes each of the theories distinguishing features in order to show how these distinctive features relate to real versus perceived control and how they may be differentially associated with childhood anxiety. We attempt to clarify the various definitions of control and the implications of these various definitions with respect to childhood anxiety, its disorders and their treatment and present a model of control that is integrative but also addresses the complexities of the different definitions of control (i.e., is multifaceted). The model developed from our review of the literature postulates that individuals differ in the extent to which they actually have control and differ, also on a continuum, in their perceptions of control. The need for this integrative model is highlighted by methodological, developmental, and clinical considerations. In particular, research has operationalized control and related constructs such as emotion regulation in ways that may be confounding actual control and perceived control. The need for an integrative but also multifaceted conceptualization of the role of control in childhood anxiety is also highlighted by clinical and developmental considerations. For instance, different facets of control may have differential relevance to clinical anxiety and at different points in childhood. PMID:16487599

  3. The interaction of castration and photoperiod in the regulation of hypophyseal and serum gonadotropin levels in male golden hamsters.

    PubMed

    Turek, F W; Elliott, J A; Alvis, J D; Menaker, M

    1975-04-01

    Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured in intact and castrate adult male hamsters maintained on photostimulatory (LD 14:10) and non-photostimulatory (LD 6:18) light:dark cycles to assess the interaction of photic stimuli and gonadal hormones on pituitary gonadotropin release. Immunoreactive serum LH and FSH levels increased 1.6- and 8-fold respectively, within 3 days after photostimulated hamsters were castrated. In contrast, castration failed to alter serum LH concentration and had only a slight, if any, effect on FSH concentration in hamsters exposed to nonstimulatory photoperiods that induced testicular atrophy. In a second experiment, male hamsters previously maintained on LD 14:10 were castrated, transferred with intact animals to LD 6:18, and killed periodically over 60 days. In intact animals, pituitary content and serum levels of LH and FSH declined substantially during exposure to the non-stimulatory LD 6:18 cycle. In castrated animals, serum LH and FSH levels which had increased 2- and 8-fold in response to the castration eventually declined to about the levels found in the intact initial control animals. In contrast to serum gonadotropins, the increased hypophyseal content of LH and FSH following castration was not reduced during exposure to LD 6:18. Exposure to nonstimulatory photoperiods does not alter the increased hypophyseal LH and FSH content observed after castration. However, our results indicate that exposure to short days renders the hypothalamic-hypophyseal neuroendocrine system governing gonadotropin release relatively insensitive to gonadal steroid hormone feedback. PMID:1120474

  4. Emotion Regulation in Adolescent Males with Attention-Deficit Hyperactivity Disorder: Testing the Effects of Comorbid Conduct Disorder

    PubMed Central

    Northover, Clare; Thapar, Anita; Langley, Kate; van Goozen, Stephanie

    2015-01-01

    Although attention-deficit hyperactivity disorder (ADHD) has been linked to emotion dysregulation, few studies have experimentally investigated this whilst controlling for the effects of comorbid conduct disorder (CD). Economic decision-making games that assess how individuals respond to offers varying in fairness have been used to study emotion regulation. The present study compared adolescent boys with ADHD (n = 90), ADHD + CD (n = 94) and typical controls (n = 47) on the Ultimatum Game and examined the contribution of ADHD and CD symptom scores and callous and unemotional traits to acceptance levels of unfair offers. There were no significant differences in acceptance rates of fair and highly unfair offers between groups, and only boys with ADHD did not significantly differ from the controls. However, the subgroup of boys with ADHD and additional high levels of aggressive CD symptoms rejected significantly more ambiguous (i.e., moderately unfair) offers than any other subgroup, suggesting impaired emotion regulation in those with ADHD and aggressive CD. Correlations within the CD group showed that the rejection rate to moderately unfair offers was predicted by aggressive CD symptom severity, but not callous and unemotional traits. These findings highlight the fact that ADHD is a heterogeneous condition from an emotion regulation point of view. PMID:26371048

  5. Integrating Theory and Research: The Development of a Research-Based Treatment Program for Juvenile Male Sex Offenders

    ERIC Educational Resources Information Center

    Calley, Nancy G.

    2007-01-01

    A research-based treatment model designed to effectively address identified factors related to juvenile sexual offending behaviors is presented. Current research, theory, and national standards related to juvenile sexual offending are each explored with the treatment model reflecting an integration of these 3 components. The use of counseling…

  6. The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation

    PubMed Central

    Inutsuka, Ayumu; Yamashita, Akira; Chowdhury, Srikanta; Nakai, Junichi; Ohkura, Masamichi; Taguchi, Toru; Yamanaka, Akihiro

    2016-01-01

    The level of wakefulness is one of the major factors affecting nociception and pain. Stress-induced analgesia supports an animal’s survival via prompt defensive responses against predators or competitors. Previous studies have shown the pharmacological effects of orexin peptides on analgesia. However, orexin neurons contain not only orexin but also other co-transmitters such as dynorphin, neurotensin and glutamate. Thus, the physiological importance of orexin neuronal activity in nociception is unknown. Here we show that adult-stage selective ablation of orexin neurons enhances pain-related behaviors, while pharmacogenetic activation of orexin neurons induces analgesia. Additionally, we found correlative activation of orexin neurons during nociception using fiber photometry recordings of orexin neurons in conscious animals. These findings suggest an integrative role for orexin neurons in nociceptive perception and pain regulation. PMID:27385517

  7. Integration of Social, Cultural, and Biomedical Strategies into an Existing Couple-Based Behavioral HIV/STI Prevention Intervention: Voices of Latino Male Couples

    PubMed Central

    Martinez, Omar; Wu, Elwin; Levine, Ethan C.; Muñoz-Laboy, Miguel; Fernandez, M. Isabel; Bass, Sarah Bauerle; Moya, Eva M.; Frasca, Timothy; Chavez-Baray, Silvia; Icard, Larry D.; Ovejero, Hugo; Carballo-Diéguez, Alex; Rhodes, Scott D.

    2016-01-01

    Introduction Successful HIV prevention and treatment requires evidence-based approaches that combine biomedical strategies with behavioral interventions that are socially and culturally appropriate for the population or community being prioritized. Although there has been a push for a combination approach, how best to integrate different strategies into existing behavioral HIV prevention interventions remains unclear. The need to develop effective combination approaches is of particular importance for men who have sex with men (MSM), who face a disproportionately high risk of HIV acquisition. Materials and Methods We collaborated with Latino male couples and providers to adapt Connect ‘n Unite, an evidence-based intervention for Black male couples, for Latino male couples. We conducted a series of three focus groups, each with two cohorts of couples, and one focus group with providers. A purposive stratified sample of 20 couples (N = 40, divided into two cohorts) and 10 providers provided insights into how to adapt and integrate social, cultural, and biomedical approaches in a couples-based HIV/AIDS behavioral intervention. Results The majority (N = 37) of the couple participants had no prior knowledge of the following new biomedical strategies: non-occupational post-exposure prophylaxis (nPEP); pre-exposure prophylaxis (PrEP); and HIV self-testing kits. After they were introduced to these biomedical interventions, all participants expressed a need for information and empowerment through knowledge and awareness of these interventions. In particular, participants suggested that we provide PrEP and HIV self-testing kits by the middle or end of the intervention. Providers suggested a need to address behavioral, social and structural issues, such as language barriers; and the promotion of client-centered approaches to increase access to, adaptation of, and adherence to biomedical strategies. Corroborating what couple participants suggested, providers agreed that

  8. Control and Regulation of Mitochondrial Energetics in an Integrated Model of Cardiomyocyte Function

    PubMed Central

    Cortassa, Sonia; O'Rourke, Brian; Winslow, Raimond L.; Aon, Miguel A.

    2009-01-01

    Understanding the regulation and control of complex networks of reactions requires analytical tools that take into account the interactions between individual network components controlling global network function. Here, we apply a generalized matrix method of control analysis to calculate flux and concentration control coefficients, as well as response coefficients, in an integrated model of excitation-contraction (EC) coupling and mitochondrial energetics (ECME model) in the cardiac ventricular myocyte. Control and regulation of oxygen consumption (VO2) was first assessed in a mitochondrion model, and then in the integrated cardiac myocyte model under resting and working conditions. The results demonstrate that in the ECME model, control of respiration is distributed among cytoplasmic ATPases and mitochondrial processes. The magnitude of control by cytoplasmic ATPases increases under working conditions. The model prediction that the respiratory chain exerts strong positive control on VO2 (control coefficient 0.89) was corroborated experimentally in cardiac trabeculae utilizing the inhibitor titration method. In the model, mitochondrial respiration displayed the highest response coefficients with respect to the concentration of cytoplasmic ATP. This was due to the high elasticity of ANT flux toward ATP in the cytoplasm. The analysis reveals the complex interdependence of sarcolemmal, cytoplasmic, and mitochondrial processes that contribute to the control of energy supply and demand in the heart. Moreover, by visualizing the structure of control of the metabolic network of the myocyte, we provide support for the emerging concept of control by diffuse loops, in which action on the network (e.g., by a pharmacological agent) may bring about changes in processes without obvious direct mechanistic links between them. PMID:19289071

  9. KChIP-Like Auxiliary Subunits of Kv4 Channels Regulate Excitability of Muscle Cells and Control Male Turning Behavior during Mating in Caenorhabditis elegans

    PubMed Central

    Chen, Xin; Ruan, Mei-Yu

    2015-01-01

    Voltage-gated Kv4 channels control the excitability of neurons and cardiac myocytes by conducting rapidly activating-inactivating currents. The function of Kv4 channels is profoundly modulated by K+ channel interacting protein (KChIP) soluble auxiliary subunits. However, the in vivo mechanism of the modulation is not fully understood. Here, we identified three C. elegans KChIP-like (ceKChIP) proteins, NCS-4, NCS-5, and NCS-7. All three ceKChIPs alter electrical characteristics of SHL-1, a C. elegans Kv4 channel ortholog, currents by slowing down inactivation kinetics and shifting voltage dependence of activation to more hyperpolarizing potentials. Native SHL-1 current is completely abolished in cultured myocytes of Triple KO worms in which all three ceKChIP genes are deleted. Reexpression of NCS-4 partially restored expression of functional SHL-1 channels, whereas NCS-4(efm), a NCS-4 mutant with impaired Ca2+-binding ability, only enhanced expression of SHL-1 proteins, but failed to transport them from the Golgi apparatus to the cell membrane in body wall muscles of Triple KO worms. Moreover, translational reporter revealed that NCS-4 assembles with SHL-1 K+ channels in male diagonal muscles. Deletion of either ncs-4 or shl-1 significantly impairs male turning, a behavior controlled by diagonal muscles during mating. The phenotype of the ncs-4 null mutant could be rescued by reexpression of NCS-4, but not NCS-4(efm), further emphasizing the importance of Ca2+ binding to ceKChIPs in regulating native SHL-1 channel function. Together, these data reveal an evolutionarily conserved mechanism underlying the regulation of Kv4 channels by KChIPs and unravel critical roles of ceKChIPs in regulating muscle cell excitability and animal behavior in C. elegans. PMID:25653349

  10. FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis

    PubMed Central

    Kato, Yasuko; Alavattam, Kris G.; Sin, Ho-Su; Meetei, Amom Ruhikanta; Pang, Qishen; Andreassen, Paul R.; Namekawa, Satoshi H.

    2015-01-01

    Fanconi anemia (FA) is a recessive X-linked and autosomal genetic disease associated with bone marrow failure and increased cancer, as well as severe germline defects such as hypogonadism and germ cell depletion. Although deficiencies in FA factors are commonly associated with germ cell defects, it remains unknown whether the FA pathway is involved in unique epigenetic events in germ cells. In this study, we generated Fancb mutant mice, the first mouse model of X-linked FA, and identified a novel function of the FA pathway in epigenetic regulation during mammalian gametogenesis. Fancb mutant mice were infertile and exhibited primordial germ cell (PGC) defects during embryogenesis. Further, Fancb mutation resulted in the reduction of undifferentiated spermatogonia in spermatogenesis, suggesting that FANCB regulates the maintenance of undifferentiated spermatogonia. Additionally, based on functional studies, we dissected the pathway in which FANCB functions during meiosis. The localization of FANCB on sex chromosomes is dependent on MDC1, a binding partner of H2AX phosphorylated at serine 139 (γH2AX), which initiates chromosome-wide silencing. Also, FANCB is required for FANCD2 localization during meiosis, suggesting that the role of FANCB in the activation of the FA pathway is common to both meiosis and somatic DNA damage responses. H3K9me2, a silent epigenetic mark, was decreased on sex chromosomes, whereas H3K9me3 was increased on sex chromosomes in Fancb mutant spermatocytes. Taken together, these results indicate that FANCB functions at critical stages of germ cell development and reveal a novel function of the FA pathway in the regulation of H3K9 methylation in the germline. PMID:26123487

  11. Regulation of Translocator Protein 18 kDa (TSPO) Expression in Rat and Human Male Germ Cells

    PubMed Central

    Manku, Gurpreet; Culty, Martine

    2016-01-01

    Translocator protein 18 kDa (TSPO) is a high affinity cholesterol- and drug-binding protein highly expressed in steroidogenic cells, such as Leydig cells, where it plays a role in cholesterol mitochondrial transport. We have previously shown that TSPO is expressed in postnatal day 3 rat gonocytes, precursors of spermatogonial stem cells. Gonocytes undergo regulated phases of proliferation and migration, followed by retinoic acid (RA)-induced differentiation. Understanding these processes is important since their disruption may lead to the formation of carcinoma in situ, a precursor of testicular germ cell tumors (TGCTs). Previously, we showed that TSPO ligands do not regulate gonocyte proliferation. In the present study, we found that TSPO expression is downregulated in differentiating gonocytes. Similarly, in F9 embryonal carcinoma cells, a mouse TGCT cell line with embryonic stem cell properties, there is a significant decrease in TSPO expression during RA-induced differentiation. Silencing TSPO expression in gonocytes increased the stimulatory effect of RA on the expression of the differentiation marker Stra8, suggesting that TSPO exerts a repressive role on differentiation. Furthermore, in normal human testes, TSPO was located not only in Leydig cells, but also in discrete spermatogenic phases such as the forming acrosome of round spermatids. By contrast, seminomas, the most common type of TGCT, presented high levels of TSPO mRNA. TSPO protein was expressed in the cytoplasmic compartment of seminoma cells, identified by their nuclear expression of the transcription factors OCT4 and AP2G. Thus, TSPO appears to be tightly regulated during germ cell differentiation, and to be deregulated in seminomas, suggesting a role in germ cell development and pathology. PMID:27608010

  12. FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis.

    PubMed

    Kato, Yasuko; Alavattam, Kris G; Sin, Ho-Su; Meetei, Amom Ruhikanta; Pang, Qishen; Andreassen, Paul R; Namekawa, Satoshi H

    2015-09-15

    Fanconi anemia (FA) is a recessive X-linked and autosomal genetic disease associated with bone marrow failure and increased cancer, as well as severe germline defects such as hypogonadism and germ cell depletion. Although deficiencies in FA factors are commonly associated with germ cell defects, it remains unknown whether the FA pathway is involved in unique epigenetic events in germ cells. In this study, we generated Fancb mutant mice, the first mouse model of X-linked FA, and identified a novel function of the FA pathway in epigenetic regulation during mammalian gametogenesis. Fancb mutant mice were infertile and exhibited primordial germ cell (PGC) defects during embryogenesis. Further, Fancb mutation resulted in the reduction of undifferentiated spermatogonia in spermatogenesis, suggesting that FANCB regulates the maintenance of undifferentiated spermatogonia. Additionally, based on functional studies, we dissected the pathway in which FANCB functions during meiosis. The localization of FANCB on sex chromosomes is dependent on MDC1, a binding partner of H2AX phosphorylated at serine 139 (γH2AX), which initiates chromosome-wide silencing. Also, FANCB is required for FANCD2 localization during meiosis, suggesting that the role of FANCB in the activation of the FA pathway is common to both meiosis and somatic DNA damage responses. H3K9me2, a silent epigenetic mark, was decreased on sex chromosomes, whereas H3K9me3 was increased on sex chromosomes in Fancb mutant spermatocytes. Taken together, these results indicate that FANCB functions at critical stages of germ cell development and reveal a novel function of the FA pathway in the regulation of H3K9 methylation in the germline.

  13. Regulation of Translocator Protein 18 kDa (TSPO) Expression in Rat and Human Male Germ Cells.

    PubMed

    Manku, Gurpreet; Culty, Martine

    2016-09-06

    Translocator protein 18 kDa (TSPO) is a high affinity cholesterol- and drug-binding protein highly expressed in steroidogenic cells, such as Leydig cells, where it plays a role in cholesterol mitochondrial transport. We have previously shown that TSPO is expressed in postnatal day 3 rat gonocytes, precursors of spermatogonial stem cells. Gonocytes undergo regulated phases of proliferation and migration, followed by retinoic acid (RA)-induced differentiation. Understanding these processes is important since their disruption may lead to the formation of carcinoma in situ, a precursor of testicular germ cell tumors (TGCTs). Previously, we showed that TSPO ligands do not regulate gonocyte proliferation. In the present study, we found that TSPO expression is downregulated in differentiating gonocytes. Similarly, in F9 embryonal carcinoma cells, a mouse TGCT cell line with embryonic stem cell properties, there is a significant decrease in TSPO expression during RA-induced differentiation. Silencing TSPO expression in gonocytes increased the stimulatory effect of RA on the expression of the differentiation marker Stra8, suggesting that TSPO exerts a repressive role on differentiation. Furthermore, in normal human testes, TSPO was located not only in Leydig cells, but also in discrete spermatogenic phases such as the forming acrosome of round spermatids. By contrast, seminomas, the most common type of TGCT, presented high levels of TSPO mRNA. TSPO protein was expressed in the cytoplasmic compartment of seminoma cells, identified by their nuclear expression of the transcription factors OCT4 and AP2G. Thus, TSPO appears to be tightly regulated during germ cell differentiation, and to be deregulated in seminomas, suggesting a role in germ cell development and pathology.

  14. Regulation of Translocator Protein 18 kDa (TSPO) Expression in Rat and Human Male Germ Cells.

    PubMed

    Manku, Gurpreet; Culty, Martine

    2016-01-01

    Translocator protein 18 kDa (TSPO) is a high affinity cholesterol- and drug-binding protein highly expressed in steroidogenic cells, such as Leydig cells, where it plays a role in cholesterol mitochondrial transport. We have previously shown that TSPO is expressed in postnatal day 3 rat gonocytes, precursors of spermatogonial stem cells. Gonocytes undergo regulated phases of proliferation and migration, followed by retinoic acid (RA)-induced differentiation. Understanding these processes is important since their disruption may lead to the formation of carcinoma in situ, a precursor of testicular germ cell tumors (TGCTs). Previously, we showed that TSPO ligands do not regulate gonocyte proliferation. In the present study, we found that TSPO expression is downregulated in differentiating gonocytes. Similarly, in F9 embryonal carcinoma cells, a mouse TGCT cell line with embryonic stem cell properties, there is a significant decrease in TSPO expression during RA-induced differentiation. Silencing TSPO expression in gonocytes increased the stimulatory effect of RA on the expression of the differentiation marker Stra8, suggesting that TSPO exerts a repressive role on differentiation. Furthermore, in normal human testes, TSPO was located not only in Leydig cells, but also in discrete spermatogenic phases such as the forming acrosome of round spermatids. By contrast, seminomas, the most common type of TGCT, presented high levels of TSPO mRNA. TSPO protein was expressed in the cytoplasmic compartment of seminoma cells, identified by their nuclear expression of the transcription factors OCT4 and AP2G. Thus, TSPO appears to be tightly regulated during germ cell differentiation, and to be deregulated in seminomas, suggesting a role in germ cell development and pathology. PMID:27608010

  15. The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint

    PubMed Central

    Negishi, Takahiro; Veis, Jiri; Hollenstein, David; Sekiya, Mizuho; Ammerer, Gustav

    2016-01-01

    The cell wall integrity (CWI) checkpoint in the budding yeast Saccharomyces cerevisiae coordinates cell wall construction and cell cycle progression. In this study, we showed that the regulation of Hcm1, a late-S-phase transcription factor, arrests the cell cycle via the cell wall integrity checkpoint. Although the HCM1 mRNA level remained unaffected when the cell wall integrity checkpoint was induced, the protein level decreased. The overproduction of Hcm1 resulted in the failure of the cell wall integrity checkpoint. We identified 39 Hcm1 phosphorylation sites, including 26 novel sites, by tandem mass spectrometry analysis. A mutational analysis revealed that phosphorylation of Hcm1 at S61, S65, and S66 is required for the proper onset of the cell wall integrity checkpoint by regulating the timely decrease in its protein level. Hyperactivation of the CWI mitogen-activated protein kinase (MAPK) signaling pathway significantly reduced the Hcm1 protein level, and the deletion of CWI MAPK Slt2 resulted in a failure to decrease Hcm1 protein levels in response to stress, suggesting that phosphorylation is regulated by CWI MAPK. In conclusion, we suggest that Hcm1 is regulated negatively by the cell wall integrity checkpoint through timely phosphorylation and degradation under stress to properly control budding yeast proliferation. PMID:26729465

  16. The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint.

    PubMed

    Negishi, Takahiro; Veis, Jiri; Hollenstein, David; Sekiya, Mizuho; Ammerer, Gustav; Ohya, Yoshikazu

    2016-03-01

    The cell wall integrity (CWI) checkpoint in the budding yeast Saccharomyces cerevisiae coordinates cell wall construction and cell cycle progression. In this study, we showed that the regulation of Hcm1, a late-S-phase transcription factor, arrests the cell cycle via the cell wall integrity checkpoint. Although the HCM1 mRNA level remained unaffected when the cell wall integrity checkpoint was induced, the protein level decreased. The overproduction of Hcm1 resulted in the failure of the cell wall integrity checkpoint. We identified 39 Hcm1 phosphorylation sites, including 26 novel sites, by tandem mass spectrometry analysis. A mutational analysis revealed that phosphorylation of Hcm1 at S61, S65, and S66 is required for the proper onset of the cell wall integrity checkpoint by regulating the timely decrease in its protein level. Hyperactivation of the CWI mitogen-activated protein kinase (MAPK) signaling pathway significantly reduced the Hcm1 protein level, and the deletion of CWI MAPK Slt2 resulted in a failure to decrease Hcm1 protein levels in response to stress, suggesting that phosphorylation is regulated by CWI MAPK. In conclusion, we suggest that Hcm1 is regulated negatively by the cell wall integrity checkpoint through timely phosphorylation and degradation under stress to properly control budding yeast proliferation.

  17. Bisphenol A regulates the estrogen receptor alpha signaling in developing hippocampus of male rats through estrogen receptor.

    PubMed

    Xu, Xiao-Bin; He, Ye; Song, Chen; Ke, Xin; Fan, Shi-Jun; Peng, Wei-Jie; Tan, Ruei; Kawata, Mitsuhiro; Matsuda, Ken-Ichi; Pan, Bing-Xing; Kato, Nobumasa

    2014-12-01

    Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development-dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus-dependent behavioral deficits in the adult rats experiencing early-life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER-dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals.

  18. Arabidopsis MALE STERILITY1 Encodes a PHD-Type Transcription Factor and Regulates Pollen and Tapetum Development[W

    PubMed Central

    Ito, Takuya; Nagata, Noriko; Yoshiba, Yoshu; Ohme-Takagi, Masaru; Ma, Hong; Shinozaki, Kazuo

    2007-01-01

    The Arabidopsis thaliana MALE STERILITY1 (MS1) gene encodes a nuclear protein with Leu zipper–like and PHD-finger motifs and is important for postmeiotic pollen development. Here, we examined MS1 function using both cell biological and molecular biological approaches. We introduced a fusion construct of MS1 and a transcriptional repression domain (MS1-SRDX) into wild-type Arabidopsis, and the transgenic plants showed a semisterile phenotype similar to that of ms1. Since the repression domain can convert various kinds of transcriptional activators to dominant repressors, this suggested that MS1 functioned as a transcriptional activator. The Leu zipper–like region and the PHD motif were required for the MS1 function. Phenotypic analysis of the ms1 mutant and the MS1-SRDX transgenic Arabidopsis indicated that MS1 was involved in formation of pollen exine and pollen cytosolic components as well as tapetum development. Next, we searched for MS1 downstream genes by analyzing publicly available microarray data and identified 95 genes affected by MS1. Using a transgenic ms1 plant showing dexamethasone-inducible recovery of fertility, we further examined whether these genes were immediately downstream of MS1. From these results, we discuss a role of MS1 in pollen and tapetum development and the conservation of MS1 function in flowering plants. PMID:18032630

  19. The development, regulation and use of biopesticides for integrated pest management.

    PubMed

    Chandler, David; Bailey, Alastair S; Tatchell, G Mark; Davidson, Gill; Greaves, Justin; Grant, Wyn P

    2011-07-12

    Over the past 50 years, crop protection has relied heavily on synthetic chemical pesticides, but their availability is now declining as a result of new legislation and the evolution of resistance in pest populations. Therefore, alternative pest management tactics are needed. Biopesticides are pest management agents based on living micro-organisms or natural products. They have proven potential for pest management and they are being used across the world. However, they are regulated by systems designed originally for chemical pesticides that have created market entry barriers by imposing burdensome costs on the biopesticide industry. There are also significant technical barriers to making biopesticides more effective. In the European Union, a greater emphasis on Integrated Pest Management (IPM) as part of agricultural policy may lead to innovations in the way that biopesticides are regulated. There are also new opportunities for developing biopesticides in IPM by combining ecological science with post-genomics technologies. The new biopesticide products that will result from this research will bring with them new regulatory and economic challenges that must be addressed through joint working between social and natural scientists, policy makers and industry. PMID:21624919

  20. CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity.

    PubMed

    Crosswhite, Patrick L; Podsiadlowska, Joanna J; Curtis, Carol D; Gao, Siqi; Xia, Lijun; Srinivasan, R Sathish; Griffin, Courtney T

    2016-06-01

    The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of Chd4 specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. Chd4 mutant embryos died before birth and exhibited severe edema, blood-filled lymphatics, and liver hemorrhage. CHD4-deficient embryos developed normal lymphovenous (LV) valves, which regulate the return of lymph to the blood circulation; however, these valves lacked the fibrin-rich thrombi that prevent blood from entering the lymphatic system. Transcripts of the urokinase plasminogen activator receptor (uPAR), which facilitates activation of the fibrin-degrading protease plasmin, were upregulated in Chd4 mutant LYVE1+ cells, and plasmin activity was elevated near the LV valves. Genetic reduction of the uPAR ligand urokinase prevented degradation of fibrin-rich thrombi at the LV valves and largely resolved the blood-filled lymphatics in Chd4 mutants. Urokinase reduction also ameliorated liver hemorrhage and prolonged embryonic survival by reducing plasmin-mediated extracellular matrix degradation around sinusoidal blood vessels. These results highlight the susceptibility of LV thrombi and liver sinusoidal vessels to plasmin-mediated damage and demonstrate the importance of CHD4 in regulating embryonic plasmin activation after mid-gestation. PMID:27140400

  1. Integrated mixed signal control IC for 500-kHz switching frequency buck regulator

    NASA Astrophysics Data System (ADS)

    Chen, Keng; Zhang, Hong

    2015-12-01

    The main purpose for this work is to study the challenges of designing a digital buck regulator using pipelined analog to digital converter (ADC). Although pipelined ADC can achieve high sampling speed, it will introduce additional phase lag to the buck circuit. Along with the latency brought by processing time of additional digital circuits, as well as the time delay associated with the switching frequency, the closed loop will be unstable; moreover, raw ADC outputs have low signal-to-noise ratio, which usually need back-end calibration. In order to compensate these phase lag and make control loop unconditional stable, as well as boost up signal-to-noise ratio of the ADC block with cost-efficient design, a finite impulse response filter followed by digital proportional-integral-derivative blocks were designed. All these digital function blocks were optimised with processing speed. In the system simulation, it can be found that this controller achieved output regulation within 10% of nominal 5 V output voltage under 1 A/µs load transient condition; moreover, with the soft-start method, there is no turn-on overshooting. The die size of this controller is controlled within 3 mm2 by using 180 nm CMOS technology.

  2. CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity

    PubMed Central

    Crosswhite, Patrick L.; Podsiadlowska, Joanna J.; Curtis, Carol D.; Gao, Siqi; Srinivasan, R. Sathish; Griffin, Courtney T.

    2016-01-01

    The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of Chd4 specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. Chd4 mutant embryos died before birth and exhibited severe edema, blood-filled lymphatics, and liver hemorrhage. CHD4-deficient embryos developed normal lymphovenous (LV) valves, which regulate the return of lymph to the blood circulation; however, these valves lacked the fibrin-rich thrombi that prevent blood from entering the lymphatic system. Transcripts of the urokinase plasminogen activator receptor (uPAR), which facilitates activation of the fibrin-degrading protease plasmin, were upregulated in Chd4 mutant LYVE1+ cells, and plasmin activity was elevated near the LV valves. Genetic reduction of the uPAR ligand urokinase prevented degradation of fibrin-rich thrombi at the LV valves and largely resolved the blood-filled lymphatics in Chd4 mutants. Urokinase reduction also ameliorated liver hemorrhage and prolonged embryonic survival by reducing plasmin-mediated extracellular matrix degradation around sinusoidal blood vessels. These results highlight the susceptibility of LV thrombi and liver sinusoidal vessels to plasmin-mediated damage and demonstrate the importance of CHD4 in regulating embryonic plasmin activation after mid-gestation. PMID:27140400

  3. The development, regulation and use of biopesticides for integrated pest management

    PubMed Central

    Chandler, David; Bailey, Alastair S.; Tatchell, G. Mark; Davidson, Gill; Greaves, Justin; Grant, Wyn P.

    2011-01-01

    Over the past 50 years, crop protection has relied heavily on synthetic chemical pesticides, but their availability is now declining as a result of new legislation and the evolution of resistance in pest populations. Therefore, alternative pest management tactics are needed. Biopesticides are pest management agents based on living micro-organisms or natural products. They have proven potential for pest management and they are being used across the world. However, they are regulated by systems designed originally for chemical pesticides that have created market entry barriers by imposing burdensome costs on the biopesticide industry. There are also significant technical barriers to making biopesticides more effective. In the European Union, a greater emphasis on Integrated Pest Management (IPM) as part of agricultural policy may lead to innovations in the way that biopesticides are regulated. There are also new opportunities for developing biopesticides in IPM by combining ecological science with post-genomics technologies. The new biopesticide products that will result from this research will bring with them new regulatory and economic challenges that must be addressed through joint working between social and natural scientists, policy makers and industry. PMID:21624919

  4. Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation

    PubMed Central

    Chambers, Joseph E; Dalton, Lucy E; Clarke, Hanna J; Malzer, Elke; Dominicus, Caia S; Patel, Vruti; Moorhead, Greg; Ron, David; Marciniak, Stefan J

    2015-01-01

    Four stress-sensing kinases phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) to activate the integrated stress response (ISR). In animals, the ISR is antagonised by selective eIF2α phosphatases comprising a catalytic protein phosphatase 1 (PP1) subunit in complex with a PPP1R15-type regulatory subunit. An unbiased search for additional conserved components of the PPP1R15-PP1 phosphatase identified monomeric G-actin. Like PP1, G-actin associated with the functional core of PPP1R15 family members and G-actin depletion, by the marine toxin jasplakinolide, destabilised the endogenous PPP1R15A-PP1 complex. The abundance of the ternary PPP1R15-PP1-G-actin complex was responsive to global changes in the polymeric status of actin, as was its eIF2α-directed phosphatase activity, while localised G-actin depletion at sites enriched for PPP1R15 enhanced eIF2α phosphorylation and the downstream ISR. G-actin's role as a stabilizer of the PPP1R15-containing holophosphatase provides a mechanism for integrating signals regulating actin dynamics with stresses that trigger the ISR. DOI: http://dx.doi.org/10.7554/eLife.04872.001 PMID:25774599

  5. Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation.

    PubMed

    Chambers, Joseph E; Dalton, Lucy E; Clarke, Hanna J; Malzer, Elke; Dominicus, Caia S; Patel, Vruti; Moorhead, Greg; Ron, David; Marciniak, Stefan J

    2015-01-01

    Four stress-sensing kinases phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) to activate the integrated stress response (ISR). In animals, the ISR is antagonised by selective eIF2α phosphatases comprising a catalytic protein phosphatase 1 (PP1) subunit in complex with a PPP1R15-type regulatory subunit. An unbiased search for additional conserved components of the PPP1R15-PP1 phosphatase identified monomeric G-actin. Like PP1, G-actin associated with the functional core of PPP1R15 family members and G-actin depletion, by the marine toxin jasplakinolide, destabilised the endogenous PPP1R15A-PP1 complex. The abundance of the ternary PPP1R15-PP1-G-actin complex was responsive to global changes in the polymeric status of actin, as was its eIF2α-directed phosphatase activity, while localised G-actin depletion at sites enriched for PPP1R15 enhanced eIF2α phosphorylation and the downstream ISR. G-actin's role as a stabilizer of the PPP1R15-containing holophosphatase provides a mechanism for integrating signals regulating actin dynamics with stresses that trigger the ISR.

  6. Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity

    PubMed Central

    Tsao, Po-Nien; Matsuoka, Chisa; Wei, Shu-Chen; Sato, Atsuyasu; Sato, Susumu; Hasegawa, Koichi; Chen, Hung-kuan; Ling, Thai-Yen; Mori, Munemasa; Cardoso, Wellington V.; Morimoto, Mitsuru

    2016-01-01

    Abnormal enlargement of the alveolar spaces is a hallmark of conditions such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. Notch signaling is crucial for differentiation and regeneration and repair of the airway epithelium. However, how Notch influences the alveolar compartment and integrates this process with airway development remains little understood. Here we report a prominent role of Notch signaling in the epithelial–mesenchymal interactions that lead to alveolar formation in the developing lung. We found that alveolar type II cells are major sites of Notch2 activation and show by Notch2-specific epithelial deletion (Notch2cNull) a unique contribution of this receptor to alveologenesis. Epithelial Notch2 was required for type II cell induction of the PDGF-A ligand and subsequent paracrine activation of PDGF receptor-α signaling in alveolar myofibroblast progenitors. Moreover, Notch2 was crucial in maintaining the integrity of the epithelial and smooth muscle layers of the distal conducting airways. Our data suggest that epithelial Notch signaling regulates multiple aspects of postnatal development in the distal lung and may represent a potential target for intervention in pulmonary diseases. PMID:27364009

  7. Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway

    PubMed Central

    Thierry, Sylvain; Thierry, Eloïse; Subra, Frédéric; Deprez, Eric; Leh, Hervé; Bury-Moné, Stéphanie; Delelis, Olivier

    2016-01-01

    Integration of HIV-1 linear DNA into host chromatin is required for high levels of viral expression, and constitutes a key therapeutic target. Unintegrated viral DNA (uDNA) can support only limited transcription but may contribute to viral propagation, persistence and/or treatment escape under specific situations. The molecular mechanisms involved in the differential expression of HIV uDNA vs integrated genome (iDNA) remain to be elucidated. Here, we demonstrate, for the first time, that the expression of HIV uDNA is mainly supported by 1-LTR circles, and regulated in the opposite way, relatively to iDNA, following NF-κB pathway modulation. Upon treatment activating the NF-κB pathway, NF-κB p65 and AP-1 (cFos/cJun) binding to HIV LTR iDNA correlates with increased iDNA expression, while uDNA expression decreases. On the contrary, inhibition of the NF-κB pathway promotes the expression of circular uDNA, and correlates with Bcl-3 and AP-1 binding to its LTR region. Finally, this study identifies NF-κB subunits and Bcl-3 as transcription factors binding the HIV promoter differently depending on viral genome topology, and opens new insights on the potential roles of episomal genomes during the HIV-1 latency and persistence. PMID:27167871

  8. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship.

    PubMed

    Kim, Hyunsoo; Huang, Wei; Jiang, Xiuli; Pennicooke, Brenton; Park, Peter J; Johnson, Mark D

    2010-02-01

    Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways. PMID:20080666

  9. Melatonin administration in diabetes: regulation of plasma Cr, V, and Mg in young male Zucker diabetic fatty rats.

    PubMed

    Navarro-Alarcon, Miguel; Ruiz-Ojeda, Francisco J; Blanca-Herrera, Rosa M; Kaki, Abdullah; Adem, Abdu; Agil, Ahmad

    2014-03-01

    The use of melatonin, a neurohormone present in plants, represents an exciting approach for the maintenance of optimum health conditions. Melatonin administration ameliorates glucose homeostasis in Zucker diabetic fatty (ZDF) rats. The objective of this study was to investigate the effects of melatonin in diabetes in relation to the levels and regulation of plasma chromium (Cr), vanadium (V), and magnesium (Mg) in Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats. At the age of 6 weeks, ZDF (n = 30) and ZL (n = 30) groups were each subdivided into three groups: control (C) (n = 10), vehicle-treated (V') (n = 10) and melatonin-treated (M) (10 mg kg(-1) per day; n = 10) groups for a 6 week period. After treatment, plasma mineral concentrations were measured by flame (Mg) and electrothermal (Cr and V) atomic absorption spectrometry. No significant differences were found between the C and V' groups (p > 0.05). Plasma Mg levels were significantly lower in C-ZDF vs. C-ZL rats, demonstrating the presence of hypomagnesemia in this diabetes mellitus model. Plasma V and Cr levels were significantly higher in M-ZDF vs. C-ZDF rats. Plasma Mg levels in ZDF rats were not affected by melatonin treatment (p > 0.05). Melatonin administration ameliorates the diabetic status of ZDF rats by enhancing plasma Cr and V concentrations. This appears to be the first report of a beneficial effect of melatonin treatment on plasma Cr and V regulation in ZDF rats.

  10. Carboxypeptidase E protects hippocampal neurons during stress in male mice by up-regulating prosurvival BCL2 protein expression.

    PubMed

    Murthy, S R K; Thouennon, E; Li, W-S; Cheng, Y; Bhupatkar, J; Cawley, N X; Lane, M; Merchenthaler, I; Loh, Y P

    2013-09-01

    Prolonged chronic stress causing elevated plasma glucocorticoids leads to neurodegeneration. Adaptation to stress (allostasis) through neuroprotective mechanisms can delay this process. Studies on hippocampal neurons have identified carboxypeptidase E (CPE) as a novel neuroprotective protein that acts extracellularly, independent of its enzymatic activity, although the mechanism of action is unclear. Here, we aim to determine if CPE plays a neuroprotective role in allostasis in mouse hippocampus during chronic restraint stress (CRS), and the molecular mechanisms involved. Quantitative RT-PCR/in situ hybridization and Western blots were used to assay for mRNA and protein. After mild CRS (1 h/d for 7 d), CPE protein and mRNA were significantly elevated in the hippocampal CA3 region, compared to naïve littermates. In addition, luciferase reporter assays identified a functional glucocorticoid regulatory element within the cpe promoter that mediated the up-regulation of CPE expression in primary hippocampal neurons following dexamethasone treatment, suggesting that circulating plasma glucocorticoids could evoke a similar effect on CPE in the hippocampus in vivo. Overexpression of CPE in hippocampal neurons, or CRS in mice, resulted in elevated prosurvival BCL2 protein/mRNA and p-AKT levels in the hippocampus; however, CPE(-/-) mice showed a decrease. Thus, during mild CRS, CPE expression is up-regulated, possibly contributed by glucocorticoids, to mediate neuroprotection of the hippocampus by enhancing BCL2 expression through AKT signaling, and thereby maintaining allostasis.

  11. LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats.

    PubMed

    Li, Ji-Yao; Chai, Biaoxin; Zhang, Weizhen; Fritze, Danielle M; Zhang, Chao; Mulholland, Michael W

    2014-02-01

    The hypothalamus plays a key role in the regulation of feeding behavior. Several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus, and ventromedial nucleus of the hypothalamus (VMH), are involved in energy homeostasis. Analysis of microarray data derived from ARC revealed that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is highly expressed. LGR4, LGR5, and LGR6 form a subfamily of closely related receptors. Recently, R-spondin (Rspo) family proteins were identified as ligands of the LGR4 subfamily. In the present study, we investigated the distribution and function of LGR4-LGR6 and Rspos (1-4) in the brain of male rat. In situ hybridization showed that LGR4 is expressed in the ARC, VMH, and median eminence of the hypothalamus. LGR4 colocalizes with neuropeptide Y, proopiomelanocortin, and brain-derived neurotrophic factor neurons. LGR5 is not detectable with in situ hybridization; LGR6 is only expressed in the epithelial lining of the lower portion of the third ventricle and median eminence. Rspo1 is expressed in the VMH and down-regulated with fasting. Rspo3 is expressed in the paraventricular nucleus and also down-regulated with fasting. Rspos 1 and 3 colocalize with the neuronal marker HuD, indicating that they are expressed by neurons. Injection of Rspo1 or Rspo3 into the third brain ventricle inhibited food intake. Rspo1 decreased neuropeptide Y and increased proopiomelanocortin expression in the ARC. Rspo1 and Rspo3 mRNA is up-regulated by insulin. These data indicate that Rspo1 and Rspo3 and their receptor LGR4 form novel circuits in the brain to regulate energy homeostasis.

  12. Hippocampal neuronal nitric oxide synthase (nNOS) is regulated by nicotine and stress in female but not in male rats.

    PubMed

    Keser, Aysegul; Balkan, Burcu; Gozen, Oguz; Kanit, Lutfiye; Pogun, Sakire

    2011-01-12

    NO (nitric oxide) produced in limbic brain regions has important roles in the regulation of autonomic nervous system and HPA axis activity, anxiety, fear learning, long-term memory formation, and depression. NO is synthesized from l-arginine in a reaction catalyzed by nitric oxide synthase (NOS). Neuronal nitric oxide synthase (nNOS), one of the three isoforms of NOS, is synthesized constitutively in nerve cells. Increasing evidence indicates that nNOS expression in the nervous system may be regulated by stress and nicotinic receptors. Furthermore, data obtained from several studies suggest that signaling pathways induced by stress and nicotinic receptors may converge on various signal transduction molecules to regulate nNOS expression in brain. In the present study, we used Western Blot analysis to test the effect of forced swim stress, chronic nicotine administration, and the combined effect of both procedures on nNOS expression in the hippocampus, amygdala and frontal cortex of the male and female rat brain. Basal nNOS levels of the three brain regions examined did not show sex differences. However, forced swim stress and chronic nicotine administration increased nNOS expression in the hippocampus of female rats. When stress and nicotine were applied together, no additional increment was observed. Stress and nicotine did not regulate nNOS expression in the amygdala and the frontal cortex of either sex. Data obtained from the present study indicate that the regulation of stress and nicotine induced-nNOS expression in rat hippocampus shows sexual dimorphism and nNOS expression in the female rat hippocampus increases by nicotine and stress.

  13. A cross-sectional study of glucose regulation in young adults with very low birth weight: impact of male gender on hyperglycaemia

    PubMed Central

    Watanabe, Hiroshi; Shirai, Kenji; Ohki, Shigeru; Genma, Rieko; Morita, Hiroshi; Inoue, Eisuke; Takeuchi, Masahiro; Maekawa, Masato; Nakamura, Hirotoshi

    2012-01-01

    Objectives To investigate glucose regulation in young adults with very low birth weight (VLBW; <1500 g) in an Asian population. Design Cross-sectional observational study. Setting A general hospital in Hamamatsu, Japan. Participants 111 young adults (42 men and 69 women; aged 19–30 years) born with VLBW between 1980 and 1990. Participants underwent standard 75 g oral glucose tolerance test (OGTT). Primary and secondary outcome measures The primary outcomes were glucose and insulin levels during OGTT and risk factors for a category of hyperglycaemia defined as follows: diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glycaemia (IFG) and non-diabetes/IGT/IFG with elevated 1 h glucose levels (>8.6 mmol/l). The secondary outcomes were the pancreatic β cell function (insulinogenic index and homeostasis model of assessment for beta cell (HOMA-β)) and insulin resistance (homeostasis model of assessment for insulin resistance (HOMA-IR)). Results Of 111 young adults with VLBW, 21 subjects (19%) had hyperglycaemia: one had type 2 diabetes, six had IGT, one had IFG and 13 had non-diabetes/IGT/IFG with elevated 1 h glucose levels. In logistic regression analysis, male gender was an independent risk factor associated with hyperglycaemia (OR 3.34, 95% CI 1.08 to 10.3, p=0.036). Male subjects had significantly higher levels of glucose and lower levels of insulin during OGTT than female subjects (p<0.001 for glucose and p=0.005 for insulin by repeated measures analysis of variance). Pancreatic β cell function was lower in men (insulinogenic index: p=0.002; HOMA-β: p=0.001), although no gender difference was found in insulin resistance (HOMA-IR: p=0.477). In male subjects, logistic regression analysis showed that small for gestational age was an independent risk factor associated with hyperglycaemia (OR 33.3, 95% CI 1.67 to 662.6, p=0.022). Conclusions 19% of individuals with VLBW already had hyperglycaemia in young adulthood, and male gender

  14. Regulation of FSHbeta and GnRH receptor gene expression in activin receptor II knockout male mice.

    PubMed

    Kumar, T Rajendra; Agno, Julio; Janovick, Jo Ann; Conn, P Michael; Matzuk, Martin M

    2003-12-30

    To examine in vivo, the local effects of inhibins and activins within the anterior pituitary, independent of their endocrine effects exerted from the gonad, in mediating FSH homeostasis, we used castrated knockout mice lacking either inhibin alpha or activin receptor II (ACVR2) alone or in combination. Compared to castrated wild-type (WT) mice, FSHbeta mRNA levels in the pituitaries of Acvr2 null mice were significantly downregulated in the absence of gonadal feedback. FSHbeta mRNA levels were not significantly higher in the pituitaries of castrated inhibin alpha null mice compared to those in Acvr2 null mice and remained the same in the pituitaries of castrated double mutant mice lacking both inhibin and ACVR2. In contrast to FSHbeta mRNA expression changes, pituitary FSH content was significantly reduced in Acvr2 null mice whereas it was only slightly upregulated in inhibin alpha null mice. Combined absence of both ACVR2 signaling and inhibins caused a decrease in FSH content compared to that in the absence of inhibins alone. These changes in pituitary content were in parallel to those in serum FSH levels in these three groups of castrated mice, suggesting that the unopposed actions of locally produced inhibins are dominant over those effects mediated by ACVR2 signaling to regulate FSH biosynthesis and secretion. Thus, our in vivo results demonstrate that within the pituitary, locally produced activins and inhibins exert their actions at distinct phases of FSH homeostasis. In an independent set of experiments, we tested whether in vivo signaling via ACVR2 is necessary for hypothalamic GnRH biosynthesis and for GnRH receptor expression. Our results demonstrate that in contrast to previous in vitro studies, signaling through ACVR2 is neither required for hypothalamic synthesis of GnRH peptide nor for expression of GnRH receptors in the anterior pituitary. We conclude that within the hypothalamic-pituitary short loop, ACVR2 signaling is critical only for FSH

  15. Maintained serum sodium in male ultra-marathoners--the role of fluid intake, vasopressin, and aldosterone in fluid and electrolyte regulation.

    PubMed

    Bürge, J; Knechtle, B; Knechtle, P; Gnädinger, M; Rüst, C A; Rüst, A C; Rosemann, T

    2011-08-01

    Exercise-associated hyponatremia (EAH) is a well know electrolyte disorder in endurance athletes. Although fluid overload is the most like etiology, recent studies, however, argued whether EAH is a disorder of vasopressin secretion. The aims of the present study were to investigate (i) the prevalence of EAH in male ultra-marathoners and (ii) whether fluid intake, aldosterone or vasopressin, as measured by copeptin, were associated with post-race serum sodium concentration ([Na+]). In 50 male ultra-marathoners in a 100 km ultra-marathon, serum [Na+], aldosterone, copeptin, serum and urine osmolality, and body mass were measured pre- and post-race. Fluid intake, renal function parameters and urine excretion were measured. No athlete developed EAH. Copeptin and aldosterone increased; a significant correlation was found between the change in copeptin and the change in serum [Na+], no correlation was found between aldosterone and serum [Na+]. Serum [Na+] increased by 1.6%; body mass decreased by 1.9 kg. The change in serum [Na+] and body mass correlated significantly and negatively. The fluid intake of ~ 0.58 l/h was positively related to the change in body mass and negatively to both post-race serum [Na+] and the change in serum [Na+]. We conclude that serum [Na+] was maintained by both the mechanisms of fluid intake and the hormonal regulation of vasopressin. PMID:21823061

  16. Maintained serum sodium in male ultra-marathoners--the role of fluid intake, vasopressin, and aldosterone in fluid and electrolyte regulation.

    PubMed

    Bürge, J; Knechtle, B; Knechtle, P; Gnädinger, M; Rüst, C A; Rüst, A C; Rosemann, T

    2011-08-01

    Exercise-associated hyponatremia (EAH) is a well know electrolyte disorder in endurance athletes. Although fluid overload is the most like etiology, recent studies, however, argued whether EAH is a disorder of vasopressin secretion. The aims of the present study were to investigate (i) the prevalence of EAH in male ultra-marathoners and (ii) whether fluid intake, aldosterone or vasopressin, as measured by copeptin, were associated with post-race serum sodium concentration ([Na+]). In 50 male ultra-marathoners in a 100 km ultra-marathon, serum [Na+], aldosterone, copeptin, serum and urine osmolality, and body mass were measured pre- and post-race. Fluid intake, renal function parameters and urine excretion were measured. No athlete developed EAH. Copeptin and aldosterone increased; a significant correlation was found between the change in copeptin and the change in serum [Na+], no correlation was found between aldosterone and serum [Na+]. Serum [Na+] increased by 1.6%; body mass decreased by 1.9 kg. The change in serum [Na+] and body mass correlated significantly and negatively. The fluid intake of ~ 0.58 l/h was positively related to the change in body mass and negatively to both post-race serum [Na+] and the change in serum [Na+]. We conclude that serum [Na+] was maintained by both the mechanisms of fluid intake and the hormonal regulation of vasopressin.

  17. Novel Role for p110β PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells

    PubMed Central

    Guillermet-Guibert, Julie; Smith, Lee B.; Halet, Guillaume; Whitehead, Maria A.; Pearce, Wayne; Rebourcet, Diane; León, Kelly; Crépieux, Pascale; Nock, Gemma; Strömstedt, Maria; Enerback, Malin; Chelala, Claude; Graupera, Mariona; Carroll, John; Cosulich, Sabina; Saunders, Philippa T. K.; Huhtaniemi, Ilpo; Vanhaesebroeck, Bart

    2015-01-01

    The organismal roles of the ubiquitously expressed class I PI3K isoform p110β remain largely unknown. Using a new kinase-dead knockin mouse model that mimics constitutive pharmacological inactivation of p110β, we document that full inactivation of p110β leads to embryonic lethality in a substantial fraction of mice. Interestingly, the homozygous p110β kinase-dead mice that survive into adulthood (maximum ~26% on a mixed genetic background) have no apparent phenotypes, other than subfertility in females and complete infertility in males. Systemic inhibition of p110β results in a highly specific blockade in the maturation of spermatogonia to spermatocytes. p110β was previously suggested to signal downstream of the c-kit tyrosine kinase receptor in germ cells to regulate their proliferation and survival. We now report that p110β also plays a germ cell-extrinsic role in the Sertoli cells (SCs) that support the developing sperm, with p110β inactivation dampening expression of the SC-specific Androgen Receptor (AR) target gene Rhox5, a homeobox gene critical for spermatogenesis. All extragonadal androgen-dependent functions remain unaffected by global p110β inactivation. In line with a crucial role for p110β in SCs, selective inactivation of p110β in these cells results in male infertility. Our study is the first documentation of the involvement of a signalling enzyme, PI3K, in the regulation of AR activity during spermatogenesis. This developmental pathway may become active in prostate cancer where p110β and AR have previously been reported to functionally interact. PMID:26132308

  18. HsfA2 Controls the Activity of Developmentally and Stress-Regulated Heat Stress Protection Mechanisms in Tomato Male Reproductive Tissues1[OPEN

    PubMed Central

    Simm, Stefan; Paupière, Marine Josephine; Theres, Klaus; Bovy, Arnaud; Schleiff, Enrico; Scharf, Klaus-Dieter

    2016-01-01

    Male reproductive tissues are more sensitive to heat stress (HS) compared to vegetative tissues, but the basis of this phenomenon is poorly understood. Heat stress transcription factors (Hsfs) regulate the transcriptional changes required for protection from HS. In tomato (Solanum lycopersicum), HsfA2 acts as coactivator of HsfA1a and is one of the major Hsfs accumulating in response to elevated temperatures. The contribution of HsfA2 in heat stress response (HSR) and thermotolerance was investigated in different tissues of transgenic tomato plants with suppressed HsfA2 levels (A2AS). Global transcriptome analysis and immunodetection of two major Hsps in vegetative and reproductive tissues showed that HsfA2 regulates subsets of HS-induced genes in a tissue-specific manner. Accumulation of HsfA2 by a moderate HS treatment enhances the capacity of seedlings to cope with a subsequent severe HS, suggesting an important role for HsfA2 in regulating acquired thermotolerance. In pollen, HsfA2 is an important coactivator of HsfA1a during HSR. HsfA2 suppression reduces the viability and germination rate of pollen that received the stress during the stages of meiosis and microspore formation but had no effect on more advanced stages. In general, pollen meiocytes and microspores are characterized by increased susceptibility to HS due to their lower capacity to induce a strong HSR. This sensitivity is partially mitigated by the developmentally regulated expression of HsfA2 and several HS-responsive genes mediated by HsfA1a under nonstress conditions. Thereby, HsfA2 is an important factor for the priming process that sustains pollen thermotolerance during microsporogenesis. PMID:26917685

  19. Redefining gonadotropin-releasing hormone (GnRH) cell groups in the male Syrian hamster: testosterone regulates GnRH mRNA in the tenia tecta.

    PubMed

    Richardson, Heather N; Parfitt, David B; Thompson, Robert C; Sisk, Cheryl L

    2002-05-01

    Gonadotropin-releasing hormone (GnRH) regulates the production of testosterone via the hypothalamic-pituitary-gonadal axis and testosterone, in turn, regulates the GnRH system via negative feedback. We compared testosterone regulation of GnRH mRNA expression in four anatomically defined GnRH cell groups in juvenile and adult male Syrian hamsters, including a rostral population of GnRH cells in the tenia tecta. In situ hybridization histochemistry (ISHH) was used to measure GnRH mRNA in brains from castrated juveniles and adults treated with 0 mg or 2.5 mg testosterone pellets for one week. ISHH was performed on coronal sections using a 35S-cRNA probe generated from Syrian hamster GnRH cDNA. Testosterone treatment resulted in a significant reduction in mean area of GnRH neurones covered by silver grains within the tenia tecta, but only a trend toward decreased GnRH mRNA in the diagonal band of Broca/organum vasculosum of the lamina terminalis (DBB/OVLT), medial septum (MS), and caudal preoptic area (cPOA). The effects of testosterone were independent of age. Frequency distribution analyses unveiled a significant reduction in the number of heavily labelled cells following testosterone treatment within the tenia tecta and MS. Simple regression analyses revealed a significant positive correlation between plasma luteinizing hormone concentrations and GnRH mRNA only in the tenia tecta. These data indicate that, overall, GnRH mRNA is modestly reduced by testosterone, and the most robust attenuation of GnRH mRNA occurs within the tenia tecta. This is the first report to link mechanisms of steroid negative feedback with tenia tecta GnRH neurones, providing a new focus for investigating brain region-specific steroidal regulation of GnRH synthesis.

  20. HsfA2 Controls the Activity of Developmentally and Stress-Regulated Heat Stress Protection Mechanisms in Tomato Male Reproductive Tissues.

    PubMed

    Fragkostefanakis, Sotirios; Mesihovic, Anida; Simm, Stefan; Paupière, Marine Josephine; Hu, Yangjie; Paul, Puneet; Mishra, Shravan Kumar; Tschiersch, Bettina; Theres, Klaus; Bovy, Arnaud; Schleiff, Enrico; Scharf, Klaus-Dieter

    2016-04-01

    Male reproductive tissues are more sensitive to heat stress (HS) compared to vegetative tissues, but the basis of this phenomenon is poorly understood. Heat stress transcription factors (Hsfs) regulate the transcriptional changes required for protection from HS In tomato (Solanum lycopersicum), HsfA2 acts as coactivator of HsfA1a and is one of the major Hsfs accumulating in response to elevated temperatures. The contribution of HsfA2 in heat stress response (HSR) and thermotolerance was investigated in different tissues of transgenic tomato plants with suppressed HsfA2 levels (A2AS). Global transcriptome analysis and immunodetection of two major Hsps in vegetative and reproductive tissues showed that HsfA2 regulates subsets of HS-induced genes in a tissue-specific manner. Accumulation of HsfA2 by a moderate HS treatment enhances the capacity of seedlings to cope with a subsequent severe HS, suggesting an important role for HsfA2 in regulating acquired thermotolerance. In pollen, HsfA2 is an important coactivator of HsfA1a during HSR HsfA2 suppression reduces the viability and germination rate of pollen that received the stress during the stages of meiosis and microspore formation but had no effect on more advanced stages. In general, pollen meiocytes and microspores are characterized by increased susceptibility to HS due to their lower capacity to induce a strong HSR This sensitivity is partially mitigated by the developmentally regulated expression of HsfA2 and several HS-responsive genes mediated by HsfA1a under nonstress conditions. Thereby, HsfA2 is an important factor for the priming process that sustains pollen thermotolerance during microsporogenesis.

  1. Sexual attractiveness of male chemicals and vocalizations in mice.

    PubMed

    Asaba, Akari; Hattori, Tatsuya; Mogi, Kazutaka; Kikusui, Takefumi

    2014-01-01

    Male-female interaction is important for finding a suitable mating partner and for ensuring reproductive success. Male sexual signals such as pheromones transmit information and social and sexual status to females, and exert powerful effects on the mate preference and reproductive biology of females. Likewise, male vocalizations are attractive to females and enhance reproductive function in many animals. Interestingly, females' preference for male pheromones and vocalizations is associated with their genetic background, to avoid inbreeding. Moreover, based on acoustic cues, olfactory signals have significant effects on mate choice in mice, suggesting mate choice involves multisensory integration. In this review, we synopsize the effects of both olfactory and auditory cues on female behavior and neuroendocrine functions. We also discuss how these male signals are integrated and processed in the brain to regulate behavior and reproductive function.

  2. Sexual attractiveness of male chemicals and vocalizations in mice

    PubMed Central

    Asaba, Akari; Hattori, Tatsuya; Mogi, Kazutaka; Kikusui, Takefumi

    2014-01-01

    Male-female interaction is important for finding a suitable mating partner and for ensuring reproductive success. Male sexual signals such as pheromones transmit information and social and sexual status to females, and exert powerful effects on the mate preference and reproductive biology of females. Likewise, male vocalizations are attractive to females and enhance reproductive function in many animals. Interestingly, females' preference for male pheromones and vocalizations is associated with their genetic background, to avoid inbreeding. Moreover, based on acoustic cues, olfactory signals have significant effects on mate choice in mice, suggesting mate choice involves multisensory integration. In this review, we synopsize the effects of both olfactory and auditory cues on female behavior and neuroendocrine functions. We also discuss how these male signals are integrated and processed in the brain to regulate behavior and reproductive function. PMID:25140125

  3. Cost Analysis of Integrating the PrePex Medical Device into a Voluntary Medical Male Circumcision Program in Zimbabwe

    PubMed Central

    Hatzold, Karin; Reed, Jason; Edgil, Dianna; Jaramillo, Juan; Castor, Delivette; Forsythe, Steven; Xaba, Sinokuthemba; Mugurungi, Owen

    2014-01-01

    Background Fourteen African countries are scaling up voluntary medical male circumcision (VMMC) for HIV prevention. Several devices that might offer alternatives to the three WHO-approved surgical VMMC procedures have been evaluated for use in adults. One such device is PrePex, which was prequalified by the WHO in May 2013. We utilized data from one of the PrePex field studies undertaken in Zimbabwe to identify cost considerations for introducing PrePex into the existing surgical circumcision program. Methods and Findings We evaluated the cost drivers and overall unit cost of VMMC at a site providing surgical VMMC as a routine service (“routine surgery site”) and at a site that had added PrePex VMMC procedures to routine surgical VMMC as part of a research study (“mixed study site”). We examined the main cost drivers and modeled hypothetical scenarios with varying ratios of surgical to PrePex circumcisions, different levels of site utilization, and a range of device prices. The unit costs per VMMC for the routine surgery and mixed study sites were $56 and $61, respectively. The two greatest contributors to unit price at both sites were consumables and staff. In the hypothetical scenarios, the unit cost increased as site utilization decreased, as the ratio of PrePex to surgical VMMC increased, and as device price increased. Conclusions VMMC unit costs for routine surgery and mixed study sites were similar. Low service utilization was projected to result in the greatest increases in unit price. Countries that wish to incorporate PrePex into their circumcision programs should plan to maximize staff utilization and ensure that sites function at maximum capacity to achieve the lowest unit cost. Further costing studies will be necessary once routine implementation of PrePex-based circumcision is established. PMID:24801515

  4. Photoperiodic regulation of seasonal reproduction, molt and body weight in the migratory male yellow-breasted bunting (Emberiza aureola).

    PubMed

    Dixit, Anand S; Sougrakpam, Ramita

    2013-09-01

    Photoperiod has been shown to be a major source of temporal information regulating reproduction and associated functions in a number of avian species. We studied seasonal cycles of testicular volume, molt and body weight in natural and temperature-controlled conditions and under different artificial photoperiods in the yellow-breasted buntings. Buntings posses seasonal cycles of testicular volume, molt, body weight and fattening with no major difference between natural and temperature-controlled conditions. These cycles follow an annual solar cycle suggesting the possibility of their photoperiodic control. To confirm this, photosensitive birds were studied under 9L/15D (close to shortest day length), 12L/12D (equinox day length) and 14L/10D (close to longest day length) for 18 months. Buntings showed testicular growth followed by regression and development of photorefractoriness; molt and body weight change only under 12L/12D and 14L/10D but not under 9L/15D. Reinitiation of above responses did not occur following initial cycles under stimulatory photoperiods precluding the possibility of circannual rhythm involvement. Birds exhibited an incomplete prenuptial molt of body feathers during gonadal stimulation under long days followed by complete postnuptial molt of body and primary feathers that progressed with gonadal regression. Exposure of photosensitive birds to light-dark cycles constituting 9-16h of light/day suggested that daily photoperiod of about 12h or more is essential in inducing testicular growth and function. These results clearly indicate that buntings are capable of fine discrimination of photoperiodic information and use annual changes in day length as an environmental factor to time their seasonal responses. PMID:23910635

  5. Cannabinoid type 1 (CB1) receptors on Sim1-expressing neurons regulate energy expenditure in male mice.

    PubMed

    Cardinal, Pierre; Bellocchio, Luigi; Guzmán-Quevedo, Omar; André, Caroline; Clark, Samantha; Elie, Melissa; Leste-Lasserre, Thierry; Gonzales, Delphine; Cannich, Astrid; Marsicano, Giovanni; Cota, Daniela

    2015-02-01

    The paraventricular nucleus of the hypothalamus (PVN) regulates energy balance by modulating not only food intake, but also energy expenditure (EE) and brown adipose tissue thermogenesis. To test the hypothesis that cannabinoid type 1 (CB1) receptor in PVN neurons might control these processes, we used the Cre/loxP system to delete CB1 from single-minded 1 (Sim1) neurons, which account for the majority of PVN neurons. On standard chow, mice lacking CB1 receptor in Sim1 neurons (Sim1-CB1-knockout [KO]) had food intake, body weight, adiposity, glucose metabolism, and EE comparable with wild-type (WT) (Sim1-CB1-WT) littermates. However, maintenance on a high-fat diet revealed a gene-by-diet interaction whereby Sim1-CB1-KO mice had decreased adiposity, improved insulin sensitivity, and increased EE, whereas feeding behavior was similar to Sim1-CB1-WT mice. Additionally, high-fat diet-fed Sim1-CB1-KO mice had increased mRNA expression of the β3-adrenergic receptor, as well as of uncoupling protein-1, cytochrome-c oxidase subunit IV and mitochondrial transcription factor A in the brown adipose tissue, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using β-blockers suggested that modulation of β-adrenergic transmission play an important role in determining EE changes observed in Sim1-CB1-KO. Finally, chemical sympathectomy abolished the obesity-resistant phenotype of Sim1-CB1-KO mice. Altogether, these findings reveal a diet-dependent dissociation in the CB1 receptor control of food intake and EE, likely mediated by the PVN, where CB1 receptors on Sim1-positive neurons do not impact food intake but hinder EE during dietary environmental challenges that promote body weight gain.

  6. Photoperiodic regulation of seasonal reproduction, molt and body weight in the migratory male yellow-breasted bunting (Emberiza aureola).

    PubMed

    Dixit, Anand S; Sougrakpam, Ramita

    2013-09-01

    Photoperiod has been shown to be a major source of temporal information regulating reproduction and associated functions in a number of avian species. We studied seasonal cycles of testicular volume, molt and body weight in natural and temperature-controlled conditions and under different artificial photoperiods in the yellow-breasted buntings. Buntings posses seasonal cycles of testicular volume, molt, body weight and fattening with no major difference between natural and temperature-controlled conditions. These cycles follow an annual solar cycle suggesting the possibility of their photoperiodic control. To confirm this, photosensitive birds were studied under 9L/15D (close to shortest day length), 12L/12D (equinox day length) and 14L/10D (close to longest day length) for 18 months. Buntings showed testicular growth followed by regression and development of photorefractoriness; molt and body weight change only under 12L/12D and 14L/10D but not under 9L/15D. Reinitiation of above responses did not occur following initial cycles under stimulatory photoperiods precluding the possibility of circannual rhythm involvement. Birds exhibited an incomplete prenuptial molt of body feathers during gonadal stimulation under long days followed by complete postnuptial molt of body and primary feathers that progressed with gonadal regression. Exposure of photosensitive birds to light-dark cycles constituting 9-16h of light/day suggested that daily photoperiod of about 12h or more is essential in inducing testicular growth and function. These results clearly indicate that buntings are capable of fine discrimination of photoperiodic information and use annual changes in day length as an environmental factor to time their seasonal responses.

  7. Diabetes reduces the cognitive function with the decrease of the visual perception and visual motor integration in male older adults.

    PubMed

    Yun, Hyo-Soon; Kim, Eunhwi; Suh, Soon-Rim; Kim, Mi-Han; Kim, Hong

    2013-01-01

    This study investigated the influence of diabetes on cognitive decline between the diabetes and non- diabetes patients and identified the associations between diabetes and cognitive function, visual perception (VP), and visual motor integration (VMI). Sixty elderly men (67.10± 1.65 yr) with and without diabetes (n= 30 in each group) who were surveyed by interview and questionnaire in South Korea were enrolled in this study. The score of Mini-Mental State Examination of Korean version (MMSE-KC), Motor-free Visual Perception Test-Vertical Format (MVPT-V), and Visual-Motor Integration 3rd Revision (VMI-3R) were assessed in all of the participants to evaluate cognitive function, VP, and VMI in each. The score of MMSE-KC in the diabetic group was significantly lower than that of the non-diabetes group (P< 0.01). Participants in the diabetes group also had lower MVPT-V and VMI-3R scores than those in the non-diabetes group (P< 0.01, respectively). Especially, the scores of figure-ground and visual memory among the subcategories of MVPT-V were significantly lower in the diabetes group than in the non-diabetes group (P< 0.01). These findings indicate that the decline in cognitive function in individuals with diabetes may be greater than that in non-diabetics. In addition, the cognitive decline in older adults with diabetes might be associated with the decrease of VP and VMI. In conclusion, we propose that VP and VMI will be helpful to monitor the change of cognitive function in older adults with diabetes as part of the routine management of diabetes-induced cognitive declines. PMID:24282807

  8. Positive regulation of Shigella flexneri virulence genes by integration host factor.

    PubMed Central

    Porter, M E; Dorman, C J

    1997-01-01

    In Shigella flexneri, expression of the plasmid-encoded virulence genes is regulated via a complex cascade involving DNA topology, specific transactivators, and the nucleoid-associated protein H-NS, which represses transcription under inappropriate environmental conditions. We have investigated the involvement of a second nucleoid-associated protein, integration host factor (IHF), in virulence gene expression. We found that transcription of the invasion-specific genes is repressed in a strain harboring an ihfA mutation, particularly on entry into the stationary phase. Expression of the virB gene, whose product is required for the activation of these structural genes, is also enhanced by IHF in the stationary phase. In contrast, the virF gene, which encodes an activator of virB, is stimulated by IHF in both the logarithmic and early stationary phases of growth, as is another virF-regulated gene, icsA. We have identified regions of the virF, virB, and icsA promoters which form IHF-dependent protein-DNA complexes in vitro and have located sequences within these regions with similarity to the consensus IHF binding site. Moreover, results from experiments in which the virF or virB gene was expressed constitutively confirm that IHF has a direct input at the level of both virF and virB transcription. Finally, we provide evidence that at the latter promoter, the primary role of IHF may be to overcome repression by the H-NS protein. To our knowledge, this is the first report of a role for IHF in controlling gene expression in S. flexneri. PMID:9352898

  9. CD44 regulates vascular endothelial barrier integrity via a PECAM-1 dependent mechanism.

    PubMed

    Flynn, Kelly M; Michaud, Michael; Canosa, Sandra; Madri, Joseph A

    2013-07-01

    Vascular integrity is a critical parameter in normal growth and development. Loss of appropriate vascular barrier function is present in various immune- and injury-mediated pathological conditions. CD44 is an adhesion molecule expressed by multiple cell types, including endothelial cells (EC). The goal of the present study was to examine how loss of CD44 affected vascular permeability. Using C57BL/6 WT and CD44-KO mice, we found no significant permeability to Evan's Blue in either strain at baseline. However, there was significantly increased histamine-induced permeability in CD44-deficient mice compared to WT counterparts. Similar results were observed in vitro, where CD44-deficient endothelial monolayers were also impermeable to 40kD-FITC dextran in the absence of vasoactive challenge, but exhibited enhanced and prolonged permeability following histamine. However, CD44-KO monolayers have reduced baseline barrier strength by electrical resistance, which correlated with increased permeability, at baseline, to smaller molecular weight 4-kD FITC-dextran, suggesting weakly formed endothelial junctions. The CD44-KO EC displayed several characteristics consistent with impaired barrier function/dysfunctional EC junctions, including differential expression, phosphorylation, and localization of endothelial junction proteins, increased matrix metalloprotease expression, and altered cellular morphology. Reduced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression by CD44-KO EC in vivo and in vitro was also observed. Reconstitution of murine CD44 or PECAM-1 restored these defects to near WT status, suggesting CD44 regulates vascular permeability and integrity through a PECAM-1 dependent mechanism.

  10. SEPT12/SPAG4/LAMINB1 Complexes Are Required for Maintaining the Integrity of the Nuclear Envelope in Postmeiotic Male Germ Cells

    PubMed Central

    Yeh, Chung-Hsin; Kuo, Pao-Lin; Wang, Ya-Yun; Wu, Ying-Yu; Chen, Mei-Feng; Lin, Ding-Yen; Lai, Tsung-Hsuan; Chiang, Han-Sun; Lin, Ying-Hung

    2015-01-01

    Male infertility affects approximately 50% of all infertile couples. The male-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile or immature sperm, and sperm with structural defects such as those caused by premature chromosomal condensation and DNA damage. Our previous studies based on a knockout mice model indicated that SEPT12 proteins are critical for the terminal morphological formation of sperm. SEPT12 mutations in men result in teratozospermia and oligozospermia. In addition, the spermatozoa exhibit morphological defects of the head and tail, premature chromosomal condensation, and nuclear damage. However, the molecular functions of SEPT12 during spermatogenesis remain unclear. To determine the molecular functions of SEPT12, we applied a yeast 2-hybrid system to identify SEPT12 interactors. Seven proteins that interact with SEPT12 were identified: SEPT family proteins (SEPT4 and SEPT6), nuclear or nuclear membrane proteins (protamine 2, sperm-associated antigen 4, and NDC1 transmembrane nucleoproine), and sperm-related structural proteins (pericentriolar material 1 and obscurin-like 1). Sperm-associated antigen 4 (SPAG4; also known as SUN4) belongs to the SUN family of proteins and acts as a linker protein between nucleoskeleton and cytoskeleton proteins and localizes in the nuclear membrane. We determined that SEPT12 interacts with SPAG4 in a male germ cell line through coimmunoprecipitation. During human spermiogenesis, SEPT12 is colocalized with SPAG4 near the nuclear periphery in round spermatids and in the centrosome region in elongating spermatids. Furthermore, we observed that SEPT12/SPAG4/LAMINB1 formed complexes and were coexpressed in the nuclear periphery of round spermatids. In addition, mutated SEPT12, which was screened from an infertile man, affected the integration of these nuclear envelope complexes through coimmunoprecipitation. This was the first study that suggested that SEPT proteins link to

  11. Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants

    PubMed Central

    Samanta, Subhasis; Thakur, Jitendra K.

    2015-01-01

    Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes. PMID:26442070

  12. Integrated stress response of vertebrates is regulated by four eIF2α kinases.

    PubMed

    Taniuchi, Shusuke; Miyake, Masato; Tsugawa, Kazue; Oyadomari, Miho; Oyadomari, Seiichi

    2016-01-01

    The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2α kinases, namely heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase, (PERK) and general control non-depressible 2 (GCN2), have been identified thus far, and they are known to be activated by heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation, respectively. Because eIF2α is phosphorylated under various stress conditions, the existence of an additional eIF2α kinase has been suggested. To validate the existence of the unidentified eIF2α kinase, we constructed an eIF2α kinase quadruple knockout cells (4KO cells) in which the four known eIF2α kinase genes were deleted using the CRISPR/Cas9-mediated genome editing. Phosphorylation of eIF2α was completely abolished in the 4KO cells by various stress stimulations. Our data suggests that the four known eIF2α kinases are sufficient for ISR and that there are no additional eIF2α kinases in vertebrates. PMID:27633668

  13. Integration of cardiac myofilament activity and regulation with pathways signaling hypertrophy and failure.

    PubMed

    de Tombe, P P; Solaro, R J

    2000-08-01

    The syndrome of congestive heart failure (CHF) is an entity of ever increasing clinical significance. CHF is characterized by a steady decrease in cardiac pump function, which is eventually lethal. The mechanisms that underlie the decline in cardiac function are incompletely understood. A central theme in solving the mystery of heart failure is the identification of mechanisms by which the myofilament contractile machine of the myocardium is altered in CHF and how these alterations act in concert with pathways that signal cell growth and death. The cardiac myofilaments are a point of confluence of signals that promote the hypertrophic/failure process. Our hypothesis is that a prevailing hemodynamic stress leads to an increased strain on the myocardium. The increased strain in turn leads to miscues of the normal physiological pathway by which heart cells are signaled to match and adapt the intensity and dynamics of their mechanical activity to prevailing hemodynamic demands. These miscues result in a maladaptation to the stressor and failure of the heart to respond to hemodynamic loads at optimal end diastolic volumes. The result is a vicious cycle exacerbating the failure. Cardiac myofilament activity, the ultimate determinant of cellular dynamics and force, is a central player in the integration and regulation of pathways that signal hypertrophy and failure.

  14. Digestive physiology of the Burmese python: broad regulation of integrated performance.

    PubMed

    Secor, Stephen M

    2008-12-01

    As an apparent adaptation to predictably long episodes of fasting, the sit-and-wait foraging Burmese python experiences unprecedented regulation of gastrointestinal and cardiovascular performance with feeding and fasting. The ingestion of a meal signals the quiescent gut tissues to start secreting digestive acid and enzymes, to upregulate intestinal brush-border enzymes and nutrient transporters, and to grow. An integrated phenomenon, digestion is also characterized by increases in the mass, and presumably the function, of the heart, pancreas, liver and kidneys. Once digestion is complete, the python's stomach and small intestine rapidly downregulate performance. Much of the modulation of intestinal function can be explained by the 5-fold increase in microvillus length and apical surface area with feeding, and the subsequent shortening of the microvilli after digestion has finished. Digestion for the Burmese python is a relatively expensive endeavor, evident by the as much as a 44-fold increase in metabolic rate and equivalent in cost to as much as 37% of the meal's energy. Their large metabolic response is supported by substantial increases in ventilation and cardiac output and the apparent catabolism of glucose and lipids. Unmatched in the magnitude of its numerous physiological responses to feeding, the Burmese python is a very attractive model for examining the capacities and regulatory mechanisms of physiological performance.

  15. Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants.

    PubMed

    Samanta, Subhasis; Thakur, Jitendra K

    2015-01-01

    Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes.

  16. Integrated stress response of vertebrates is regulated by four eIF2α kinases

    PubMed Central

    Taniuchi, Shusuke; Miyake, Masato; Tsugawa, Kazue; Oyadomari, Miho; Oyadomari, Seiichi

    2016-01-01

    The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2α kinases, namely heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase, (PERK) and general control non-depressible 2 (GCN2), have been identified thus far, and they are known to be activated by heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation, respectively. Because eIF2α is phosphorylated under various stress conditions, the existence of an additional eIF2α kinase has been suggested. To validate the existence of the unidentified eIF2α kinase, we constructed an eIF2α kinase quadruple knockout cells (4KO cells) in which the four known eIF2α kinase genes were deleted using the CRISPR/Cas9-mediated genome editing. Phosphorylation of eIF2α was completely abolished in the 4KO cells by various stress stimulations. Our data suggests that the four known eIF2α kinases are sufficient for ISR and that there are no additional eIF2α kinases in vertebrates. PMID:27633668

  17. Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia.

    PubMed

    Trino, Stefania; De Luca, Luciana; Simeon, Vittorio; Laurenzana, Ilaria; Morano, Annalisa; Caivano, Antonella; La Rocca, Francesco; Pietrantuono, Giuseppe; Bianchino, Gabriella; Grieco, Vitina; Signorino, Elisabetta; Fragasso, Alberto; Bochicchio, Maria Teresa; Venturi, Claudia; Rosti, Gianantonio; Martinelli, Giovanni; Del Vecchio, Luigi; Cilloni, Daniela; Musto, Pellegrino

    2016-01-01

    Endocytosis is the major regulator process of tyrosine kinase receptor (RTK) functional activities. Bridging integrator 1 (BIN1) is a key protein involved in RTK intracellular trafficking. Here, we report, by studying 34 patients with chronic myeloid leukemia (CML) at diagnosis, that BIN1 gene is downregulated in CML as compared to healthy controls, suggesting an altered endocytosis of RTKs. Rab interactor 1 (RIN1), an activator of BIN1, displayed a similar behavior. Treatment of 57 patients by tyrosine kinase inhibitors caused, along with BCR-ABL1 inactivation, an increase of BIN1 and RIN1 expression, potentially restoring endocytosis. There was a significant inverse correlation between BIN1-RIN1 and BCR-ABL1 expression. In vitro experiments on both CML and nontumorigenic cell lines treated with Imatinib confirmed these results. In order to provide another proof in favor of BIN1 and RIN1 endocytosis function in CML, we demonstrated that Imatinib induced, in K562 cell line, BIN1-RIN1 upregulation accompanied by a parallel AXL receptor internalization into cytoplasmic compartment. This study shows a novel deregulated mechanism in CML patients, indicating BIN1 and RIN1 as players in the maintenance of the abnormal RTK signaling in this hematological disease.

  18. Study of the impacts of regulations affecting the acceptance of integrated community energy systems. Final report

    SciTech Connect

    Feurer, Duane A.; Weaver, Clifford L.; Rielley, Kevin J.; Gallagher, Kevin C.; Harmon, Susan B.; Hejna, David T.; Kitch, Edmund W.

    1981-01-01

    A detailed description is presented of the laws and programs of the State of North Carolina governing the regulation of public energy utilities, the siting of energy generating and transmission facilities, the municipal franchising of public energy utilities, and the prescription of rates to be charged by utilities including attendant problems of cost allocations, rate base and operating expense determinations, and rate of return allowances. These laws and programs are analyzed to identify impediments which they may present to the implementation of Integrated Community Energy Systems (ICES). This report is one of fifty-one separate volumes which describe such regulatory programs at the Federal level and in each state as background to the report entitled Community Energy Systems and the Law of Public Utilities - Volume One: An Overview. This report also contains a summary of a strategy described in Volume One - An Overview for overcoming these impediments by working within the existing regulatory framework and by making changes in the regulatory programs to enhance the likelihood of ICES implementation.

  19. Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice

    PubMed Central

    Jiang, Yebin; Zhao, Jenny J.; Mohr, Andreas; Roemer, Frank

    2010-01-01

    During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in postnatal skeletal development. Opt encodes a widely expressed rER-localized integral membrane protein containing a conserved SUN (Sad1/Unc-84 homology) domain. Mice lacking Opt develop acute onset skeletal defects that include impaired bone formation and spontaneous fractures. These defects result in part from a cell-autonomous failure of osteoblast maturation and a posttranscriptional decline in type I collagen synthesis, which is concordant with minimal rER expansion. By identifying Opt as a crucial regulator of bone formation in the mouse, our results uncover a novel rER-mediated control point in osteoblast function and implicate human Opt as a candidate gene for brittle bone disorders. PMID:20440000

  20. Preservice Teachers' Capacity to Teach Self-Regulated Learning: Integrating Learning from Problems and Learning from Successes

    ERIC Educational Resources Information Center

    Michalsky, Tova; Schechter, Chen

    2013-01-01

    Using a quasi-experimental design, we integrated systematic learning from problematic and successful experiences into teachers' preparatory programs and examined how such learning affected preservice physics teachers' capacity to teach students self-regulated learning (SRL). Results indicated that preservice teachers who contemplated both…

  1. Volition Completes the Puzzle: Development and Evaluation of an Integrative Trait Model of Self-Regulated Learning

    ERIC Educational Resources Information Center

    Dörrenbächer, Laura; Perels, Franziska

    2015-01-01

    Most self-regulated learning theories are imbedded within a social-cognitive framework and comprise cognitive, metacognitive and motivational components. Nevertheless, these theories partly neglect volition, which is necessary for implementing learning intentions. Therefore, the present study is frontline as it aimed to integrate volition within a…

  2. BDNF–ERK–CREB signalling mediates the role of miR-132 in the regulation of the effects of oleanolic acid in male mice

    PubMed Central

    Yi, Li-Tao; Li, Jing; Liu, Bin-Bin; Luo, Liu; Liu, Qing; Geng, Di

    2014-01-01

    Background Although previous study has demonstrated that brain-derived neurotrophic factor (BDNF) is involved in the antidepressant-like effect of oleanolic acid, there is little information regarding the details of the molecular mechanism involved in this effect. Methods We used a chronic unpredictable mild stress (CUMS) model to test the antidepressant-like effect of oleanolic acid on depressant-like behaviour, miR-132 expression and synaptic protein expression in the male mouse hippocampus. Furthermore, we explored the possible signalling pathways associated with miR-132 expression that mediate the effect of oleanolic acid on neuronal proliferation. Results The results demonstrated that a 3-week treatment with oleanolic acid ameliorated CUMS-induced anhedonic and anxiogenic behaviours. Furthermore, we found that oleanolic acid led to the BDNF-related phosphorylation and activation of extracellular signal-regulated kinases (ERK) and cyclic adenosine monophosphate response element binding protein (CREB), which was associated with the upregulation of miR-132 and hippocampal neuronal proliferation. Moreover, experiments with an miR-132 antagomir revealed that targeting miR-132 led to inhibition of neuronal proliferation and the postsynaptic density protein 95, but did not affect presynaptic protein synapsin I. Limitations Several other stimuli can also induce CREB phosphorylation in the hippocampus. Thus, regulation of miR-132 may not be restricted to neurotrophic signalling. Conclusion Our results show that oleanolic acid induces the upregulation of miR-132, which serves as an important regulator of neurotrophic actions, mainly through the activation of the hippocampal BDNF–ERK–CREB signalling pathways. PMID:25079084

  3. The effect of acute alcohol intoxication on gut wall integrity in healthy male volunteers; a randomized controlled trial.

    PubMed

    de Jong, W J; Cleveringa, A M; Greijdanus, B; Meyer, P; Heineman, E; Hulscher, J B

    2015-02-01

    The aim of the study is to determine the effect of acute alcohol consumption on enterocytes. Chronic alcohol consumption has been known to induce a decrease in gut wall integrity in actively drinking alcoholics and patients with alcohol-induced liver disease. Data on the extent of the damage induced by acute alcohol consumption in healthy human beings is scarce. Studies show that heavy incidental alcohol consumption is a growing problem in modern society. Data on this matter may provide insights into the consequences of this behavior for healthy individuals. In a randomized clinical trial in crossover design, 15 healthy volunteers consumed water one day and alcohol the other. One blood sample was collected pre-consumption, five every hour post-consumption, and one after 24 h. Intestinal fatty acid binding protein (I-FABP) was used as a marker for enterocyte damage. Liver fatty acid binding protein (L-FABP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were used as markers for hepatocyte damage. Lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) were used as a measure of translocation. Interleukin-6 (IL-6) was used to assess the acute inflammatory response to endotoxemia. Alcohol consumption caused a significant increase in serum I- and L-FABP levels, compared to water consumption. Levels increased directly post-consumption and decreased to normal levels within 4 h. LBP, sCD14, and IL-6 levels were not significantly higher in the alcohol group. Moderate acute alcohol consumption immediately damages the enterocyte but does not seem to cause endotoxemia. PMID:25559494

  4. The effect of acute alcohol intoxication on gut wall integrity in healthy male volunteers; a randomized controlled trial.

    PubMed

    de Jong, W J; Cleveringa, A M; Greijdanus, B; Meyer, P; Heineman, E; Hulscher, J B

    2015-02-01

    The aim of the study is to determine the effect of acute alcohol consumption on enterocytes. Chronic alcohol consumption has been known to induce a decrease in gut wall integrity in actively drinking alcoholics and patients with alcohol-induced liver disease. Data on the extent of the damage induced by acute alcohol consumption in healthy human beings is scarce. Studies show that heavy incidental alcohol consumption is a growing problem in modern society. Data on this matter may provide insights into the consequences of this behavior for healthy individuals. In a randomized clinical trial in crossover design, 15 healthy volunteers consumed water one day and alcohol the other. One blood sample was collected pre-consumption, five every hour post-consumption, and one after 24 h. Intestinal fatty acid binding protein (I-FABP) was used as a marker for enterocyte damage. Liver fatty acid binding protein (L-FABP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were used as markers for hepatocyte damage. Lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) were used as a measure of translocation. Interleukin-6 (IL-6) was used to assess the acute inflammatory response to endotoxemia. Alcohol consumption caused a significant increase in serum I- and L-FABP levels, compared to water consumption. Levels increased directly post-consumption and decreased to normal levels within 4 h. LBP, sCD14, and IL-6 levels were not significantly higher in the alcohol group. Moderate acute alcohol consumption immediately damages the enterocyte but does not seem to cause endotoxemia.

  5. Stakeholders' perspectives on the regulation and integration of complementary and alternative medicine products in Lebanon: a qualitative study

    PubMed Central

    2011-01-01

    Background The regulation of the markets for Complementary and Alternative Medicine (CAM) products presents a global challenge. There is a dearth of studies that have examined or evaluated the regulatory policies of CAM products in the Eastern Mediterranean Region (EMR). We investigate the regulatory frameworks and the barriers for the proper regulation and integration of CAM products in Lebanon, as an example of an EMR country with a weak public infrastructure. Methods We utilized a qualitative study design involving a series of semi-structured interviews with stakeholders of the CAM market in Lebanon. Snowball sampling was used to identify interviewees; interviews continued until the "saturation" point was reached. A total of 16 interviews were carried out with decision makers, representatives of professional associations, academic researchers, CAM product importers, policy makers and a media representative. Interviews were transcribed and thematic analysis of scripts was carried out. Results There was a consensus among all stakeholders that the regulation of the market for CAM products in Lebanon needs to be strengthened. Thematic analysis identified a number of impediments jeopardizing the safety of public consumption and hindering the integration of CAM therapies into mainstream medicine; including: weak infrastructure, poor regulation, ineffective policies and politics, weak CAM awareness and sub-optimal coordination and cooperation among stakeholders. With respect to policy instruments, voluntary instruments (self regulation) were deemed ineffective by stakeholders due to poor awareness of both users and providers on safe use of CAM products. Stakeholders' rather recommended the adoption of a combination of mixed (enhancing public awareness and integration of CAM into medical and nursing curricula) and compulsory (stricter governmental regulation) policy instruments for the regulation of the market for CAM products. Conclusions The current status quo with

  6. Alternations in neuroendocrine and endocrine regulation of reproduction in male goldfish (Carassius auratus) following an acute and chronic exposure to vinclozolin, in vivo.

    PubMed

    Golshan, Mahdi; Hatef, Azadeh; Zare, Ava; Socha, Magdalena; Milla, Sylvain; Gosiewski, Grzegorz; Fontaine, Pascal; Sokołowska-Mikołajczyk, Mirosława; Habibi, Hamid R; Alavi, Sayyed Mohammad Hadi

    2014-10-01

    The fungicide vinclozolin (VZ) is in use globally and known to disrupt reproductive function in male. The present study tested the hypothesis that VZ disrupts testicular function in goldfish (Carassius auratus) by affecting brain-pituitary-testis axis. Goldfish were exposed to 100, 400 and 800 μg/L VZ and 5 μg/L 17β-estradiol (E2) for comparison. In VZ treated goldfish, 11-ketotesteosterone (11-KT) secretion was changed depending on dose and duration period of treatment. Following 7 days of exposure, 11-KT was decreased in goldfish exposed to 800 μg/L VZ, while it was increased in goldfish exposed to 100 μg/L VZ after 30 days of exposure. Circulating E2 level was unchanged in VZ treated goldfish, however the E2/11-KT ratio was increased in a concentration-related manner. In E2 treated goldfish, circulatory 11-KT and E2 levels were decreased and increased, respectively, which resulted in an increase in the E2/11-KT ratio. Exposure to VZ at 100 μg/L caused a significant increase in the circulatory luteinizing hormone (LH) after 30 days. In E2 treated fish circulatory LH was decreased, significantly. Transcripts of genes encoding gonadotropin-releasing hormone and androgen receptor in the brain, and those of genes encoding LH and follicle-stimulating hormone receptors, StAR, CYP17, and 3β-HSD in the testis changed in VZ-treated goldfish depending on concentration and period of treatment. mRNA of genes encoding vitellogenin and estrogen receptor in the liver and cytochrome P450 aromatase in the brain were increased in E2-treated goldfish. The results suggest that VZ-induced changes in 11-KT were due to disruption in brain-pituitary-testis axis and provide integrated characterization of VZ-related reproductive disorders in male fish.

  7. The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner

    PubMed Central

    2012-01-01

    Background CTCF is a highly conserved and essential zinc finger protein expressed in virtually all cell types. In conjunction with cohesin, it organizes chromatin into loops, thereby regulating gene expression and epigenetic events. The function of CTCFL or BORIS, the testis-specific paralog of CTCF, is less clear. Results Using immunohistochemistry on testis sections and fluorescence-based microscopy on intact live seminiferous tubules, we show that CTCFL is only transiently present during spermatogenesis, prior to the onset of meiosis, when the protein co-localizes in nuclei with ubiquitously expressed CTCF. CTCFL distribution overlaps completely with that of Stra8, a retinoic acid-inducible protein essential for the propagation of meiosis. We find that absence of CTCFL in mice causes sub-fertility because of a partially penetrant testicular atrophy. CTCFL deficiency affects the expression of a number of testis-specific genes, including Gal3st1 and Prss50. Combined, these data indicate that CTCFL has a unique role in spermatogenesis. Genome-wide RNA expression studies in ES cells expressing a V5- and GFP-tagged form of CTCFL show that genes that are downregulated in CTCFL-deficient testis are upregulated in ES cells. These data indicate that CTCFL is a male germ cell gene regulator. Furthermore, genome-wide DNA-binding analysis shows that CTCFL binds a consensus sequence that is very similar to that of CTCF. However, only ~3,700 out of the ~5,700 CTCFL- and ~31,000 CTCF-binding sites overlap. CTCFL binds promoters with loosely assembled nucleosomes, whereas CTCF favors consensus sites surrounded by phased nucleosomes. Finally, an ES cell-based rescue assay shows that CTCFL is functionally different from CTCF. Conclusions Our data suggest that nucleosome composition specifies the genome-wide binding of CTCFL and CTCF. We propose that the transient expression of CTCFL in spermatogonia and preleptotene spermatocytes serves to occupy a subset of promoters and

  8. Regulation of plasma testosterone, corticosterone, and metabolites in response to stress, reproductive stage, and social challenges in a desert male songbird.

    PubMed

    Deviche, Pierre; Beouche-Helias, Benjamin; Davies, Scott; Gao, Sisi; Lane, Samuel; Valle, Shelley

    2014-07-01

    In many male vertebrates, the secretion of reproductive (gonadal androgens) and adrenocortical (glucocorticoids) hormones varies seasonally and in response to environmental stimuli, and these hormones exert numerous behavioral and metabolic effects. We performed two field studies on adult male Rufous-winged Sparrows, Peucaea carpalis, a Sonoran Desert rain-dependent sedentary species, to (a) determine seasonal changes in initial (baseline) and acute stress-induced plasma testosterone (T), corticosterone (CORT), and two metabolites (uric acid and glucose) and (b) compare the effects of two types of social challenge (song playback or simulated territorial intrusion consisting of song playback plus exposure to a live decoy bird) on plasma T, CORT, these metabolites, and territorial behavior. Initial plasma T was higher during the summer breeding period than during post-breeding molt. Acute stress resulting from capture and restraint for 30 min decreased plasma T in breeding condition birds but not in the fall, revealing that this decrease is seasonally regulated. Initial plasma CORT did not change seasonally, but plasma CORT increased in response to acute stress. This increase was likewise seasonally regulated, being relatively smaller during autumnal molt than in the summer. We found no evidence that acute stress levels of CORT are functionally related to stress-depressed plasma T and, therefore, that plasma T decreases during stress as a result of elevated plasma CORT. Thirty minutes of exposure to simulated territorial intrusion resulted in different behavior than 30 min of exposure to song playback, with increased time spent near the decoy and decreased number of overhead flights. Neither type of social challenge influenced plasma T, thus offering no support for the hypothesis that plasma T either responds to or mediates the behavioral effects of social challenge. Exposure to both social challenges elevated plasma CORT, but simulated territorial intrusion was more

  9. Regulation of plasma testosterone, corticosterone, and metabolites in response to stress, reproductive stage, and social challenges in a desert male songbird.

    PubMed

    Deviche, Pierre; Beouche-Helias, Benjamin; Davies, Scott; Gao, Sisi; Lane, Samuel; Valle, Shelley

    2014-07-01

    In many male vertebrates, the secretion of reproductive (gonadal androgens) and adrenocortical (glucocorticoids) hormones varies seasonally and in response to environmental stimuli, and these hormones exert numerous behavioral and metabolic effects. We performed two field studies on adult male Rufous-winged Sparrows, Peucaea carpalis, a Sonoran Desert rain-dependent sedentary species, to (a) determine seasonal changes in initial (baseline) and acute stress-induced plasma testosterone (T), corticosterone (CORT), and two metabolites (uric acid and glucose) and (b) compare the effects of two types of social challenge (song playback or simulated territorial intrusion consisting of song playback plus exposure to a live decoy bird) on plasma T, CORT, these metabolites, and territorial behavior. Initial plasma T was higher during the summer breeding period than during post-breeding molt. Acute stress resulting from capture and restraint for 30 min decreased plasma T in breeding condition birds but not in the fall, revealing that this decrease is seasonally regulated. Initial plasma CORT did not change seasonally, but plasma CORT increased in response to acute stress. This increase was likewise seasonally regulated, being relatively smaller during autumnal molt than in the summer. We found no evidence that acute stress levels of CORT are functionally related to stress-depressed plasma T and, therefore, that plasma T decreases during stress as a result of elevated plasma CORT. Thirty minutes of exposure to simulated territorial intrusion resulted in different behavior than 30 min of exposure to song playback, with increased time spent near the decoy and decreased number of overhead flights. Neither type of social challenge influenced plasma T, thus offering no support for the hypothesis that plasma T either responds to or mediates the behavioral effects of social challenge. Exposure to both social challenges elevated plasma CORT, but simulated territorial intrusion was more

  10. Mesangial cell αvβ8-integrin regulates glomerular capillary integrity and repair

    PubMed Central

    Lakhe-Reddy, Sujata; Li, Vincent; Arnold, Thomas D.; Khan, Shenaz

    2014-01-01

    αvβ8-Integrin is most abundantly expressed in the kidney, brain, and female reproductive organs, and its cognate ligand is latent transforming growth factor (LTGF)-β. Kidney αvβ8-integrin localizes to mesangial cells, and global β8-integrin gene (Itgb8) deletion results in embryonic lethality due to impaired placentation and cerebral hemorrhage. To circumvent the lethality and better define kidney αvβ8-integrin function, Cre-lox technology was used to generate mesangial-specific Itgb8-null mice. Platelet-derived growth factor-β receptor (PDGFBR)-Cre mice crossed with a reporter strain revealed functional Cre recombinase activity in a predicted mesangial pattern. However, mating between two different PDGFBR-Cre or Ren1d-Cre strains with Itgb8 flox/− mice consistently resulted in incomplete recombination, with no renal phenotype in mosaic offspring. Induction of a renal phenotype with Habu snake venom, a reversible mesangiolytic agent, caused exaggerated glomerular capillary microaneurysms and delayed recovery in Cre+/− PDGFRB flox/− mice compared with Cre+/− PDGFRB flox/+ control mice. To establish the mechanism, in vitro experiments were conducted in Itgb8-null versus Itgb8-expressing mesangial cells and fibroblasts, which revealed β8-integrin-regulated adhesion to Arg-Gly-Asp (RGD) peptides within a mesangial-conditioned matrix as well as β8-integrin-dependent migration on RGD-containing LTGF-β or vitronectin matrices. We speculate that kidney αvβ8-integrin indirectly controls glomerular capillary integrity through mechanical tension generated by binding RGD peptides in the mesangial matrix, and healing after glomerular injury may be facilitated by mesangial cell migration, which is guided by transient β8-integrin interactions with RGD ligands. PMID:24740792

  11. Mesangial cell αvβ8-integrin regulates glomerular capillary integrity and repair.

    PubMed

    Lakhe-Reddy, Sujata; Li, Vincent; Arnold, Thomas D; Khan, Shenaz; Schelling, Jeffrey R

    2014-06-15

    αvβ8-Integrin is most abundantly expressed in the kidney, brain, and female reproductive organs, and its cognate ligand is latent transforming growth factor (LTGF)-β. Kidney αvβ8-integrin localizes to mesangial cells, and global β8-integrin gene (Itgb8) deletion results in embryonic lethality due to impaired placentation and cerebral hemorrhage. To circumvent the lethality and better define kidney αvβ8-integrin function, Cre-lox technology was used to generate mesangial-specific Itgb8-null mice. Platelet-derived growth factor-β receptor (PDGFBR)-Cre mice crossed with a reporter strain revealed functional Cre recombinase activity in a predicted mesangial pattern. However, mating between two different PDGFBR-Cre or Ren1(d)-Cre strains with Itgb8 (flox/-) mice consistently resulted in incomplete recombination, with no renal phenotype in mosaic offspring. Induction of a renal phenotype with Habu snake venom, a reversible mesangiolytic agent, caused exaggerated glomerular capillary microaneurysms and delayed recovery in Cre(+/-) PDGFRB (flox/-) mice compared with Cre(+/-) PDGFRB (flox/+) control mice. To establish the mechanism, in vitro experiments were conducted in Itgb8-null versus Itgb8-expressing mesangial cells and fibroblasts, which revealed β8-integrin-regulated adhesion to Arg-Gly-Asp (RGD) peptides within a mesangial-conditioned matrix as well as β8-integrin-dependent migration on RGD-containing LTGF-β or vitronectin matrices. We speculate that kidney αvβ8-integrin indirectly controls glomerular capillary integrity through mechanical tension generated by binding RGD peptides in the mesangial matrix, and healing after glomerular injury may be facilitated by mesangial cell migration, which is guided by transient β8-integrin interactions with RGD ligands.

  12. How Far Have We Moved toward the Integration of Theory and Practice in Self-Regulation?

    ERIC Educational Resources Information Center

    Boekaerts, Monique; Cascallar, Eduardo

    2006-01-01

    In this article, we address four main questions, including: What is self-regulated learning for? What key strategies do students need to guide and direct their own learning process? What cues in the learning environment trigger self-regulation strategies? What can teachers do to help student to self-regulate their learning, motivation, and effort…

  13. Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins.

    PubMed

    Zhang, Wenwei; Bu, So Young; Mashek, Mara T; O-Sullivan, InSug; Sibai, Zakaria; Khan, Salmaan A; Ilkayeva, Olga; Newgard, Christopher B; Mashek, Douglas G; Unterman, Terry G

    2016-04-12

    Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the liver. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. We report that FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2). We also find that ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic, and lipogenic gene expression and metabolism. These results indicate that intrahepatic lipolysis plays a critical role in mediating and integrating the regulation of glucose and lipid metabolism downstream of FoxO proteins. PMID:27050511

  14. A comparison of hydration effect on body fluid and temperature regulation between Malaysian and Japanese males exercising at mild dehydration in humid heat

    PubMed Central

    2014-01-01

    Background This study investigated the effect of hydration differences on body fluid and temperature regulation between tropical and temperate indigenes exercising in the heat. Methods Ten Japanese and ten Malaysian males with matched physical characteristics (height, body weight, and peak oxygen consumption) participated in this study. Participants performed exercise for 60 min at 55% peak oxygen uptake followed by a 30-min recovery at 32°C and 70% relative air humidity with hydration (4 times each, 3 mL per kg body weight, 37°C) or without hydration. Rectal temperature, skin temperature, heart rate, skin blood flow, and blood pressure were measured continuously. The percentage of body weight loss and total sweat loss were calculated from body weight measurements. The percentage change in plasma volume was estimated from hemoglobin concentration and hematocrit. Results Malaysian participants had a significantly lower rectal temperature, a smaller reduction in plasma volume, and a lower heart rate in the hydrated condition than in the non-hydrated condition at the end of exercise (P <0.05), whereas Japanese participants showed no difference between the two hydration conditions. Hydration induced a greater total sweat loss in both groups (P <0.05), and the percentage of body weight loss in hydrated Malaysians was significantly less than in hydrated Japanese (P <0.05). A significant interaction between groups and hydration conditions was observed for the percentage of mean cutaneous vascular conductance during exercise relative to baseline (P <0.05). Conclusions The smaller reduction in plasma volume and percentage body weight loss in hydrated Malaysians indicated an advantage in body fluid regulation. This may enable Malaysians to reserve more blood for circulation and heat dissipation and thereby maintain lower rectal temperatures in a hydrated condition. PMID:24490869

  15. i-SERF: An Integrated Self-Evaluated and Regulated Framework for Deploying Web 2.0 Technologies in the Educational Process

    ERIC Educational Resources Information Center

    Karvounidis, Theodoros; Himos, Konstantinos; Bersimis, Sotirios; Douligeris, Christos

    2015-01-01

    In this paper we propose i-SERF (integrated-Self Evaluated and Regulated Framework) an integrated self-evaluated and regulated framework, which facilitates synchronous and asynchronous education, focusing on teaching and learning in higher education. The i-SERF framework is a two-layered framework that takes into account various elements of…

  16. Evaluation of the effects of testosterone and luteinizing hormone on regulation of β-amyloid in male 3xTg-AD mice.

    PubMed

    Rosario, Emily R; Carroll, Jenna C; Pike, Christian J

    2012-07-23

    During normal aging, men experience a significant decline in testosterone levels and a compensatory elevation in levels of gonadotropin luteinizing hormone (LH). Both low testosterone and elevated LH have been identified as significant risk factors for the development of Alzheimer's disease (AD) in men. It is unclear whether changes in testosterone or LH primarily underlie the relationship with AD, and therefore may be a more suitable therapeutic target. To examine this issue, we compared levels of β-amyloid (Aβ) immunoreactivity in male 3xTg-AD mice under varying experimental conditions associated with relatively low or high levels of testosterone and/or LH. In gonadally intact mice, Aβ accumulation increased after treatment with the gonadotropin-releasing hormone agonist leuprolide, which inhibits the hypothalamic-pituitary-gonadal (HPG) axis and reduces both testosterone and LH levels. In gonadectomized (GDX) mice with low testosterone and high LH, we also observed increased Aβ levels. Treatment of GDX mice with testosterone significantly reduced Aβ levels. In contrast, leuprolide did not significantly decrease Aβ levels and moreover, inhibited the Aβ-lowering effect of testosterone. Evaluation of hippocampal-dependent behavior revealed parallel findings, with performance in GDX mice improved by testosterone but not leuprolide. These data suggest that Aβ-lowering actions of testosterone are mediated directly by androgen pathways rather than indirectly via regulation of LH and the HPG axis. These findings support the clinical evaluation of androgen therapy in the prevention and perhaps treatment of AD in hypogonadal men.

  17. cMonkey2: Automated, systematic, integrated detection of co-regulated gene modules for any organism

    PubMed Central

    Reiss, David J.; Plaisier, Christopher L.; Wu, Wei-Ju; Baliga, Nitin S.

    2015-01-01

    The cMonkey integrated biclustering algorithm identifies conditionally co-regulated modules of genes (biclusters). cMonkey integrates various orthogonal pieces of information which support evidence of gene co-regulation, and optimizes biclusters to be supported simultaneously by one or more of these prior constraints. The algorithm served as the cornerstone for constructing the first global, predictive Environmental Gene Regulatory Influence Network (EGRIN) model for a free-living cell, and has now been applied to many more organisms. However, due to its computational inefficiencies, long run-time and complexity of various input data types, cMonkey was not readily usable by the wider community. To address these primary concerns, we have significantly updated the cMonkey algorithm and refactored its implementation, improving its usability and extendibility. These improvements provide a fully functioning and user-friendly platform for building co-regulated gene modules and the tools necessary for their exploration and interpretation. We show, via three separate analyses of data for E. coli, M. tuberculosis and H. sapiens, that the updated algorithm and inclusion of novel scoring functions for new data types (e.g. ChIP-seq and transcription factor over-expression [TFOE]) improve discovery of biologically informative co-regulated modules. The complete cMonkey2 software package, including source code, is available at https://github.com/baliga-lab/cmonkey2. PMID:25873626

  18. Male contraception

    PubMed Central

    Mathew, Vivek; Bantwal, Ganapathi

    2012-01-01

    Contraception is an accepted route for the control of population explosion in the world. Traditionally hormonal contraceptive methods have focused on women. Male contraception by means of hormonal and non hormonal methods is an attractive alternative. Hormonal methods of contraception using testosterone have shown good results. Non hormonal reversible methods of male contraception like reversible inhibition of sperm under guidanceare very promising. In this article we have reviewed the current available options for male contraception. PMID:23226635

  19. Condoms - male

    MedlinePlus

    ... Rubbers; Male condoms; Contraceptive - condom; Contraception - condom; Barrier method - condom ... infections.) Latex rubber Polyurethane Condoms are the only method of birth control for men that are not ...

  20. Chronic Losartan Treatment Up-Regulates AT1R and Increases the Heart Vulnerability to Acute Onset of Ischemia and Reperfusion Injury in Male Rats

    PubMed Central

    Song, Minwoo A.; Dasgupta, Chiranjib; Zhang, Lubo

    2015-01-01

    Inhibition of angiotensin II type 1 receptor (AT1R) is an important therapy in the management of hypertension, particularly in the immediate post-myocardial infarction period. Yet, the role of AT1R in the acute onset of myocardial ischemia and reperfusion injury still remains controversial. Thus, the present study determined the effects of chronic losartan treatment on heart ischemia and reperfusion injury in rats. Losartan (10 mg/kg/day) was administered to six-month-old male rats via an osmotic pump for 14 days and hearts were then isolated and were subjected to ischemia and reperfusion injury in a Langendorff preparation. Losartan significantly decreased mean arterial blood pressure. However, heart weight, left ventricle to body weight ratio and baseline cardiac function were not significantly altered by the losartan treatment. Of interest, chronic in vivo losartan treatment significantly increased ischemia-induced myocardial injury and decreased post-ischemic recovery of left ventricular function. This was associated with significant increases in AT1R and PKCδ expression in the left ventricle. In contrast, AT2R and PKCε were not altered. Furthermore, losartan treatment significantly increased microRNA (miR)-1, -15b, -92a, -133a, -133b, -210, and -499 expression but decreased miR-21 in the left ventricle. Of importance, addition of losartan to isolated heart preparations blocked the effect of increased ischemic-injury induced by in vivo chronic losartan treatment. The results demonstrate that chronic losartan treatment up-regulates AT1R/PKCδ and alters miR expression patterns in the heart, leading to increased cardiac vulnerability to ischemia and reperfusion injury. PMID:26168042

  1. Chronic Losartan Treatment Up-Regulates AT1R and Increases the Heart Vulnerability to Acute Onset of Ischemia and Reperfusion Injury in Male Rats.

    PubMed

    Song, Minwoo A; Dasgupta, Chiranjib; Zhang, Lubo

    2015-01-01

    Inhibition of angiotensin II type 1 receptor (AT1R) is an important therapy in the management of hypertension, particularly in the immediate post-myocardial infarction period. Yet, the role of AT1R in the acute onset of myocardial ischemia and reperfusion injury still remains controversial. Thus, the present study determined the effects of chronic losartan treatment on heart ischemia and reperfusion injury in rats. Losartan (10 mg/kg/day) was administered to six-month-old male rats via an osmotic pump for 14 days and hearts were then isolated and were subjected to ischemia and reperfusion injury in a Langendorff preparation. Losartan significantly decreased mean arterial blood pressure. However, heart weight, left ventricle to body weight ratio and baseline cardiac function were not significantly altered by the losartan treatment. Of interest, chronic in vivo losartan treatment significantly increased ischemia-induced myocardial injury and decreased post-ischemic recovery of left ventricular function. This was associated with significant increases in AT1R and PKCδ expression in the left ventricle. In contrast, AT2R and PKCε were not altered. Furthermore, losartan treatment significantly increased microRNA (miR)-1, -15b, -92a, -133a, -133b, -210, and -499 expression but decreased miR-21 in the left ventricle. Of importance, addition of losartan to isolated heart preparations blocked the effect of increased ischemic-injury induced by in vivo chronic losartan treatment. The results demonstrate that chronic losartan treatment up-regulates AT1R/PKCδ and alters miR expression patterns in the heart, leading to increased cardiac vulnerability to ischemia and reperfusion injury.

  2. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass

    PubMed Central

    Petretto, Enrico; Sarwar, Rizwan; Grieve, Ian; Lu, Han; Kumaran, Mande K; Muckett, Phillip J; Mangion, Jonathan; Schroen, Blanche; Benson, Matthew; Punjabi, Prakash P; Prasad, Sanjay K; Pennell, Dudley J; Kiesewetter, Chris; Tasheva, Elena S; Corpuz, Lolita M; Webb, Megan D; Conrad, Gary W; Kurtz, Theodore W; Kren, Vladimir; Fischer, Judith; Hubner, Norbert; Pinto, Yigal M; Pravenec, Michal; Aitman, Timothy J; Cook, Stuart A

    2009-01-01

    Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript2 (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of ~22,000 transcripts, OGN transcript abundance had the highest correlation with LVM. We further confirmed a role for Ogn in the in vivo regulation of LVM in Ogn knockout mice. Taken together, these data implicate Ogn as a key regulator of LVM in rats, mice and humans, and suggest that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis. PMID:18443592

  3. Top-down attention regulates the neural expression of audiovisual integration.

    PubMed

    Morís Fernández, Luis; Visser, Maya; Ventura-Campos, Noelia; Ávila, César; Soto-Faraco, Salvador

    2015-10-01

    The interplay between attention and multisensory integration has proven to be a difficult question to tackle. There are almost as many studies showing that multisensory integration occurs independently from the focus of attention as studies implying that attention has a profound effect on integration. Addressing the neural expression of multisensory integration for attended vs. unattended stimuli can help disentangle this apparent contradiction. In the present study, we examine if selective attention to sound pitch influences the expression of audiovisual integration in both behavior and neural activity. Participants were asked to attend to one of two auditory speech streams while watching a pair of talking lips that could be congruent or incongruent with the attended speech stream. We measured behavioral and neural responses (fMRI) to multisensory stimuli under attended and unattended conditions while physical stimulation was kept constant. Our results indicate that participants recognized words more accurately from an auditory stream that was both attended and audiovisually (AV) congruent, thus reflecting a benefit due to AV integration. On the other hand, no enhancement was found for AV congruency when it was unattended. Furthermore, the fMRI results indicated that activity in the superior temporal sulcus (an area known to be related to multisensory integration) was contingent on attention as well as on audiovisual congruency. This attentional modulation extended beyond heteromodal areas to affect processing in areas classically recognized as unisensory, such as the superior temporal gyrus or the extrastriate cortex, and to non-sensory areas such as the motor cortex. Interestingly, attention to audiovisual incongruence triggered responses in brain areas related to conflict processing (i.e., the anterior cingulate cortex and the anterior insula). Based on these results, we hypothesize that AV speech integration can take place automatically only when both

  4. MULTIPASS, a rice R2R3-type MYB transcription factor, regulates adaptive growth by integrating multiple hormonal pathways.

    PubMed

    Schmidt, Romy; Schippers, Jos H M; Mieulet, Delphine; Obata, Toshihiro; Fernie, Alisdair R; Guiderdoni, Emmanuel; Mueller-Roeber, Bernd

    2013-10-01

    Growth regulation is an important aspect of plant adaptation during environmental perturbations. Here, the role of MULTIPASS (OsMPS), an R2R3-type MYB transcription factor of rice, was explored. OsMPS is induced by salt stress and expressed in vegetative and reproductive tissues. Over-expression of OsMPS reduces growth under non-stress conditions, while knockdown plants display increased biomass. OsMPS expression is induced by abscisic acid and cytokinin, but is repressed by auxin, gibberellin and brassinolide. Growth retardation caused by OsMPS over-expression is partially restored by auxin application. Expression profiling revealed that OsMPS negatively regulates the expression of EXPANSIN (EXP) and cell-wall biosynthesis as well as phytohormone signaling genes. Furthermore, the expression of OsMPS-dependent genes is regulated by auxin, cytokinin and abscisic acid. Moreover, we show that OsMPS is a direct upstream regulator of OsEXPA4, OsEXPA8, OsEXPB2, OsEXPB3, OsEXPB6 and the endoglucanase genes OsGLU5 and OsGLU14. The multiple responses of OsMPS and its target genes to various hormones suggest an integrative function of OsMPS in the cross-talk between phytohormones and the environment to regulate adaptive growth.

  5. Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation

    PubMed Central

    Botchkarev, Vladimir A.

    2016-01-01

    The epidermal differentiation program is regulated at several levels including signaling pathways, lineage-specific transcription factors, and epigenetic regulators that establish well-coordinated process of terminal differentiation resulting in formation of the epidermal barrier. The epigenetic regulatory machinery operates at several levels including modulation of covalent DNA/histone modifications, as well as through higher-order chromatin remodeling to establish long-range topological interactions between the genes and their enhancer elements. Epigenetic regulators exhibit both activating and repressive effects on chromatin in keratinocytes (KCs): whereas some of them promote terminal differentiation, the others stimulate proliferation of progenitor cells, as well as inhibit premature activation of terminal differentiation-associated genes. Transcription factor-regulated and epigenetic mechanisms are highly connected, and the p63 transcription factor has an important role in the higher-order chromatin remodeling of the KC-specific gene loci via direct control of the genome organizer Satb1 and ATP-dependent chromatin remodeler Brg1. However, additional efforts are required to fully understand the complexity of interactions between distinct transcription factors and epigenetic regulators in the control of KC differentiation. Further understanding of these interactions and their alterations in different pathological skin conditions will help to progress toward the development of novel approaches for the treatment of skin disorders by targeting epigenetic regulators and modulating chromatin organization in KCs. PMID:26551942

  6. A neural connection between the central part of the medial preoptic nucleus and the bed nucleus of the stria terminalis to regulate sexual behavior in male rats.

    PubMed

    Maejima, Sho; Ohishi, Naoya; Yamaguchi, Shohei; Tsukahara, Shinji

    2015-10-01

    The medial preoptic nucleus (MPN) is a regulatory center for male sexual behavior. It consists of sexually dimorphic structures that are male biased, and these structures are found in the central part of the MPN (MPNc). The bed nucleus of the stria terminalis (BNST) also participates in male sexual behavior, and receives efferent neural projections from the MPNc. In this study, we examined if MPNc neurons projecting to the BNST are activated in male rats displaying sexual behavior. Fluoro-Gold (FG; a retrograde neural tracer) was injected into the BNST of male rats, which were separated into two groups: (1) those in contact with estrous female rats and displayed sexual behavior followed by ejaculation and (2) those without contact with estrous female rats. In both groups, protein expression of c-Fos (a neuronal activity marker) and calbindin (a location marker of the MPNc) were detected by fluorescent immunohistochemistry. The number of c-Fos-immunoreactive cells with or without FG labeling in the MPNc was also measured. The number of c-Fos-immunoreactive cells significantly increased following ejaculation. Approximately 10% of FG-labeled cells in ejaculation male rats were immunoreactive for c-Fos, and this percentage value was significantly higher in this group compared with control male rats. Overall, these results suggest that efferent projections from the MPNc to the BNST function to control sexual behavior in male rats.

  7. The questionnaire on autonomic regulation: a useful concept for integrative medicine?

    PubMed

    Kröz, Matthias; Reif, Marcus; Pranga, Danilo; Zerm, Roland; Schad, Friedemann; Baars, Erik Wim; Girke, Matthias

    2016-09-01

    The concept of autonomic regulation (aR) reflects the relevance of the function of different autonomic systems for health. aR can be captured by questionnaires. We differentiate between a trait or constitutional aR questionnaire version including 12 (short-version) or 18 items, respectively, with three subscales (orthostatic-circulatory, rest/activity and digestive regulation), and an 18-item state aR questionnaire on the preceding week with four subscales (rest/activity, orthostatic-circulatory, thermo- and digestive regulation). The validated questionnaires show satisfying to good reliability and robust validity with clear construct validity. In this article, we summarized the actually available literature on aR and the use of aR questionnaires in clinical and observational studies. We described the relationship of high aR with health and in case of low aR or loss of regulation with disease and functional disorder in the three (four) different subscales and functional systems, such as rest/activity, orthostatic-circulatory or digestive regulation (thermoregulation) with the consecutive therapeutic need. Finally, we gave perspectives of its further application in clinical research. PMID:27641604

  8. Acinus integrates AKT1 and subapoptotic caspase activities to regulate basal autophagy

    PubMed Central

    Nandi, Nilay; Tyra, Lauren K.; Stenesen, Drew

    2014-01-01

    How cellular stresses up-regulate autophagy is not fully understood. One potential regulator is the Drosophila melanogaster protein Acinus (Acn), which is necessary for autophagy induction and triggers excess autophagy when overexpressed. We show that cell type–specific regulation of Acn depends on proteolysis by the caspase Dcp-1. Basal Dcp-1 activity in developing photoreceptors is sufficient for this cleavage without a need for apoptosis to elevate caspase activity. On the other hand, Acn was stabilized by loss of Dcp-1 function or by the presence of a mutation in Acn that eliminates its conserved caspase cleavage site. Acn stability also was regulated by AKT1-mediated phosphorylation. Flies that expressed stabilized forms of Acn, either the phosphomimetic AcnS641,731D or the caspase-resistant AcnD527A, exhibited enhanced basal autophagy. Physiologically, these flies showed improvements in processes known to be autophagy dependent, including increased starvation resistance, reduced Huntingtin-induced neurodegeneration, and prolonged life span. These data indicate that AKT1 and caspase-dependent regulation of Acn stability adjusts basal autophagy levels. PMID:25332163

  9. Findings from Integrated Behavioral and Biologic Survey among Males Who Inject Drugs (MWID) — Vietnam, 2009–2010: Evidence of the Need for an Integrated Response to HIV, Hepatitis B Virus, and Hepatitis C Virus

    PubMed Central

    Nadol, Patrick; O’connor, Siobhan; Duong, Hao; Le, Linh-Vi N.; Thang, Pham Hong; Tram, Tran Hong; Ha, Hoang Thi Thanh; Mcconnell, Michelle S.; Partridge, Jeff; Kaldor, John; Law, Matthew; Nguyen, Tuan Anh

    2015-01-01

    Introduction Given the overlapping modes of transmission of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), understanding the burden and relationship of these infections is critical for an effective response. Representative data on these infections among males who inject drugs (MWID), the key high-risk population for HIV in Vietnam, are currently lacking. Methods Data and stored specimens from Vietnam’s 2009-2010 Integrated Biologic and Behavioral Survey, a cross-sectional study among high-risk populations, were used for this analysis. Plasma samples were tested for HIV, HBV, and HCV using commercial assays. A questionnaire was administered to provide demographic, behavior, and service-uptake information. Provincial-level analyses were conducted to profile MWID enrollees and to provide estimates on the prevalence of HIV, HBV, and HCV infection. Results Among 3010 MWID sampled across 10 provinces, the median (range) HIV prevalence was 28.1% (1.0%-55.5%). Median prevalence for current HBV infection (HBsAg+) was 14.1% (11.7%-28.0%), for previous exposure to HBV (total anti-HBc+) was 71.4% (49.9%-83.1%), and for current or past HCV infection (HCV Ag/Ab+) was 53.8% (10.9%-80.8%). In adjusted analysis, HBsAg+ (aOR: 2.09, 1.01-4.34) and HCV Ag/Ab+ (aOR: 19.58, 13.07-29.33) status were significantly associated with HIV infection; the association with total anti-HBc+ approached significance (aOR: 1.29, 0.99-1.68). Conclusion The prevalence and association between HIV, HBV, and HCV are high among MWID in Vietnam. These findings indicate the need for integrated policies and practice that for the surveillance, prevention, screening, and treatment of both HIV and viral hepatitis among MWID in Vietnam. PMID:25692469

  10. Sexual experience affects reproductive behavior and preoptic androgen receptors in male mice

    PubMed Central

    Swaney, William T.; Dubose, Brittany N.; Curley, James P.; Champagne, Frances A.

    2012-01-01

    Reproductive behavior in male rodents is made up of anticipatory and consummatory elements which are regulated in the brain by sensory systems, reward circuits and hormone signaling. Gonadal steroids play a key role in the regulation of male sexual behavior via steroid receptors in the hypothalamus and preoptic area. Typical patterns of male reproductive behavior have been characterized, however these are not fixed but are modulated by adult experience. We assessed the effects of repeated sexual experience on male reproductive behavior of C57BL/6 mice; including measures of olfactory investigation of females, mounting, intromission and ejaculation. The effects of sexual experience on the number of cells expressing either androgen receptor (AR) or estrogen receptor alpha (ERα) in the primary brain nuclei regulating male sexual behavior was also measured. Sexually experienced male mice engaged in less sniffing of females before initiating sexual behavior and exhibited shorter latencies to mount and intromit, increased frequency of intromission, and increased duration of intromission relative to mounting. No changes in numbers of ERα-positive cells were observed, however sexually experienced males had increased numbers of AR-positive cells in the medial preoptic area (MPOA); the primary regulatory nucleus for male sexual behavior. These results indicate that sexual experience results in a qualitative change in male reproductive behavior in mice that is associated with increased testosterone sensitivity in the MPOA and that this nucleus may play a key integrative role in mediating the effects of sexual experience on male behavior. PMID:22266118

  11. MEDIATOR25 acts as an integrative hub for the regulation of jasmonate-responsive gene expression in Arabidopsis.

    PubMed

    Çevik, Volkan; Kidd, Brendan N; Zhang, Peijun; Hill, Claire; Kiddle, Steve; Denby, Katherine J; Holub, Eric B; Cahill, David M; Manners, John M; Schenk, Peer M; Beynon, Jim; Kazan, Kemal

    2012-09-01

    The PHYTOCHROME AND FLOWERING TIME1 gene encoding the MEDIATOR25 (MED25) subunit of the eukaryotic Mediator complex is a positive regulator of jasmonate (JA)-responsive gene expression in Arabidopsis (Arabidopsis thaliana). Based on the function of the Mediator complex as a bridge between DNA-bound transcriptional activators and the RNA polymerase II complex, MED25 has been hypothesized to function in association with transcriptional regulators of the JA pathway. However, it is currently not known mechanistically how MED25 functions to regulate JA-responsive gene expression. In this study, we show that MED25 physically interacts with several key transcriptional regulators of the JA signaling pathway, including the APETALA2 (AP2)/ETHYLENE RESPONSE FACTOR (ERF) transcription factors OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59 and ERF1 as well as the master regulator MYC2. Physical interaction detected between MED25 and four group IX AP2/ERF transcription factors was shown to require the activator interaction domain of MED25 as well as the recently discovered Conserved Motif IX-1/EDLL transcription activation motif of MED25-interacting AP2/ERFs. Using transcriptional activation experiments, we also show that OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59- and ERF1-dependent activation of PLANT DEFENSIN1.2 as well as MYC2-dependent activation of VEGETATIVE STORAGE PROTEIN1 requires a functional MED25. In addition, MED25 is required for MYC2-dependent repression of pathogen defense genes. These results suggest an important role for MED25 as an integrative hub within the Mediator complex during the regulation of JA-associated gene expression. PMID:22822211

  12. Health and social care regulation in Wales: an integrated system of political, corporate and professional governance for improving public health.

    PubMed

    Jewell, Tony; Wilkinson, Jane

    2008-11-01

    Wales is developing a unique integrated system of governance to improve public health, which is diverging from some recent developments in the rest of the UK but shares many common features. There is a focus on strengthening collaborative working and co-ordination between bodies inspecting, regulating and auditing health and social care. Systems are being developed that are proportionate to the level of risk, eliminate unnecessary burdens of external review and support the improvement of services for patients, service users and carers. This is consistent with the Assembly Government's aim to improve the way that public services are delivered in Wales, including strengthening input from the public in the planning, delivery and reporting of regulation and inspection work. The test in the future will be how far we can demonstrate quantitatively and qualitatively the added value from our uniquely Welsh approach, built as it is on devolution and the aspirations for small-country governance. PMID:19058471

  13. Coregulation, dysregulation, self-regulation: an integrative analysis and empirical agenda for understanding adult attachment, separation, loss, and recovery.

    PubMed

    Sbarra, David A; Hazan, Cindy

    2008-05-01

    An integrative framework is proposed for understanding how multiple biological and psychological systems are regulated in the context of adult attachment relationships, dysregulated by separation and loss experiences, and, potentially, re-regulated through individual recovery efforts. Evidence is reviewed for a coregulatory model of normative attachment, defined as a pattern of interwoven physiology between romantic partners that results from the conditioning of biological reward systems and the emergence of felt security within adult pair bonds. The loss of coregulation can portend a state of biobehavioral dysregulation, ranging from diffuse psychophysiological arousal and disorganization to a full-blown (and highly organized) stress response. The major task for successful recovery is adopting a self-regulatory strategy that attenuates the dysregulating effects of the attachment disruption. Research evidence is reviewed across multiple levels of analysis, and the article concludes with a series of testable research questions on the interconnected nature of attachment, loss, and recovery processes.

  14. Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach

    PubMed Central

    Lee, Mark N; Roy, Matthew; Ong, Shao-En; Mertins, Philipp; Villani, Alexandra-Chloé; Li, Weibo; Dotiwala, Farokh; Sen, Jayita; Doench, John G; Orzalli, Megan H; Kramnik, Igor; Knipe, David M; Lieberman, Judy; Carr, Steven A; Hacohen, Nir

    2013-01-01

    The innate immune system senses viral DNA that enters mammalian cells, or in aberrant situations self-DNA, and triggers type I interferon production. Here we present an integrative approach that combines quantitative proteomics, genomics and small molecule perturbations to identify genes involved in this pathway. We silenced 809 candidate genes, measured the response to dsDNA and connected resulting hits with the known signaling network. We identified ABCF1 as a critical protein that associates with dsDNA and the DNA-sensing components HMGB2 and IFI204. We also found that CDC37 regulates the stability of the signaling molecule TBK1 and that chemical inhibition of the CDC37-HSP90 interaction and several other pathway regulators potently modulates the innate immune response to DNA and retroviral infection. PMID:23263557

  15. Designing adaptive integral sliding mode control for heart rate regulation during cycle-ergometer exercise using bio-feedback.

    PubMed

    Argha, Ahmadreza; Su, Steven W; Nguyen, Hung; Celler, Branko G

    2015-01-01

    This paper considers our developed control system which aims to regulate the exercising subjects' heart rate (HR) to a predefined profile. The controller would be an adaptive integral sliding mode controller. Here it is assumed that the controller commands are interpreted as biofeedback auditory commands. These commands can be heard and implemented by the exercising subject as a part of the control-loop. However, transmitting a feedback signal while the pedals are not in the appropriate position to efficiently exert force may lead to a cognitive disengagement of the user from the feedback controller. To address this problem this paper will employ a different form of control system regarding as "actuator-based event-driven control system". This paper will claim that the developed event-driven controller makes it possible to effectively regulate HR to a predetermined HR profile.

  16. Health and social care regulation in Wales: an integrated system of political, corporate and professional governance for improving public health.

    PubMed

    Jewell, Tony; Wilkinson, Jane

    2008-11-01

    Wales is developing a unique integrated system of governance to improve public health, which is diverging from some recent developments in the rest of the UK but shares many common features. There is a focus on strengthening collaborative working and co-ordination between bodies inspecting, regulating and auditing health and social care. Systems are being developed that are proportionate to the level of risk, eliminate unnecessary burdens of external review and support the improvement of services for patients, service users and carers. This is consistent with the Assembly Government's aim to improve the way that public services are delivered in Wales, including strengthening input from the public in the planning, delivery and reporting of regulation and inspection work. The test in the future will be how far we can demonstrate quantitatively and qualitatively the added value from our uniquely Welsh approach, built as it is on devolution and the aspirations for small-country governance.

  17. Rad54 is required for the normal development of male and female germ cells and contributes to the maintainance of their genome integrity after genotoxic stress

    PubMed Central

    Messiaen, S; Le Bras, A; Duquenne, C; Barroca, V; Moison, D; Déchamps, N; Doussau, M; Bauchet, A-L; Guerquin, M-J; Livera, G; Essers, J; Kanaar, R; Habert, R; Bernardino-Sgherri, J

    2013-01-01

    Rad54 is an important factor in the homologous recombination pathway of DNA double-strand break repair. However, Rad54 knockout (KO) mice do not exhibit overt phenotypes at adulthood, even when exposed to radiation. In this study, we show that in Rad54 KO mouse the germline is actually altered. Compared with the wild-type (WT) animals, these mice have less premeiotic germ cells. This germ cell loss is found as early as in E11.5 embryos, suggesting an early failure during mutant primordial germ cells development. Both testicular and ovarian KO germ cells exhibited high radiation sensitivity leading to a long-term gametogenesis defect at adulthood. The KO female germline was particularly affected displaying decreased litter size or sterility. Spermatogenesis recovery after irradiation was slower and incomplete in Rad54 KO mice compared with that of WT mice, suggesting that loss of germ stem cell precursors is not fully compensated along the successive rounds of spermatogenesis. Finally, spermatogenesis recovery after postnatal irradiation is in part regulated by glial-cell-line-derived neurotrophic factor (GDNF) in KO but not in irradiated WT mice, suggesting that Sertoli cell GDNF production is stimulated upon substantial germ cell loss only. Our findings suggest that Rad54 has a key function in maintaining genomic integrity of the developing germ cells. PMID:23949223

  18. Integrative analyses shed new light on human ribosomal protein gene regulation

    PubMed Central

    Li, Xin; Zheng, Yiyu; Hu, Haiyan; Li, Xiaoman

    2016-01-01

    Ribosomal protein genes (RPGs) are important house-keeping genes that are well-known for their coordinated expression. Previous studies on RPGs are largely limited to their promoter regions. Recent high-throughput studies provide an unprecedented opportunity to study how human RPGs are transcriptionally modulated and how such transcriptional regulation may contribute to the coordinate gene expression in various tissues and cell types. By analyzing the DNase I hypersensitive sites under 349 experimental conditions, we predicted 217 RPG regulatory regions in the human genome. More than 86.6% of these computationally predicted regulatory regions were partially corroborated by independent experimental measurements. Motif analyses on these predicted regulatory regions identified 31 DNA motifs, including 57.1% of experimentally validated motifs in literature that regulate RPGs. Interestingly, we observed that the majority of the predicted motifs were shared by the predicted distal and proximal regulatory regions of the same RPGs, a likely general mechanism for enhancer-promoter interactions. We also found that RPGs may be differently regulated in different cells, indicating that condition-specific RPG regulatory regions still need to be discovered and investigated. Our study advances the understanding of how RPGs are coordinately modulated, which sheds light to the general principles of gene transcriptional regulation in mammals. PMID:27346035

  19. Toward a Conceptual Model of Mentoring Research: Integration with Self-Regulated Learning

    ERIC Educational Resources Information Center

    Schunk, Dale H.; Mullen, Carol A.

    2013-01-01

    In this article, we present a model for academic mentoring research that incorporates theory and research on self-regulated learning. Academic mentoring research has increased in recent years, and researchers have linked mentoring with positive outcomes for protégés and mentors. This research, however, has not investigated the process whereby…

  20. Metacognition in Self-Regulated Multimedia Learning: Integrating Behavioural, Psychophysiological and Introspective Measures

    ERIC Educational Resources Information Center

    Antonietti, Alessandro; Colombo, Barbara; Di Nuzzo, Chiara

    2015-01-01

    This study aims at investigating students' strategies--as revealed by behavioural, psychophysiological and introspective measures--which are applied during the free exploration of multimedia instructional presentations, which requires students to self-regulate their learning processes. Two multimedia presentations were constructed and presented to…

  1. Achievement Goal Orientations and Self-Regulation in Writing: An Integrative Perspective

    ERIC Educational Resources Information Center

    Kaplan, Avi; Lichtinger, Einat; Gorodetsky, Malka

    2009-01-01

    This study tested the hypothesis that self-regulation of writing is a multifaceted modular construct and that students would perceive different goal orientations for writing as involving the application of different writing strategies. Two hundred eleven Jewish Israeli high school students engaged in a writing assignment and then reported on their…

  2. 77 FR 1640 - Federal Acquisition Regulation; Public Access to the Federal Awardee Performance and Integrity...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... Information System; Correction AGENCY: Department of Defense (DoD), General Services Administration (GSA), and... Performance and Integrity Information System (FAPIIS), excluding past performance reviews, shall be made... correction to the final rule that was published in the Federal Register at 77 FR 197 on January 3, 2012....

  3. 77 FR 197 - Federal Acquisition Regulation; Public Access to the Federal Awardee Performance and Integrity...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-03

    ... will soon be able to evaluate the business ethics and quality of potential contractor clients.... Background DoD, GSA, and NASA published an interim rule in the Federal Register at 76 FR 4188 on January 24... public the data in FAPIIS will benefit contractors with records of business integrity and...

  4. 75 FR 14059 - Federal Acquisition Regulation; FAR Case 2008-027, Federal Awardee Performance and Integrity...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-23

    ... ability to evaluate the business ethics and expected performance quality of prospective contractors and... designed to significantly enhance the Government's ability to evaluate the business ethics and quality of... satisfactory record of integrity and business ethics, or comparable information relating to a grant....

  5. 77 FR 54843 - Integrated Mortgage Disclosures Under the Real Estate Settlement Procedure Act (Regulation X) and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-06

    ... August 23, 2012. See 77 FR 51116 (Aug. 23, 2012). Comments on the integrated rules and forms are due... period for the proposed amendments to 12 CFR 1026.4 contained in the Bureau's notice at 77 FR 51116 (Aug...)) and proposed changes to the definition of the finance charge (in proposed Sec. 1026.4). \\1\\ 77...

  6. 7 CFR 4290.1940 - Integration of this part with other regulations applicable to USDA's programs.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Agriculture (Continued) RURAL BUSINESS-COOPERATIVE SERVICE AND RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE RURAL BUSINESS INVESTMENT COMPANY (âRBICâ) PROGRAM Miscellaneous § 4290.1940 Integration of this... applicable to this part, the Secretary will comply with subpart V of 7 CFR part 3015,...

  7. The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration

    NASA Astrophysics Data System (ADS)

    Choudhury, Rajarshi; Roy, Sreerupa Ghose; Tsai, Yihsuan S.; Tripathy, Ashutosh; Graves, Lee M.; Wang, Zefeng

    2014-01-01

    Alternative splicing of pre-messenger RNA (mRNA) is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA-binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The carboxy-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk (extracellular signal-regulated protein kinase) pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq, we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk-regulated cell proliferation.

  8. TLR4 down-regulation identifies high risk HPV infection and integration in head and neck squamous cell carcinomas.

    PubMed

    Pannone, Giuseppe; Bufo, Pantaleo; Pace, Mirella; Lepore, Silvia; Russo, Giuseppe M; Rubini, Corrado; Franco, Renato; Aquino, Gabriella; Santoro, Angela; Campisi, Giuseppina; Rodolico, Vito; Bucci, Eduardo; Ilardi, Gennaro; Mascolo, Massimo; Merolla, Francesco; Lo Muzio, Lorenzo; Natalicchio, Iole; Colella, Giuseppe; Laurenzana, Ilaria; Trino, Stefania; Leonardi, Rosalia; Bucci, Paolo

    2016-01-01

    TLRs are main actors of the innate immune response against HPV. There are very few studies on the role of TLRs mediated HPV clearance in Head and Neck oncology. Our aim was to evaluate whether TLR4 expression identifies HPV infection and/or HR-HPV integration status in oral and oropharyngeal cancers. By immunohistochemistry we assessed TLR4 levels in OSCC/OPSCC. To detect viral integration or episomic status In situ hybridization for HPV-DNA and Pyro-sequencing techniques have been performed. The relationship between TLR4 expression with HPV infection status has been investigated. ISH HPV positive samples have reported lower levels of TLR4 intensity than negative samples (p = .002). There was no statistical correlation between TLR4 intensity and PCR HPV results (p more than 0.0.5). Point-biserial correlation coefficient revealed significant association between TLR4 expression and HR-HPV integration status (p = .0001) and between TLR4 expression index and HR-HPV infection (p = .001). These data have shown that TLR4 down-regulation is strongly associated to both HPV-16 infection and its integration into the host DNA. PMID:26709642

  9. Integration of genetic, genomic and transcriptomic information identifies putative regulators of adventitious root formation in Populus

    DOE PAGES

    Ribeiro, Cintia L.; Silva, Cynthia M.; Drost, Derek R.; Novaes, Evandro; Novaes, Carolina R. D. B.; Dervinis, Christopher; Kirst, Matias

    2016-03-16

    In this study, adventitious roots (AR) develop from tissues other than the primary root, in a process physiologically regulated by phytohormones. Adventitious roots provide structural support and contribute to water and nutrient absorption, and are critical for commercial vegetative propagation of several crops. Here we quantified the number of AR, root architectural traits and root biomass in cuttings from a pseudo-backcross population of Populus deltoides and Populus trichocarpa. Quantitative trait loci (QTL) mapping and whole-transcriptome analysis of individuals with alternative QTL alleles for AR number were used to identify putative regulators of AR development. As a result, parental individuals andmore » progeny showed extensive segregation for AR developmental traits. Quantitative trait loci for number of AR mapped consistently in the same interval of linkage group (LG) II and LG XIV, explaining 7–10 % of the phenotypic variation. A time series transcriptome analysis identified 26,121 genes differentially expressed during AR development, particularly during the first 24 h after cuttings were harvested. Of those, 1929 genes were differentially regulated between individuals carrying alternative alleles for the two QTL for number of AR, in one or more time point. Eighty-one of these genes were physically located within the QTL intervals for number of AR, including putative homologs of the Arabidopsis genes SUPERROOT2 (SUR2) and TRYPTOPHAN SYNTHASE ALPHA CHAIN (TSA1), both of which are involved in the auxin indole-3-acetic acid (IAA) biosynthesis pathway. In conclusion, this study suggests the involvement of two genes of the tryptophan-dependent auxin biosynthesis pathway, SUR2 and TSA1, in the regulation of a critical trait for the clonal propagation of woody species. A possible model for this regulation is that poplar individuals that have poor AR formation synthesize auxin indole-3-acetic acid (IAA) primarily through the tryptophan (Trp) pathway. Much of

  10. Early ethanol and water intake: choice mechanism and total fluid regulation operate in parallel in male alcohol preferring (P) and both Wistar and Sprague Dawley rats.

    PubMed

    Azarov, Alexey V; Woodward, Donald J

    2014-01-17

    The goal of this study was to clarify similar and distinctly different parameters of fluid intake during early phases of ethanol and water choice drinking in alcohol preferring P-rat vs. non-selected Wistar and Sprague Dawley (SD) rats. Precision information on the drinking amounts and timing is needed to analyze micro-behavioral components of the acquisition of ethanol intake and to enable a search for its causal activity patterns within individual CNS circuits. The experiment followed the standard ethanol-drinking test used in P-rat selective breeding, with access to water, then 10% ethanol (10E) as sole fluids, and next to ethanol/water choice. The novelty of the present approach was to eliminate confounding prandial elevations of fluid intake, by time-separating daily food from fluid access. P-rat higher initial intakes of water and 10E as sole fluids suggest adaptations to ethanol-induced dehydration in P vs. Wistar and SD rats. P-rat starting and overall ethanol intake during the choice period were the highest. The absolute extent of ethanol intake elevation during choice period was greatest in Wistar and their final intake levels approached those of P-rat, contrary to the hypothesis that selection would produce the strongest elevation of ethanol intake. The total daily fluid during ethanol/water choice period was strikingly similar between P, Wistar and SD rats. This supports the hypothesis for a universal system that gauges the overall intake volume by titrating and integrating ethanol and water drinking fluctuations, and indicates a stable daily level of total fluid as a main regulated parameter of fluid intake across the three lines in choice conditions. The present findings indicate that a stable daily level of total fluid comprises an independent physiological limit for daily ethanol intake. Ethanol drinking, in turn, stays under the ceiling of this limit, driven by a parallel mechanism of ethanol/water choice.

  11. [The Integration and Regulation of Hormone-Sensitive Lipase in Reproductive System].

    PubMed

    Wang, Wei-yi; Xu, Guo-Heng

    2015-02-01

    Hormone-sensitive lipase (HSL) has long been considered as a classical rate-limiting enzyme during lipolysis since it was first described in 1960s. HSL is regulated mainly by catecholamine, including adrenalin. Studies in recent years indicated that the substrates for HSL are not only triglycerides, but also diacylglycerol with the catalytic activity is ten times that of triglycerides, glycerol esters and cholesterol esters, which overthrow the opinion that HSL is specific to triglyceride. The scientists have generated HSL gene knockout mice and confirmed HSL is widely located in the reproductive system, which indicates that HSL may play an important role in the regulation of physiological and pathophysiological process in the reproductive system. Here, we will focus on the features of the HSL gene, mRNA and its protein, and summarize the HSL functions in the reproductive system.

  12. Metal interaction with redox regulation: an integrating concept in metal carcinogenesis?

    PubMed

    Hartwig, Andrea

    2013-02-01

    The carcinogenicity of cadmium, arsenic, and chromium(VI) compounds has been recognized for some decades. However, the underlying molecular mechanisms seem to be complex and are not completely understood at present. Although, with the exception of chromium(VI), direct DNA damage seems to be of minor importance, interactions with DNA repair processes, tumor suppressor functions, and signal transduction pathways have been described in diverse biological systems. In addition to the induction of damage to cellular macromolecules by reactive oxygen species, the interference with cellular redox regulation by reaction with redox-sensitive protein domains or amino acids may provide one plausible mechanism involved in metal carcinogenicity. Consequences are the distortion of zinc-binding structures and the activation or inactivation of redox-regulated signal transduction pathways, provoking metal-induced genomic instability. Nevertheless, the relevance of the respective mechanisms depends on the actual metal or metal species under consideration and more research is needed to further strengthen this hypothesis.

  13. Control and Regulation of Integrated Mitochondrial Function in Metabolic and Transport Networks

    PubMed Central

    Cortassa, Sonia; O’Rourke, Brian; Winslow, Raimond L.; Aon, Miguel A.

    2009-01-01

    The pattern of flux and concentration control coefficients in an integrated mitochondrial energetics model is examined by applying a generalized matrix method of control analysis to calculate control coefficients, as well as response coefficients The computational model of Cortassa et al. encompasses oxidative phosphorylation, the TCA cycle, and Ca2+ dynamics. Control of ATP synthesis, TCA cycle, and ANT fluxes were found to be distributed among various mitochondrial processes. Control is shared by processes associated with ATP/ADP production and transport, as well as by Ca2+ dynamics. The calculation also analyzed the control of the concentrations of key regulatory ions and metabolites (Ca2+, NADH, ADP). The approach we have used demonstrates how properties of integrated systems may be understood through applications of computational modeling and control analysis. PMID:19468321

  14. Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass

    PubMed Central

    Davey, Jonathan R.; Watt, Kevin I.; Parker, Benjamin L.; Chaudhuri, Rima; Ryall, James G.; Cunningham, Louise; Qian, Hongwei; Sartorelli, Vittorio; Chamberlain, Jeffrey; James, David E.

    2016-01-01

    The transforming growth factor-β (TGF-β) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that follistatin-based interventions (which modulate TGF-β network activity) can promote muscle hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by follistatin exposure, which included repression of ankyrin repeat and SOCS box protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating that Asb2 is a TGF-β network–responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished follistatin-induced muscle hypertrophy. These findings provide insight into the program of transcription and translation events governing follistatin-mediated adaptation of skeletal muscle attributes and identify Asb2 as a regulator of muscle mass implicated in the potential mechanistic dysfunction between follistatin-mediated muscle growth in young and old muscles. PMID:27182554

  15. Grassland species differentially regulate proline concentrations under future climate conditions: an integrated biochemical and modelling approach.

    PubMed

    AbdElgawad, Hamada; De Vos, Dirk; Zinta, Gaurav; Domagalska, Malgorzata A; Beemster, Gerrit T S; Asard, Han

    2015-10-01

    Proline (Pro) is a versatile metabolite playing a role in the protection of plants against environmental stresses. To gain a deeper understanding of the regulation of Pro metabolism under predicted future climate conditions, including drought stress, elevated temperature and CO2 , we combined measurements in contrasting grassland species (two grasses and two legumes) at multiple organisational levels, that is, metabolite concentrations, enzyme activities and gene expression. Drought stress (D) activates Pro biosynthesis and represses its catabolism, and elevated temperature (DT) further elevated its content. Elevated CO2 attenuated the DT effect on Pro accumulation. Computational pathway control analysis allowed a mechanistic understanding of the regulatory changes in Pro metabolism. This analysis indicates that the experimentally observed coregulation of multiple enzymes is more effective in modulating Pro concentrations than regulation of a single step. Pyrroline-5-carboxylate synthetase (P5CS) and pyrroline-5-carboxylate reductase (P5CR) play a central role in grasses (Lolium perenne, Poa pratensis), and arginase (ARG), ornithine aminotransferase (OAT) and P5CR play a central role in legumes (Medicago lupulina, Lotus corniculatus). Different strategies in the regulation of Pro concentrations under stress conditions were observed. In grasses the glutamate pathway is activated predominantly, and in the legumes the ornithine pathway, possibly related to differences in N-nutritional status. PMID:26037253

  16. Grassland species differentially regulate proline concentrations under future climate conditions: an integrated biochemical and modelling approach.

    PubMed

    AbdElgawad, Hamada; De Vos, Dirk; Zinta, Gaurav; Domagalska, Malgorzata A; Beemster, Gerrit T S; Asard, Han

    2015-10-01

    Proline (Pro) is a versatile metabolite playing a role in the protection of plants against environmental stresses. To gain a deeper understanding of the regulation of Pro metabolism under predicted future climate conditions, including drought stress, elevated temperature and CO2 , we combined measurements in contrasting grassland species (two grasses and two legumes) at multiple organisational levels, that is, metabolite concentrations, enzyme activities and gene expression. Drought stress (D) activates Pro biosynthesis and represses its catabolism, and elevated temperature (DT) further elevated its content. Elevated CO2 attenuated the DT effect on Pro accumulation. Computational pathway control analysis allowed a mechanistic understanding of the regulatory changes in Pro metabolism. This analysis indicates that the experimentally observed coregulation of multiple enzymes is more effective in modulating Pro concentrations than regulation of a single step. Pyrroline-5-carboxylate synthetase (P5CS) and pyrroline-5-carboxylate reductase (P5CR) play a central role in grasses (Lolium perenne, Poa pratensis), and arginase (ARG), ornithine aminotransferase (OAT) and P5CR play a central role in legumes (Medicago lupulina, Lotus corniculatus). Different strategies in the regulation of Pro concentrations under stress conditions were observed. In grasses the glutamate pathway is activated predominantly, and in the legumes the ornithine pathway, possibly related to differences in N-nutritional status.

  17. The role of sugars in integrating environmental signals during the regulation of leaf senescence.

    PubMed

    Wingler, Astrid; Purdy, Sarah; MacLean, Jamie A; Pourtau, Nathalie

    2006-01-01

    Although leaf senescence results in a loss of photosynthetic carbon fixation, the senescence-dependent release of nutrients, especially of nitrogen, is important for the growth of young leaves and for reproduction. Environmental regulation of senescence is therefore a vital factor in the carbon and nitrogen economy of plants. Leaf senescence is a highly plastic trait that is affected by a range of different environmental factors including light, nutrient supply, CO2 concentration, and abiotic and biotic stress. In this review, the focus is on the impact of environmental conditions on sugar accumulation and sugar signalling during senescence. By signalling a high availability of carbon relative to nitrogen in the old leaves, sugar accumulation can trigger leaf senescence. Sugar-induced senescence is therefore particularly important under low nitrogen availability and may also play a role in light signalling. Whether or not sugars are involved in regulating the senescence response of plants to elevated CO2 remains unresolved. Senescence can be delayed or accelerated in elevated CO2 and no clear relationship between sugar accumulation and senescence has been found. Plasticity in the response to environmental factors, such as daylength and sugar accumulation, varies between different Arabidopsis accessions. This natural variation can be exploited to analyse the genetic basis of the regulation of senescence and the consequences for growth and fecundity. Different evolutionary strategies, i.e. early senescence combined with a high reproductive effort or late senescence combined with a low reproductive effort, may be an important adaptation of Arabidopsis accessions to their natural habitat.

  18. Melatonin and male reproduction.

    PubMed

    Li, Chunjin; Zhou, Xu

    2015-06-15

    Melatonin is a neurohormone secreted by the pineal gland whose concentrations in the body are regulated by both the dark-light and seasonal cycles. The reproductive function of seasonal breeding animals is clearly influenced by the circadian variation in melatonin levels. Moreover, a growing body of evidence indicates that melatonin has important effects in the reproduction of some non-seasonal breeding animals. In males, melatonin affects reproductive regulation in three main ways. First, it regulates the secretion of two key neurohormones, GnRH and LH. Second, it regulates testosterone synthesis and testicular maturation. Third, as a potent free radical scavenger that is both lipophilic and hydrophilic, it prevents testicular damage caused by environmental toxins or inflammation. This review summarizes the existing data on the possible biological roles of melatonin in male reproduction. Overall, the literature data indicate that melatonin affects the secretion of both gonadotropins and testosterone while also improving sperm quality. This implies that it has important effects on the regulation of testicular development and male reproduction.

  19. Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity.

    PubMed

    Chen, Chieh V; Brummet, Jennifer L; Jordan, Cynthia L; Breedlove, S Marc

    2016-02-01

    We previously found that androgen receptor (AR) activity mediates two effects of T in adult male mice: reduction of anxiety-like behaviors and dampening of the hypothalamic-pituitary-adrenal response to stress. To determine whether brain ARs mediate these effects, we used the Cre/loxP technology seeking to disable AR throughout the central nervous system (CNS). Female mice carrying the floxed AR allele (ARlox) were crossed with males carrying cre recombinase transgene controlled by the nestin promoter (NesCre), producing cre in developing neurons and glia. Among male offspring, four genotypes resulted: males carrying ARlox and NesCre (NesARko), and three control groups (wild types, NesCre, and ARlox). Reporter mice indicated ubiquitous Cre expression throughout the CNS. Nevertheless, AR immunocytochemistry in NesARko mice revealed efficient knockout (KO) of AR in some brain regions (hippocampus and medial prefrontal cortex [mPFC]), but not others. Substantial AR protein was seen in the amygdala and hypothalamus among other regions, whereas negligible AR remained in others like the bed nucleus of the stria terminalis and dorsal periaqueductal gray. This selective KO allowed for testing the role of AR in hippocampus and mPFC. Males were castrated and implanted with T at postnatal day 60 before testing on postnatal day 90-100. In contrast with males with global KO of AR, T still modulated anxiety-related behavior and hypothalamic-pituitary-adrenal activity in NesARko males. These results leave open the possibility that AR acting in the CNS mediates these effects of T, but demonstrate that AR is not required in the hippocampus or mPFC for T's anxiolytic effects.

  20. Integrating bioinformatic resources to predict transcription factors interacting with cis-sequences conserved in co-regulated genes

    PubMed Central

    2014-01-01

    Background Using motif detection programs it is fairly straightforward to identify conserved cis-sequences in promoters of co-regulated genes. In contrast, the identification of the transcription factors (TFs) interacting with these cis-sequences is much more elaborate. To facilitate this, we explore the possibility of using several bioinformatic and experimental approaches for TF identification. This starts with the selection of co-regulated gene sets and leads first to the prediction and then to the experimental validation of TFs interacting with cis-sequences conserved in the promoters of these co-regulated genes. Results Using the PathoPlant database, 32 up-regulated gene groups were identified with microarray data for drought-responsive gene expression from Arabidopsis thaliana. Application of the binding site estimation suite of tools (BEST) discovered 179 conserved sequence motifs within the corresponding promoters. Using the STAMP web-server, 49 sequence motifs were classified into 7 motif families for which similarities with known cis-regulatory sequences were identified. All motifs were subjected to a footprintDB analysis to predict interacting DNA binding domains from plant TF families. Predictions were confirmed by using a yeast-one-hybrid approach to select interacting TFs belonging to the predicted TF families. TF-DNA interactions were further experimentally validated in yeast and with a Physcomitrella patens transient expression system, leading to the discovery of several novel TF-DNA interactions. Conclusions The present work demonstrates the successful integration of several bioinformatic resources with experimental approaches to predict and validate TFs interacting with conserved sequence motifs in co-regulated genes. PMID:24773781

  1. RegulonDB version 9.0: high-level integration of gene regulation, coexpression, motif clustering and beyond.

    PubMed

    Gama-Castro, Socorro; Salgado, Heladia; Santos-Zavaleta, Alberto; Ledezma-Tejeida, Daniela; Muñiz-Rascado, Luis; García-Sotelo, Jair Santiago; Alquicira-Hernández, Kevin; Martínez-Flores, Irma; Pannier, Lucia; Castro-Mondragón, Jaime Abraham; Medina-Rivera, Alejandra; Solano-Lira, Hilda; Bonavides-Martínez, César; Pérez-Rueda, Ernesto; Alquicira-Hernández, Shirley; Porrón-Sotelo, Liliana; López-Fuentes, Alejandra; Hernández-Koutoucheva, Anastasia; Del Moral-Chávez, Víctor; Rinaldi, Fabio; Collado-Vides, Julio

    2016-01-01

    RegulonDB (http://regulondb.ccg.unam.mx) is one of the most useful and important resources on bacterial gene regulation,as it integrates the scattered scientific knowledge of the best-characterized organism, Escherichia coli K-12, in a database that organizes large amounts of data. Its electronic format enables researchers to compare their results with the legacy of previous knowledge and supports bioinformatics tools and model building. Here, we summarize our progress with RegulonDB since our last Nucleic Acids Research publication describing RegulonDB, in 2013. In addition to maintaining curation up-to-date, we report a collection of 232 interactions with small RNAs affecting 192 genes, and the complete repertoire of 189 Elementary Genetic Sensory-Response units (GENSOR units), integrating the signal, regulatory interactions, and metabolic pathways they govern. These additions represent major progress to a higher level of understanding of regulated processes. We have updated the computationally predicted transcription factors, which total 304 (184 with experimental evidence and 120 from computational predictions); we updated our position-weight matrices and have included tools for clustering them in evolutionary families. We describe our semiautomatic strategy to accelerate curation, including datasets from high-throughput experiments, a novel coexpression distance to search for 'neighborhood' genes to known operons and regulons, and computational developments. PMID:26527724

  2. N-hypermannose glycosylation disruption enhances recombinant protein production by regulating secretory pathway and cell wall integrity in Saccharomyces cerevisiae.

    PubMed

    Tang, Hongting; Wang, Shenghuan; Wang, Jiajing; Song, Meihui; Xu, Mengyang; Zhang, Mengying; Shen, Yu; Hou, Jin; Bao, Xiaoming

    2016-01-01

    Saccharomyces cerevisiae is a robust host for heterologous protein expression. The efficient expression of cellulases in S. cerevisiae is important for the consolidated bioprocess that directly converts lignocellulose into valuable products. However, heterologous proteins are often N-hyperglycosylated in S. cerevisiae, which may affect protein activity. In this study, the expression of three heterologous proteins, β-glucosidase, endoglucanase and cellobiohydrolase, was found to be N-hyperglycosylated in S. cerevisiae. To block the formation of hypermannose glycan, these proteins were expressed in strains with deletions in key Golgi mannosyltransferases (Och1p, Mnn9p and Mnn1p), respectively. Their extracellular activities improved markedly in the OCH1 and MNN9 deletion strains. Interestingly, truncation of the N-hypermannose glycan did not increase the specific activity of these proteins, but improved the secretion yield. Further analysis showed OCH1 and MNN9 deletion up-regulated genes in the secretory pathway, such as protein folding and vesicular trafficking, but did not induce the unfolded protein response. The cell wall integrity was also affected by OCH1 and MNN9 deletion, which contributed to the release of secretory protein extracellularly. This study demonstrated that mannosyltransferases disruption improved protein secretion through up-regulating secretory pathway and affecting cell wall integrity and provided new insights into glycosylation engineering for protein secretion. PMID:27156860

  3. N-hypermannose glycosylation disruption enhances recombinant protein production by regulating secretory pathway and cell wall integrity in Saccharomyces cerevisiae

    PubMed Central

    Tang, Hongting; Wang, Shenghuan; Wang, Jiajing; Song, Meihui; Xu, Mengyang; Zhang, Mengying; Shen, Yu; Hou, Jin; Bao, Xiaoming

    2016-01-01

    Saccharomyces cerevisiae is a robust host for heterologous protein expression. The efficient expression of cellulases in S. cerevisiae is important for the consolidated bioprocess that directly converts lignocellulose into valuable products. However, heterologous proteins are often N-hyperglycosylated in S. cerevisiae, which may affect protein activity. In this study, the expression of three heterologous proteins, β-glucosidase, endoglucanase and cellobiohydrolase, was found to be N-hyperglycosylated in S. cerevisiae. To block the formation of hypermannose glycan, these proteins were expressed in strains with deletions in key Golgi mannosyltransferases (Och1p, Mnn9p and Mnn1p), respectively. Their extracellular activities improved markedly in the OCH1 and MNN9 deletion strains. Interestingly, truncation of the N-hypermannose glycan did not increase the specific activity of these proteins, but improved the secretion yield. Further analysis showed OCH1 and MNN9 deletion up-regulated genes in the secretory pathway, such as protein folding and vesicular trafficking, but did not induce the unfolded protein response. The cell wall integrity was also affected by OCH1 and MNN9 deletion, which contributed to the release of secretory protein extracellularly. This study demonstrated that mannosyltransferases disruption improved protein secretion through up-regulating secretory pathway and affecting cell wall integrity and provided new insights into glycosylation engineering for protein secretion. PMID:27156860

  4. RegulonDB version 9.0: high-level integration of gene regulation, coexpression, motif clustering and beyond

    PubMed Central

    Gama-Castro, Socorro; Salgado, Heladia; Santos-Zavaleta, Alberto; Ledezma-Tejeida, Daniela; Muñiz-Rascado, Luis; García-Sotelo, Jair Santiago; Alquicira-Hernández, Kevin; Martínez-Flores, Irma; Pannier, Lucia; Castro-Mondragón, Jaime Abraham; Medina-Rivera, Alejandra; Solano-Lira, Hilda; Bonavides-Martínez, César; Pérez-Rueda, Ernesto; Alquicira-Hernández, Shirley; Porrón-Sotelo, Liliana; López-Fuentes, Alejandra; Hernández-Koutoucheva, Anastasia; Moral-Chávez, Víctor Del; Rinaldi, Fabio; Collado-Vides, Julio

    2016-01-01

    RegulonDB (http://regulondb.ccg.unam.mx) is one of the most useful and important resources on bacterial gene regulation,as it integrates the scattered scientific knowledge of the best-characterized organism, Escherichia coli K-12, in a database that organizes large amounts of data. Its electronic format enables researchers to compare their results with the legacy of previous knowledge and supports bioinformatics tools and model building. Here, we summarize our progress with RegulonDB since our last Nucleic Acids Research publication describing RegulonDB, in 2013. In addition to maintaining curation up-to-date, we report a collection of 232 interactions with small RNAs affecting 192 genes, and the complete repertoire of 189 Elementary Genetic Sensory-Response units (GENSOR units), integrating the signal, regulatory interactions, and metabolic pathways they govern. These additions represent major progress to a higher level of understanding of regulated processes. We have updated the computationally predicted transcription factors, which total 304 (184 with experimental evidence and 120 from computational predictions); we updated our position-weight matrices and have included tools for clustering them in evolutionary families. We describe our semiautomatic strategy to accelerate curation, including datasets from high-throughput experiments, a novel coexpression distance to search for ‘neighborhood’ genes to known operons and regulons, and computational developments. PMID:26527724

  5. RegulonDB version 9.0: high-level integration of gene regulation, coexpression, motif clustering and beyond.

    PubMed

    Gama-Castro, Socorro; Salgado, Heladia; Santos-Zavaleta, Alberto; Ledezma-Tejeida, Daniela; Muñiz-Rascado, Luis; García-Sotelo, Jair Santiago; Alquicira-Hernández, Kevin; Martínez-Flores, Irma; Pannier, Lucia; Castro-Mondragón, Jaime Abraham; Medina-Rivera, Alejandra; Solano-Lira, Hilda; Bonavides-Martínez, César; Pérez-Rueda, Ernesto; Alquicira-Hernández, Shirley; Porrón-Sotelo, Liliana; López-Fuentes, Alejandra; Hernández-Koutoucheva, Anastasia; Del Moral-Chávez, Víctor; Rinaldi, Fabio; Collado-Vides, Julio

    2016-01-01

    RegulonDB (http://regulondb.ccg.unam.mx) is one of the most useful and important resources on bacterial gene regulation,as it integrates the scattered scientific knowledge of the best-characterized organism, Escherichia coli K-12, in a database that organizes large amounts of data. Its electronic format enables researchers to compare their results with the legacy of previous knowledge and supports bioinformatics tools and model building. Here, we summarize our progress with RegulonDB since our last Nucleic Acids Research publication describing RegulonDB, in 2013. In addition to maintaining curation up-to-date, we report a collection of 232 interactions with small RNAs affecting 192 genes, and the complete repertoire of 189 Elementary Genetic Sensory-Response units (GENSOR units), integrating the signal, regulatory interactions, and metabolic pathways they govern. These additions represent major progress to a higher level of understanding of regulated processes. We have updated the computationally predicted transcription factors, which total 304 (184 with experimental evidence and 120 from computational predictions); we updated our position-weight matrices and have included tools for clustering them in evolutionary families. We describe our semiautomatic strategy to accelerate curation, including datasets from high-throughput experiments, a novel coexpression distance to search for 'neighborhood' genes to known operons and regulons, and computational developments.

  6. Pedagogical Work, Stress Regulation and Work-Related Well-Being among Early Childhood Professionals in Integrated Special Day-Care Groups

    ERIC Educational Resources Information Center

    Nislin, Mari A.; Sajaniemi, Nina K.; Sims, Margaret; Suhonen, Eira; Maldonado Montero, Enrique F.; Hirvonen, Ari; Hyttinen, Sirpa

    2016-01-01

    The aim of this study was to investigate the relationship between early childhood professionals' (ECPs) stress regulation (using salivary cortisol and alpha-amylase [AA] measurements), work engagement and the quality of their pedagogical work in integrated special day-care groups. Participants were 89 ECPs from 21 integrated special day-care…

  7. Hepatic CYP1A, 2B, 2C, 2E and 3A regulation by methoxychlor in male and female rats.

    PubMed

    Oropeza-Hernández, Luis F; López-Romero, Ricardo; Albores, Arnulfo

    2003-09-15

    The effect on liver cytochrome P450 (CYP) by i.p. injections of methoxychlor (MXC) in corn oil at 0, 100, 150, 200 or 250 mg/kg twice daily for 3 days was investigated in adult male and female Wistar rats. The MXC injection (100 mg/kg b.w.) caused a similar increase of total CYP content in males and females as compared with controls who received the vehicle only. In males, this increase continued up to 250 mg/kg. As to the induction of specific CYP activities, the effect of MXC was found to be sex dependent with three different patterns. Males showed the greatest increases of ethoxy- and methoxyresorufin-O-dealkylase (EROD and MROD, respectively), two CYP1A1/1A2-related activities. On the contrary, females were more responsive than males for pentoxyresorufin-O-dealkylase (PROD) and benzyloxyresorufin-O-dearylase (BROD), two CYP2B-related activities. Finally, p-nitrophenol hydroxylase (PNPH), a CYP2E1-related activity, showed a similar small, although statistically significant, increase for both sexes. As to CYP apoprotein levels, CYP1A1 and CYP2B1/2B2 showed greater increases in females than in males; whereas, interestingly, CYP2E1 induction was higher in males than in females. These results indicate overall that gender modulates CYP expression after MXC injection both qualitatively and quantitatively, and, therefore, this pesticide is not a pure PB inducer. Moreover, the statistically significant increase of CYP3A2 apoprotein expression observed in females and also, to a lower extent, in males, and the decrease of CYP2C11 apoprotein found in males, two sex-related enzymes, may explain the reported endocrine disrupting effect of MXC. The relevance of the different patterns of rat liver CYP induction observed after MXC treatment, in relationship to the speculated endocrine disrupting potential of MXC in humans potentially exposed to this pesticide, needs further investigation.

  8. Integrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network.

    PubMed

    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-02-01

    Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.

  9. Arabidopsis plastid AMOS1/EGY1 integrates abscisic acid signaling to regulate global gene expression response to ammonium stress.

    PubMed

    Li, Baohai; Li, Qing; Xiong, Liming; Kronzucker, Herbert J; Krämer, Ute; Shi, Weiming

    2012-12-01

    Ammonium (NH(4)(+)) is a ubiquitous intermediate of nitrogen metabolism but is notorious for its toxic effects on most organisms. Extensive studies of the underlying mechanisms of NH(4)(+) toxicity have been reported in plants, but it is poorly understood how plants acclimate to high levels of NH(4)(+). Here, we identified an Arabidopsis (Arabidopsis thaliana) mutant, ammonium overly sensitive1 (amos1), that displays severe chlorosis under NH(4)(+) stress. Map-based cloning shows amos1 to carry a mutation in EGY1 (for ethylene-dependent, gravitropism-deficient, and yellow-green-like protein1), which encodes a plastid metalloprotease. Transcriptomic analysis reveals that among the genes activated in response to NH(4)(+), 90% are regulated dependent on AMOS1/EGY1. Furthermore, 63% of AMOS1/EGY1-dependent NH(4)(+)-activated genes contain an ACGTG motif in their promoter region, a core motif of abscisic acid (ABA)-responsive elements. Consistent with this, our physiological, pharmacological, transcriptomic, and genetic data show that ABA signaling is a critical, but not the sole, downstream component of the AMOS1/EGY1-dependent pathway that regulates the expression of NH(4)(+)-responsive genes and maintains chloroplast functionality under NH(4)(+) stress. Importantly, abi4 mutants defective in ABA-dependent and retrograde signaling, but not ABA-deficient mutants, mimic leaf NH(4)(+) hypersensitivity of amos1. In summary, our findings suggest that an NH(4)(+)-responsive plastid retrograde pathway, which depends on AMOS1/EGY1 function and integrates with ABA signaling, is required for the regulation of expression of NH(4)(+)-responsive genes that maintain chloroplast integrity in the presence of high NH(4)(+) levels. PMID:23064408

  10. Integrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network

    PubMed Central

    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-01-01

    Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions. PMID:24198249

  11. Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program

    PubMed Central

    Miyagawa, Shinichi; Moon, Anne; Haraguchi, Ryuma; Inoue, Chie; Harada, Masayo; Nakahara, Chiaki; Suzuki, Kentaro; Matsumaru, Daisuke; Kaneko, Takehito; Matsuo, Isao; Yang, Lei; Taketo, Makoto M.; Iguchi, Taisen; Evans, Sylvia M.; Yamada, Gen

    2009-01-01

    Embryonic appendicular structures, such as the limb buds and the developing external genitalia, are suitable models with which to analyze the reciprocal interactions of growth factors in the regulation of outgrowth. Although several studies have evaluated the individual functions of different growth factors in appendicular growth, the coordinated function and integration of input from multiple signaling cascades is poorly understood. We demonstrate that a novel signaling cascade governs formation of the embryonic external genitalia [genital tubercle (GT)]. We show that the dosage of Shh signal is tightly associated with subsequent levels of Wnt/β-catenin activity and the extent of external genitalia outgrowth. In Shh-null mouse embryos, both expression of Wnt ligands and Wnt/β-catenin signaling activity are downregulated. β-catenin gain-of-function mutation rescues defective GT outgrowth and Fgf8 expression in Shh-null embryos. These data indicate that Wnt/β-catenin signaling in the distal urethral epithelium acts downstream of Shh signaling during GT outgrowth. The current data also suggest that Wnt/β-catenin regulates Fgf8 expression via Lef/Tcf binding sites in a 3′ conserved enhancer. Fgf8 induces phosphorylation of Erk1/2 and cell proliferation in the GT mesenchyme in vitro, yet Fgf4/8 compound-mutant phenotypes indicate dispensable functions of Fgf4/8 and the possibility of redundancy among multiple Fgfs in GT development. Our results provide new insights into the integration of growth factor signaling in the appendicular developmental programs that regulate external genitalia development. PMID:19906864

  12. Pressure Regulator With Internal Ejector Circulation Pump, Flow and Pressure Measurement Porting, and Fuel Cell System Integration Options

    NASA Technical Reports Server (NTRS)

    Vasquez, Arturo

    2011-01-01

    An advanced reactant pressure regulator with an internal ejector reactant circulation pump has been developed to support NASA's future fuel cell power systems needs. These needs include reliable and safe operation in variable-gravity environments, and for exploration activities with both manned and un manned vehicles. This product was developed for use in Proton Exchange Membrane Fuel Cell (PEMFC) power plant reactant circulation systems, but the design could also be applied to other fuel cell system types, (e.g., solid-oxide or alkaline) or for other gas pressure regulation and circulation needs. The regulator design includes porting for measurement of flow and pressure at key points in the system, and also includes several fuel cell system integration options. NASA has recognized ejectors as a viable alternative to mechanical pumps for use in spacecraft fuel cell power systems. The ejector motive force is provided by a variable, high-pressure supply gas that travels through the ejector s jet nozzle, whereby the pressure energy of the fluid stream is converted to kinetic energy in the gas jet. The ejector can produce circulation-to-consumption-flow ratios that are relatively high (2-3 times), and this phenomenon can potentially (with proper consideration of the remainder of the fuel cell system s design) be used to provide completely for reactant pre-humidification and product water removal in a fuel cell system. Specifically, a custom pressure regulator has been developed that includes: (1) an ejector reactant circulation pump (with interchangeable jet nozzles and mixer sections, gas-tight sliding and static seals in required locations, and internal fluid porting for pressure-sensing at the regulator's control elements) and (2) internal fluid porting to allow for flow rate and system pressure measurements. The fluid porting also allows for inclusion of purge, relief, and vacuum-breaker check valves on the regulator assembly. In addition, this regulator could also

  13. A search for immunocontraceptive agent from marine sources--role of antispermatheca globulin of Telescopium telescopium on fertility regulation in male rat.

    PubMed

    Pakrashi, A; Datta, U; Choudhury, A

    1992-11-01

    Polyclonal antisera were developed in rabbits against 'spermatheca', the reproductive gland of T. telescopium, a marine mollusc. The gland contains spermatozoa. Antisera and its IgG fraction (ASTG) indicated common antigenic determinants by immunodiffusion and had titer values 81920 and 1280 against crude antigen extract. Cycling female rats when exposed to passively immunized male rats with different doses of ASTG, had reduction in implantation sites and litter size. Females had pseudopregnancy when exposed to higher doses of immunized males and had normal cycle after 20 days in average. ASTG in male rats caused decrease in weight of the reproductive glands, alteration in sperm concentration, motility and morphology, formation of multinucleated giant cells and vacuoles leading to arrest of spermatogenesis and reduction in seminiferous tubular diameter. The effects were dose dependent with reversible infertility. The results indicate presence of a common antigenic determinants which cross-react with vertebrates and existence of common relation through phylogenetic evolution and their immune responses. PMID:1284054

  14. New methods for tightly regulated gene expression and highly efficient chromosomal integration of cloned genes for Methanosarcina species

    DOE PAGES

    Guss, Adam M.; Rother, Michael; Zhang, Jun Kai; Kulkkarni, Gargi; Metcalf, William W.

    2008-01-01

    A highly efficient method for chromosomal integration of cloned DNA into Methanosarcina spp. was developed utilizing the site-specific recombination system from the Streptomyces phage φC31. Host strains expressing the φC31 integrase gene and carrying an appropriate recombination site can be transformed with non-replicating plasmids carrying the complementary recombination site at efficiencies similar to those obtained with self-replicating vectors. We have also constructed a series of hybrid promoters that combine the highly expressed M. barkeri P mcrB promoter with binding sites for the tetracycline-responsive, bacterial TetR protein. These promoters are tightly regulated by the presence or absence of tetracycline inmore » strains that express the tetR gene. The hybrid promoters can be used in genetic experiments to test gene essentiality by placing a gene of interest under their control. Thus, growth of strains with tetR -regulated essential genes becomes tetracycline-dependent. A series of plasmid vectors that utilize the site-specific recombination system for construction of reporter gene fusions and for tetracycline regulated expression of cloned genes are reported. These vectors were used to test the efficiency of translation at a variety of start codons. Fusions using an ATG start site were the most active, whereas those using GTG and TTG were approximately one half or one fourth as active, respectively. The CTG fusion was 95% less active than the ATG fusion.« less

  15. The splicing activator DAZAP1 integrates splicing control into MEK/Erk regulated cell proliferation and migration

    PubMed Central

    Choudhury, Rajarshi; Roy, Sreerupa Ghose; Tsai, Yihsuan S.; Tripathy, Ashutosh; Graves, Lee M.; Wang, Zefeng

    2014-01-01

    Alternative splicing of pre-mRNA is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The C-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk regulated cell proliferation. PMID:24452013

  16. New methods for tightly regulated gene expression and highly efficient chromosomal integration of cloned genes for Methanosarcina species

    PubMed Central

    Guss, Adam M.; Rother, Michael; Zhang, Jun Kai; Kulkkarni, Gargi; Metcalf, William W.

    2008-01-01

    A highly efficient method for chromosomal integration of cloned DNA into Methanosarcina spp. was developed utilizing the site-specific recombination system from the Streptomyces phage φC31. Host strains expressing the φC31 integrase gene and carrying an appropriate recombination site can be transformed with non-replicating plasmids carrying the complementary recombination site at efficiencies similar to those obtained with self-replicating vectors. We have also constructed a series of hybrid promoters that combine the highly expressed M. barkeri PmcrB promoter with binding sites for the tetracycline-responsive, bacterial TetR protein. These promoters are tightly regulated by the presence or absence of tetracycline in strains that express the tetR gene. The hybrid promoters can be used in genetic experiments to test gene essentiality by placing a gene of interest under their control. Thus, growth of strains with tetR-regulated essential genes becomes tetracycline-dependent. A series of plasmid vectors that utilize the site-specific recombination system for construction of reporter gene fusions and for tetracycline regulated expression of cloned genes are reported. These vectors were used to test the efficiency of translation at a variety of start codons. Fusions using an ATG start site were the most active, whereas those using GTG and TTG were approximately one half or one fourth as active, respectively. The CTG fusion was 95% less active than the ATG fusion. PMID:19054746

  17. Induction of lactogenesis in transgenic virgin pigs: evidence for gene and integration site-specific hormonal regulation.

    PubMed

    Shamay, A; Pursel, V G; Wall, R J; Hennighausen, L

    1992-02-01

    Five month-old transgenic female pigs from three lines carrying the mouse whey acidic protein (WAP) gene and nontransgenic female littermates were implanted with slow-release estrogen and progesterone pellets. Histological analysis of biopsies taken at the time of implantation and 4 weeks later revealed that mammary alveolar development had occurred upon hormonal stimulation in vivo. beta-Casein and beta-lactoglobulin mRNA was found in all induced animals, and WAP mRNA was detected in two of the three transgenic pigs. Differential hormonal regulation between the transgenes in the three lines and also between endogenous milk protein genes was observed in induced mammary tissue cultured in vitro. In the presence of insulin, hydrocortisone, and PRL, beta-casein and WAP mRNA levels increased in all transgenic pigs. In contrast, beta-lactoglobulin mRNA had reached or exceeded lactational levels in response to the in vivo induction, and no further increase was observed in vitro. This suggests that the regulation of the beta-lactoglobulin gene is distinct from that of beta-casein and WAP. Differences were also observed during pregnancy; whereas beta-lactoglobulin gene expression was induced in early pregnancy, a time when PRL levels are low, WAP mRNA levels increased sharply around parturition. Finally, the observation that hormonal regulation of WAP transgenes greatly differed between the three lines suggests that chromatin surrounding the integration site can modify the response of transcription elements. PMID:1569963

  18. An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics

    PubMed Central

    Sheldon, Claire A.; Kwon, Young Joon; Liu, Grant T.; McCormack, Shana E.

    2015-01-01

    Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues. PMID:25420176

  19. Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions

    PubMed Central

    Zheng, Wei; Nurmi, Harri; Appak, Sila; Sabine, Amélie; Bovay, Esther; Korhonen, Emilia A.; Orsenigo, Fabrizio; Lohela, Marja; D’Amico, Gabriela; Holopainen, Tanja; Leow, Ching Ching; Dejana, Elisabetta; Petrova, Tatiana V.; Augustin, Hellmut G.; Alitalo, Kari

    2014-01-01

    Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell–cell junctions that form during lymphatic development. PMID:25030698

  20. Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions.

    PubMed

    Zheng, Wei; Nurmi, Harri; Appak, Sila; Sabine, Amélie; Bovay, Esther; Korhonen, Emilia A; Orsenigo, Fabrizio; Lohela, Marja; D'Amico, Gabriela; Holopainen, Tanja; Leow, Ching Ching; Dejana, Elisabetta; Petrova, Tatiana V; Augustin, Hellmut G; Alitalo, Kari

    2014-07-15

    Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development. PMID:25030698

  1. Integrated elastomeric components for autonomous regulation of sequential and oscillatory flow switching in microfluidic devices

    NASA Astrophysics Data System (ADS)

    Mosadegh, Bobak; Kuo, Chuan-Hsien; Tung, Yi-Chung; Torisawa, Yu-Suke; Bersano-Begey, Tommaso; Tavana, Hossein; Takayama, Shuichi

    2010-06-01

    A critical need for enhancing the usability and capabilities of microfluidic technologies is the development of standardized, scalable and versatile control systems. Electronically controlled valves and pumps typically used for dynamic flow regulation, although useful, can limit convenience, scalability and robustness. This shortcoming has motivated the development of device-embedded non-electrical flow-control systems. Existing approaches to regulate operation timing on-chip, however, still require external signals such as timed generation of fluid flow, bubbles, liquid plugs or droplets or an alteration of chemical compositions or temperature. Here, we describe a strategy to provide device-embedded flow switching and clocking functions. Physical gaps and cavities interconnected by holes are fabricated into a three-layer elastomer structure to form networks of fluidic gates that can spontaneously generate cascading and oscillatory flow output using only a constant flow of Newtonian fluids as the device input. The resulting microfluidic substrate architecture is simple, scalable and should be applicable to various materials. This flow-powered fluidic gating scheme brings the autonomous signal processing ability of microelectronic circuits to microfluidics where there is the added diversity in current information of having distinct chemical or particulate species and richness in current operation of having chemical reactions and physical interactions.

  2. ANKRD53 interacts with DDA3 and regulates chromosome integrity during mitosis.

    PubMed

    Kim, Seul; Jang, Chang-Young

    2016-02-12

    Spindle dynamics drives chromosome movement and mitotic progression during mitosis. Microtubule (MT)-associated proteins (MAPs) regulate MT stabilization/destabilization and MT polymerization/depolymerization for congression of sister chromatids at the mitotic equator and subsequent segregation toward the spindle poles. Here, we identified ANKRD53 as a novel DDA3-interacting protein through proteomic analysis. Based on expression profiles, ANKRD53 is phosphorylated by mitotic kinases during mitosis. In ANKRD53-depleted HeLa cells, the progression of mitosis was delayed and the number of unaligned chromosomes increased substantially. In addition, spindle MT polymerization decreased and the spindle assembly checkpoint (SAC) was concomitantly activated by the decreased spindle dynamics in ANKRD53-depleted cells. Although ANKRD53 is recruited to the mitotic spindle by DDA3, it counteracts the activity of DDA3 for spindle MT polymerization. Furthermore, ANKRD53 depletion increased the number of bi-nuclei and polylobed nuclei. Thus, ANKRD53 is recruited to the mitotic spindle by DDA3 and acts as a regulator of spindle dynamics and cytokinesis.

  3. Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions.

    PubMed

    Zheng, Wei; Nurmi, Harri; Appak, Sila; Sabine, Amélie; Bovay, Esther; Korhonen, Emilia A; Orsenigo, Fabrizio; Lohela, Marja; D'Amico, Gabriela; Holopainen, Tanja; Leow, Ching Ching; Dejana, Elisabetta; Petrova, Tatiana V; Augustin, Hellmut G; Alitalo, Kari

    2014-07-15

    Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development.

  4. Cbk1 regulation of the RNA binding protein Ssd1 integrates cell fate with translational control

    PubMed Central

    Jansen, Jaclyn M.; Wanless, Antony G.; Seidel, Christopher W.; Weiss, Eric L.

    2009-01-01

    Summary Spatial control of gene expression, at the level of both transcription and translation, is critical for cellular differentiation [1-4]. In budding yeast, the conserved Ndr/warts kinase Cbk1 localizes to the new daughter cell where it acts as a cell fate determinant. Cbk1 both induces a daughter-specific transcriptional program and promotes morphogenesis in a less well-defined role [5-8]. Cbk1 is essential in cells expressing functional Ssd1, an RNA binding protein of unknown function [9-11]. We show that Cbk1 inhibits Ssd1 in vivo. Loss of this regulation dramatically slows bud expansion, leading to highly aberrant cell wall organization at the site of cell growth. Ssd1 associates with specific mRNAs, a significant number of which encode cell wall remodeling proteins. Translation of these messages is rapidly and specifically suppressed when Cbk1 is inhibited; this suppression requires Ssd1. Transcription of several of these Ssd1-associated mRNAs is also regulated by Cbk1, indicating that the kinase controls both the transcription and translation of daughter-specific mRNAs. This work suggests a novel system by which cells coordinate localized expression of genes involved in processes critical for cell growth and division. PMID:19962308

  5. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.

    PubMed

    Jha, Abhishek K; Huang, Stanley Ching-Cheng; Sergushichev, Alexey; Lampropoulou, Vicky; Ivanova, Yulia; Loginicheva, Ekaterina; Chmielewski, Karina; Stewart, Kelly M; Ashall, Juliet; Everts, Bart; Pearce, Edward J; Driggers, Edward M; Artyomov, Maxim N

    2015-03-17

    Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes. PMID:25786174

  6. Nuclear pore complex integrity requires Lnp1, a regulator of cortical endoplasmic reticulum

    PubMed Central

    Casey, Amanda K.; Chen, Shuliang; Novick, Peter; Ferro-Novick, Susan; Wente, Susan R.

    2015-01-01

    The nuclear envelope (NE) and endoplasmic reticulum (ER) are components of the same contiguous membrane system and yet have distinct cellular functions. Mounting evidence suggests roles for some ER proteins in the NE for proper nuclear pore complex (NPC) structure and function. In this study, we identify a NE role in Saccharomyces cerevisiae for Lnp1 and Sey1, proteins required for proper cortical ER formation. Both lnp1Δ and sey1Δ mutants exhibit synthetic genetic interactions with mutants in genes encoding key NPC structural components. Both Lnp1 and Sey1 physically associate with other ER components that have established NPC roles, including Rtn1, Yop1, Pom33, and Per33. Of interest, lnp1Δ rtn1Δ mutants but not rtn1Δ sey1Δ mutants exhibit defects in NPC distribution. Furthermore, the essential NPC assembly factor Ndc1 has altered interactions in the absence of Sey1. Lnp1 dimerizes in vitro via its C-terminal zinc finger motif, a property that is required for proper ER structure but not NPC integrity. These findings suggest that Lnp1's role in NPC integrity is separable from functions in the ER and is linked to Ndc1 and Rtn1 interactions. PMID:26041935

  7. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.

    PubMed

    Jha, Abhishek K; Huang, Stanley Ching-Cheng; Sergushichev, Alexey; Lampropoulou, Vicky; Ivanova, Yulia; Loginicheva, Ekaterina; Chmielewski, Karina; Stewart, Kelly M; Ashall, Juliet; Everts, Bart; Pearce, Edward J; Driggers, Edward M; Artyomov, Maxim N

    2015-03-17

    Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.

  8. Violence between Couples: Profiling the Male Abuser.

    ERIC Educational Resources Information Center

    Ponzetti,James J. Jr.; And Others

    1982-01-01

    Presents an integrative review of the literature on spousal violence as it relates to the abusive male. Suggests various issues that need to be addressed before effective intervention with abusive males can proceed. (Author)

  9. Skeletal receptors for steroid-family regulating glycoprotein hormones: A multilevel, integrated physiological control system.

    PubMed

    Blair, Harry C; Robinson, Lisa J; Sun, Li; Isales, Carlos; Davies, Terry F; Zaidi, Mone

    2011-12-01

    Pituitary glycoprotein hormone receptors, including ACTH-R, TSH-R, and FSH-R, occur in bone. Their skeletal expression reflects that central endocrine control is evolutionarily recent. ACTH receptors, in osteoblasts or the adrenal cortex, drive VEGF synthesis. VEGF is essential to maintain vasculature. In bone, ACTH suppression by glucocorticoids can cause osteonecrosis. TSH receptors occur on osteoblasts and osteoclasts, in both cases reducing activity. Thus, TSH directly reduces skeletal turnover, consistent with evolutionary adaptation to stress. FSH receptors accelerate bone resorption, whereas estrogen promotes bone formation, the forces usually balancing. With ovarian failure, low estrogen with high FSH causes rapid bone loss. The skeletal FSH effect in the menopause seems paradoxical, but it is a logical adaptation in lactation, where prolonged FSH elevation also occurs. In addition to receptors, there is some synthesis of pituitary glycoproteins at distributed sites; this is not well studied, but it may further modify the paradigm of central endocrine regulation.

  10. Pharmaceutical regulation in the European Community: barriers to single market integration.

    PubMed

    Orzack, L H; Kaitin, K I; Lasagna, L

    1992-01-01

    The European Community (EC) plans to create a single market for pharmaceutical medicines, but the drug industry is closely linked to cultural and societal values concerning health; to the national regulatory agencies responsible for the evaluation of safety, quality, and efficacy of new drugs; to multinational and domestic companies competing in national and international markets; and to varied interest groups of professionals and consumers organized along national and multinational lines. We review the history of the EC's policy proposals, examine reactions from all these interested parties, and assess the prospects for integration into a single market. The contentious debate that continues among the parties over national prerogatives, industrial interests, professional mandates, and consumer concerns clouds the prospects for a system of centralized drug registration that will be acceptable to all EC member states.

  11. Integrative analyses of genetic variation in enzyme activities of primary carbohydrate metabolism reveal distinct modes of regulation in Arabidopsis thaliana

    PubMed Central

    Keurentjes, Joost JB; Sulpice, Ronan; Gibon, Yves; Steinhauser, Marie-Caroline; Fu, Jingyuan; Koornneef, Maarten; Stitt, Mark; Vreugdenhil, Dick

    2008-01-01

    Background Plant primary carbohydrate metabolism is complex and flexible, and is regulated at many levels. Changes of transcript levels do not always lead to changes in enzyme activities, and these do not always affect metabolite levels and fluxes. To analyze interactions between these three levels of function, we have performed parallel genetic analyses of 15 enzyme activities involved in primary carbohydrate metabolism, transcript levels for their encoding structural genes, and a set of relevant metabolites. Quantitative analyses of each trait were performed in the Arabidopsis thaliana Ler × Cvi recombinant inbred line (RIL) population and subjected to correlation and quantitative trait locus (QTL) analysis. Results Traits affecting primary metabolism were often correlated, possibly due to developmental control affecting multiple genes, enzymes, or metabolites. Moreover, the activity QTLs of several enzymes co-localized with the expression QTLs (eQTLs) of their structural genes, or with metabolite accumulation QTLs of their substrates or products. In addition, many trait-specific QTLs were identified, revealing that there is also specific regulation of individual metabolic traits. Regulation of enzyme activities often occurred through multiple loci, involving both cis- and trans-acting transcriptional or post-transcriptional control of structural genes, as well as independently of the structural genes. Conclusion Future studies of the regulatory processes in primary carbohydrate metabolism will benefit from an integrative genetic analysis of gene transcription, enzyme activity, and metabolite content. The multiparallel QTL analyses of the various interconnected transducers of biological information flow, described here for the first time, can assist in determining the causes and consequences of genetic regulation at different levels of complex biological systems. PMID:18710526

  12. Bioavailability and Environmental Regulation - Integrating a Fate & Effects Model with a Biotic Ligand Model for Copper in Seawater

    NASA Astrophysics Data System (ADS)

    Rivera, I.; Chadwick, B.; Rosen, G.; Wang, P. F.; Paquin, P.; Santore, R.; Ryan, A.

    2015-12-01

    Understanding the bioavailability of metals in the aquatic environment is important for defining appropriate regulatory constraints. A failure to recognize the importance of bioavailability factors on metal toxicity can result in criteria that are over- or under-protective. USEPA addresses the tendency of the national Water Quality Criterion (WQC) for regulation of copper in marine waters to underestimate the natural attenuation of copper toxicity in harbors by the application of site-specific Water Quality Standards (WQS). Which provides the level of protection intended by the WQC, and establishes realistic regulatory objectives. However, development of site-specific WQS involves a long-term effort, and does not account for temporal variation. The toxicity model seawater-Biotic Ligand Model (BLM) was developed and integrated with the existing Curvilinear Hydrodynamics in 3 Dimensions (CH3D) transport & fate model to create an efficient tool for development of site-specific WQS in harbors. The integrated model was demonstrated at a harbor-wide scale in San Diego Bay and Pearl Harbor, and accounted for the natural physical, chemical, biological and toxicological characteristics of the harbor to achieve more scientifically based compliance. In both harbors the spatial and temporal distributions of copper species, toxic effects, and Water Effect Ratio predicted by the integrated model are comparable to previous data. The model was further demonstrated in Shelter Island Yacht Basin (SIYB) marina in San Diego Bay. The integrated model agreed with toxicological and chemical approaches by indicating negligible bioavailability as well as no toxicity; but for a single event, even though an increasing gradient in Cu was observed both horizontally and vertically, with concentrations that reached levels well above current regulatory thresholds. These results support the incorporation by USEPA of the seawater-BLM in a full-strength seawater criterion.

  13. Urban Head Start Teachers' Classroom Interactions with Black Male Preschoolers Identified as "Challenging" or "Externalizing": Opportunities for Teaching Self-Regulation

    ERIC Educational Resources Information Center

    Nunley, Patricia L.

    2012-01-01

    At the earliest grade levels, young Black males, who have been identified by their teachers as "challenging" (in psychological terminology, exhibiting externalizing behavior), have the same disproportionate rate of school suspension and expulsion as their older counterparts (Gilliam, 2005; Lewis, Butler, Bonner, & Joubert, 2010;…

  14. Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior.

    PubMed

    Hahn, Yun Kyung; Podhaizer, Elizabeth M; Farris, Sean P; Miles, Michael F; Hauser, Kurt F; Knapp, Pamela E

    2015-03-01

    HIV-associated damage to the central nervous system results in cognitive and motor deficits. Anti-retroviral therapies reduce the severity of symptoms, yet the proportion of patients affected has remained the same or increased. Although approximately half of HIV-infected patients worldwide are women, the question of whether biological sex influences outcomes of HIV infection has received little attention. We explored this question for both behavioral and cellular/morphologic endpoints, using a transgenic mouse that inducibly expresses HIV-1 Tat in the brain. After 3 months of HIV-1 Tat exposure, both sexes showed similar reduced open field ambulation. Male Tat(+) mice also showed reduced forelimb grip strength and enhanced anxiety in a light-dark box assay. Tat(+) males did not improve over 12 weeks of repeated rotarod testing, indicating a motor memory deficit. Male mice also had more cellular deficits in the striatum. Neither sex showed a change in volume or total neuron numbers. Both had equally reduced oligodendroglial populations and equivalent microglial increases. However, astrogliosis and microglial nitrosative stress were higher in males. Dendrites on medium spiny neurons in male Tat(+) mice had fewer spines, and levels of excitatory and inhibitory pre- and post-synaptic proteins were disrupted. Our results predict sex as a determinant of HIV effects in brain. Increased behavioral deficits in males correlated with glial activation and synaptic damage, both of which are implicated in cognitive/motor impairments in patients. Tat produced by residually infected cells despite antiretroviral therapy may be an important determinant of the synaptodendritic instability and behavioral deficits accompanying chronic infection.

  15. ATF4 is involved in the regulation of simulated microgravity induced integrated stress response

    NASA Astrophysics Data System (ADS)

    Li, Yingxian; Li, Qi; Wang, Xiaogang; Sun, Qiao; Wan, Yumin; Li, Yinghui; Bai, Yanqiang

    Objective: Many important metabolic and signaling pathways have been identified as being affected by microgravity, thereby altering cellular functions such as proliferation, differentiation, maturation and cell survival. It has been demonstrated that microgravity could induce all kinds of stress response such as endoplasmic reticulum stress and oxidative stress et al. ATF4 belongs to the ATF/CREB family of basic region leucine zipper transcription factors. ATF4 is induced by stress signals including anoxia/hypoxia, ER stress, amino acid deprivation and oxidative stress. ATF4 regulates the expression of genes involved in oxidative stress, amino acid synthesis, differentiation, metastasis and angiogenesis. The aim of this study was to examine the changes of ATF4 under microgravity, and to investigate the role of ATF4 in microgravity induced stress. MethodsMEF cells were cultured in clinostat to simulate microgravity. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to examine mRNA and protein levels of ATF4 expression under simulated microgravity in MEF cells. ROS levels were measured with the use of the fluorescent signal H2DCF-DA. GFP-XBP1 stably transfected cell lines was used to detect the extent of ER stress under microgravity by the intensity of GFP. Dual luciferase reporter assay was used to detect the activity of ATF4. Co-immunoprecipitation was performed to analyze protein interaction. Results: ATF4 protein levels in MEF cells increased under simulated microgravity. However, ATF4 mRNA levels were consistent. XBP1 splicing can be induced due to ER stress caused by simulated microgravity. At the same time, ROS levels were also increased. Increased ATF4 could promote the expression of CHOP, which is responsible for cell apoptosis. ATF4 also play an important role in cellular anti-oxidant stress. In ATF4 -/-MEF cells, the ROS levels after H2O2 treatment were obviously higher than that of wild type cells. HDAC4 was

  16. Integrating Skills and Wills Instruction in Self-Regulated Science Text Reading for Secondary Students

    NASA Astrophysics Data System (ADS)

    Michalsky, Tova

    2013-07-01

    This study investigated the effectiveness of cognitive-metacognitive versus motivational components of the IMPROVE self-regulatory model, used while reading scientific texts, for 10th graders' scientific literacy and self-regulated learning (SRL). Three treatment groups (N = 198) received one type of self-addressable questions while reading scientific texts: cognitive-metacognitive (CogMet), motivational (Mot), or combined (CogMetMot). Control group received no self-addressed questions (noSRL). One measure assessed scientific literacy, and two measures assessed SRL: (a) as an aptitude-pre/post questionnaires assessing self-perceived SRL, and (b) as an event-audiotaping participants' thinking-aloud SRL behaviors in real-time learning experiences and data coding illustrating SRL changes. Findings indicated that treatment groups significantly outperformed the non-treatment group. No differences emerged between CogMet and Mot, whereas fully combined SRL support (CogMetMot) was most effective. Theoretical and practical implications of this preliminary study are discussed.

  17. Virtual welding equipment for simulation of GMAW processes with integration of power source regulation

    NASA Astrophysics Data System (ADS)

    Reisgen, Uwe; Schleser, Markus; Mokrov, Oleg; Zabirov, Alexander

    2011-06-01

    A two dimensional transient numerical analysis and computational module for simulation of electrical and thermal characteristics during electrode melting and metal transfer involved in Gas-Metal-Arc-Welding (GMAW) processes is presented. Solution of non-linear transient heat transfer equation is carried out using a control volume finite difference technique. The computational module also includes controlling and regulation algorithms of industrial welding power sources. The simulation results are the current and voltage waveforms, mean voltage drops at different parts of circuit, total electric power, cathode, anode and arc powers and arc length. We describe application of the model for normal process (constant voltage) and for pulsed processes with U/I and I/I-modulation modes. The comparisons with experimental waveforms of current and voltage show that the model predicts current, voltage and electric power with a high accuracy. The model is used in simulation package SimWeld for calculation of heat flux into the work-piece and the weld seam formation. From the calculated heat flux and weld pool sizes, an equivalent volumetric heat source according to Goldak model, can be generated. The method was implemented and investigated with the simulation software SimWeld developed by the ISF at RWTH Aachen University.

  18. Splicing regulation: From a parts list of regulatory elements to an integrated splicing code

    PubMed Central

    Wang, Zefeng; Burge, Christopher B.

    2008-01-01

    Alternative splicing of pre-mRNAs is a major contributor to both proteomic diversity and control of gene expression levels. Splicing is tightly regulated in different tissues and developmental stages, and its disruption can lead to a wide range of human diseases. An important long-term goal in the splicing field is to determine a set of rules or “code” for splicing that will enable prediction of the splicing pattern of any primary transcript from its sequence. Outside of the core splice site motifs, the bulk of the information required for splicing is thought to be contained in exonic and intronic cis-regulatory elements that function by recruitment of sequence-specific RNA-binding protein factors that either activate or repress the use of adjacent splice sites. Here, we summarize the current state of knowledge of splicing cis-regulatory elements and their context-dependent effects on splicing, emphasizing recent global/genome-wide studies and open questions. PMID:18369186

  19. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread.

    PubMed

    Li, Xiujuan; Padhan, Narendra; Sjöström, Elisabet O; Roche, Francis P; Testini, Chiara; Honkura, Naoki; Sáinz-Jaspeado, Miguel; Gordon, Emma; Bentley, Katie; Philippides, Andrew; Tolmachev, Vladimir; Dejana, Elisabetta; Stan, Radu V; Vestweber, Dietmar; Ballmer-Hofer, Kurt; Betsholtz, Christer; Pietras, Kristian; Jansson, Leif; Claesson-Welsh, Lena

    2016-01-01

    The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms. PMID:27005951

  20. An integrative affect regulation process model of internalized weight bias and intuitive eating in college women.

    PubMed

    Webb, Jennifer B; Hardin, Abigail S

    2016-07-01

    The present study extended the weight stigma and well-being process model (Tylka et al., 2014) by examining three affect regulation pathways that may help simultaneously explain the predicted inverse association between internalized weight bias and intuitive eating. A weight-diverse sample of 333 college women completed an online survey assessing internalized weight stigma, intuitive eating, body shame, body image flexibility, and self-compassion. Self-reported height and weight were used to calculate body mass index (BMI). Non-parametric bootstrap resampling procedures were computed to ascertain the presence of the indirect effects of internalized weight bias on intuitive eating via the three hypothesized mediators controlling for BMI in a combined model. Results demonstrated that body image flexibility significantly and self-compassion marginally contributed unique variance in accounting for this relationship. Our preliminary cross-sectional findings contribute to a nascent body of scholarship seeking to provide a theoretically-driven understanding of how negative and positive forms of experiencing and relating to the body may co-occur within individuals. Results also point to potential target variables to consider incorporating in later-stage efforts to promote more adaptive ways of eating amidst internalized weight stigma. PMID:26893074

  1. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis

    PubMed Central

    Tressel, Sarah L; Kaneider, Nicole C; Kasuda, Shogo; Foley, Caitlin; Koukos, Georgios; Austin, Karyn; Agarwal, Anika; Covic, Lidija; Opal, Steven M; Kuliopulos, Athan

    2011-01-01

    Sepsis is a deadly disease characterized by the inability to regulate the inflammatory–coagulation response in which the endothelium plays a key role. The cause of this perturbation remains poorly understood and has hampered the development of effective therapeutics. Matrix metalloproteases (MMPs) are involved in the host response to pathogens, but can also cause uncontrolled tissue damage and contribute to mortality. We found that human sepsis patients had markedly elevated plasma proMMP-1 and active MMP-1 levels, which correlated with death at 7 and 28 days after diagnosis. Likewise, septic mice had increased plasma levels of the MMP-1 ortholog, MMP-1a. We identified mouse MMP-1a as an agonist of protease-activated receptor-1 (PAR1) on endothelial cells. MMP-1a was released from endothelial cells in septic mice. Blockade of MMP-1 activity suppressed endothelial barrier disruption, disseminated intravascular coagulation (DIC), lung vascular permeability as well as the cytokine storm and improved survival, which was lost in PAR1-deficient mice. Infusion of human MMP-1 increased lung vascular permeability in normal wild-type mice but not in PAR1-deficient mice. These findings implicate MMP-1 as an important activator of PAR1 in sepsis and suggest that therapeutics that target MMP1-PAR1 may prove beneficial in the treatment of sepsis. PMID:21591259

  2. Integrity and Regeneration of Mechanotransduction Machinery Regulate Aminoglycoside Entry and Sensory Cell Death

    PubMed Central

    Huth, Markus E.; Luk, Lauren; Kim, John; Chai, Renjie; Ricci, Anthony J.; Cheng, Alan G.

    2013-01-01

    Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23+/+ and Cdh23v2J/+ mice, but failed to detect GTTR uptake in Cdh23v2J/v2J hair cells. Pre-treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23v2J/v2J and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity. PMID:23359017

  3. Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO

    PubMed Central

    Hurley, Amanda; Li, Zhijie; Ventocilla, Christian; Jeffrey, Philip D.; Semmelhack, Martin F.; Fairman, Robert; Bassler, Bonnie L.; Hughson, Frederick M.

    2016-01-01

    In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family. Autoinducer binding inactivates the receptors’ kinase activities, leading to dephosphorylation and inhibition of the downstream response regulator LuxO. Here, we report the X-ray structure of LuxO in its unphosphorylated, autoinhibited state. Our structure reveals that LuxO, a bacterial enhancer-binding protein of the AAA+ ATPase superfamily, is inhibited by an unprecedented mechanism in which a linker that connects the catalytic and regulatory receiver domains occupies the ATPase active site. The conformational change that accompanies receiver domain phosphorylation likely disrupts this interaction, providing a mechanistic rationale for LuxO activation. We also determined the crystal structure of the LuxO catalytic domain bound to a broad-spectrum inhibitor. The inhibitor binds in the ATPase active site and recapitulates elements of the natural regulatory mechanism. Remarkably, a single inhibitor molecule may be capable of inhibiting an entire LuxO oligomer. PMID:27219477

  4. Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO.

    PubMed

    Boyaci, Hande; Shah, Tayyab; Hurley, Amanda; Kokona, Bashkim; Li, Zhijie; Ventocilla, Christian; Jeffrey, Philip D; Semmelhack, Martin F; Fairman, Robert; Bassler, Bonnie L; Hughson, Frederick M

    2016-05-01

    In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family. Autoinducer binding inactivates the receptors' kinase activities, leading to dephosphorylation and inhibition of the downstream response regulator LuxO. Here, we report the X-ray structure of LuxO in its unphosphorylated, autoinhibited state. Our structure reveals that LuxO, a bacterial enhancer-binding protein of the AAA+ ATPase superfamily, is inhibited by an unprecedented mechanism in which a linker that connects the catalytic and regulatory receiver domains occupies the ATPase active site. The conformational change that accompanies receiver domain phosphorylation likely disrupts this interaction, providing a mechanistic rationale for LuxO activation. We also determined the crystal structure of the LuxO catalytic domain bound to a broad-spectrum inhibitor. The inhibitor binds in the ATPase active site and recapitulates elements of the natural regulatory mechanism. Remarkably, a single inhibitor molecule may be capable of inhibiting an entire LuxO oligomer.

  5. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

    PubMed Central

    Li, Xiujuan; Padhan, Narendra; Sjöström, Elisabet O.; Roche, Francis P.; Testini, Chiara; Honkura, Naoki; Sáinz-Jaspeado, Miguel; Gordon, Emma; Bentley, Katie; Philippides, Andrew; Tolmachev, Vladimir; Dejana, Elisabetta; Stan, Radu V.; Vestweber, Dietmar; Ballmer-Hofer, Kurt; Betsholtz, Christer; Pietras, Kristian; Jansson, Leif; Claesson-Welsh, Lena

    2016-01-01

    The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2Y949F/Y949F mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms. PMID:27005951

  6. Intracellular protein O-GlcNAc modification integrates nutrient status with transcriptional and metabolic regulation.

    PubMed

    Nagel, Alexis K; Ball, Lauren E

    2015-01-01

    The inducible, nutrient-sensitive posttranslational modification of protein Ser/Thr residues with O-linked β-N-acetylglucosamine (O-GlcNAc) occurs on histones, transcriptional regulators, metabolic enzymes, oncogenes, tumor suppressors, and many critical intermediates of growth factor signaling. Cycling of O-GlcNAc modification on and off of protein substrates is catalyzed by the actions of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. To date, there are less than 150 publications addressing the role of O-GlcNAc modification in cancer and over half were published in the last 2 years. These studies have clearly established that increased expression of OGT and hyper-O-GlcNAcylation is common to human cancers of breast, prostate, colon, lung, and pancreas. Furthermore, attenuating OGT activity reduces tumor growth in vitro and metastasis in vivo. This chapter discusses the structure and function of the O-GlcNAc cycling enzymes, mechanisms by which protein O-GlcNAc modification sense changes in nutrient status, the influence of O-GlcNAc cycling enzymes on glucose metabolism, and provides an overview of recent observations regarding the role of O-GlcNAcylation in cancer.

  7. Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples

    PubMed Central

    Gara, Sudheer Kumar; Wang, Yonghong; Patel, Dhaval; Liu-Chittenden, Yi; Jain, Meenu; Boufraqech, Myriem; Zhang, Lisa; Meltzer, Paul S.; Kebebew, Electron

    2015-01-01

    To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics. PMID:26446994

  8. Dynamic myosin phosphorylation regulates contractile pulses and tissue integrity during epithelial morphogenesis

    PubMed Central

    Vasquez, Claudia G.; Tworoger, Mike

    2014-01-01

    Apical constriction is a cell shape change that promotes epithelial bending. Activation of nonmuscle myosin II (Myo-II) by kinases such as Rho-associated kinase (Rok) is important to generate contractile force during apical constriction. Cycles of Myo-II assembly and disassembly, or pulses, are associated with apical constriction during Drosophila melanogaster gastrulation. It is not understood whether Myo-II phosphoregulation organizes contractile pulses or whether pulses are important for tissue morphogenesis. Here, we show that Myo-II pulses are associated with pulses of apical Rok. Mutants that mimic Myo-II light chain phosphorylation or depletion of myosin phosphatase inhibit Myo-II contractile pulses, disrupting both actomyosin coalescence into apical foci and cycles of Myo-II assembly/disassembly. Thus, coupling dynamic Myo-II phosphorylation to upstream signals organizes contractile Myo-II pulses in both space and time. Mutants that mimic Myo-II phosphorylation undergo continuous, rather than incremental, apical constriction. These mutants fail to maintain intercellular actomyosin network connections during tissue invagination, suggesting that Myo-II pulses are required for tissue integrity during morphogenesis. PMID:25092658

  9. Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples.

    PubMed

    Gara, Sudheer Kumar; Wang, Yonghong; Patel, Dhaval; Liu-Chittenden, Yi; Jain, Meenu; Boufraqech, Myriem; Zhang, Lisa; Meltzer, Paul S; Kebebew, Electron

    2015-10-30

    To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics.

  10. Development of Cell Culture Microdevice Integrated with Piezoelectric Thin Film Actuator for On-Chip Regulation of Cell Functions

    NASA Astrophysics Data System (ADS)

    Kawashima, Takahiro; Yamada, Yuhei; Matsuzawa, Yuuta; Nagai, Moeto; Shibata, Takayuki; Masuzawa, Toru; Kimura, Tsuyoshi; Kishida, Akio

    2012-10-01

    To develop a cell culture microdevice integrated with piezoelectric thin film actuators for on-chip cell function regulation, we investigated various fabrication processes including the formation of a lead zirconate titanate (PZT) thin film using a sol-gel method as a piezoelectric thin film actuator and PZT thin film patterning. According to our proposed batch fabrication process, a prototype cell culture microdevice with 16 microchambers and PZT actuators was successfully fabricated on a 20 ×20 mm2 Si substrate. Moreover, we used the fabricated prototype device to investigate the effects of applied voltage and frequency on diaphragm displacement. The device sufficiently delivered mechanical vibratory stimuli to cells in culture solution. Moreover, in a feasibility study using living cells, we observed that mechanical vibratory stimulation affected cell adhesion.

  11. The NF-YC–RGL2 module integrates GA and ABA signalling to regulate seed germination in Arabidopsis

    PubMed Central

    Liu, Xu; Hu, Pengwei; Huang, Mingkun; Tang, Yang; Li, Yuge; Li, Ling; Hou, Xingliang

    2016-01-01

    The antagonistic crosstalk between gibberellic acid (GA) and abscisic acid (ABA) plays a pivotal role in the modulation of seed germination. However, the molecular mechanism of such phytohormone interaction remains largely elusive. Here we show that three Arabidopsis NUCLEAR FACTOR-Y C (NF-YC) homologues NF-YC3, NF-YC4 and NF-YC9 redundantly modulate GA- and ABA-mediated seed germination. These NF-YCs interact with the DELLA protein RGL2, a key repressor of GA signalling. The NF-YC–RGL2 module targets ABI5, a gene encoding a core component of ABA signalling, via specific CCAAT elements and collectively regulates a set of GA- and ABA-responsive genes, thus controlling germination. These results suggest that the NF-YC–RGL2–ABI5 module integrates GA and ABA signalling pathways during seed germination. PMID:27624486

  12. Integrating Co-Morbid Depression and Chronic Physical Disease Management: Identifying and Resolving Failures in Self-Regulation

    PubMed Central

    Detweiler-Bedell, Jerusha B.; Friedman, Michael A.; Leventhal, Howard; Miller, Ivan W.; Leventhal, Elaine A.

    2008-01-01

    Research suggests that treatments for depression among individuals with chronic physical disease do not improve disease outcomes significantly, and chronic disease management programs do not necessarily improve mood. For individuals experiencing co-morbid depression and chronic physical disease, demands on the self-regulation system are compounded, leading to a rapid depletion of self-regulatory resources. Because disease and depression management are not integrated, patients lack the understanding needed to prioritize self-regulatory goals in a way that makes disease and depression management synergistic. A framework in which the management of co-morbidity is considered alongside the management of either condition alone offers benefits to researchers and practitioners and may help improve clinical outcomes. PMID:18848740

  13. The NF-YC-RGL2 module integrates GA and ABA signalling to regulate seed germination in Arabidopsis.

    PubMed

    Liu, Xu; Hu, Pengwei; Huang, Mingkun; Tang, Yang; Li, Yuge; Li, Ling; Hou, Xingliang

    2016-01-01

    The antagonistic crosstalk between gibberellic acid (GA) and abscisic acid (ABA) plays a pivotal role in the modulation of seed germination. However, the molecular mechanism of such phytohormone interaction remains largely elusive. Here we show that three Arabidopsis NUCLEAR FACTOR-Y C (NF-YC) homologues NF-YC3, NF-YC4 and NF-YC9 redundantly modulate GA- and ABA-mediated seed germination. These NF-YCs interact with the DELLA protein RGL2, a key repressor of GA signalling. The NF-YC-RGL2 module targets ABI5, a gene encoding a core component of ABA signalling, via specific CCAAT elements and collectively regulates a set of GA- and ABA-responsive genes, thus controlling germination. These results suggest that the NF-YC-RGL2-ABI5 module integrates GA and ABA signalling pathways during seed germination.

  14. The NF-YC-RGL2 module integrates GA and ABA signalling to regulate seed germination in Arabidopsis.

    PubMed

    Liu, Xu; Hu, Pengwei; Huang, Mingkun; Tang, Yang; Li, Yuge; Li, Ling; Hou, Xingliang

    2016-01-01

    The antagonistic crosstalk between gibberellic acid (GA) and abscisic acid (ABA) plays a pivotal role in the modulation of seed germination. However, the molecular mechanism of such phytohormone interaction remains largely elusive. Here we show that three Arabidopsis NUCLEAR FACTOR-Y C (NF-YC) homologues NF-YC3, NF-YC4 and NF-YC9 redundantly modulate GA- and ABA-mediated seed germination. These NF-YCs interact with the DELLA protein RGL2, a key repressor of GA signalling. The NF-YC-RGL2 module targets ABI5, a gene encoding a core component of ABA signalling, via specific CCAAT elements and collectively regulates a set of GA- and ABA-responsive genes, thus controlling germination. These results suggest that the NF-YC-RGL2-ABI5 module integrates GA and ABA signalling pathways during seed germination. PMID:27624486

  15. Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets.

    PubMed

    Gegenbauer, Kristina; Elia, Giuliano; Blanco-Fernandez, Alfonso; Smolenski, Albert

    2012-04-19

    Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein for the G-α-q and G-α-i subunits of heterotrimeric G-proteins that turns off signaling by G-protein coupled receptors. RGS18 is highly expressed in platelets. In the present study, we show that the 14-3-3γ protein binds to phosphorylated serines 49 and 218 of RGS18. Platelet activation by thrombin, thromboxane A2, or ADP stimulates the association of 14-3-3 and RGS18, probably by increasing the phosphorylation of serine 49. In contrast, treatment of platelets with prostacyclin and nitric oxide, which trigger inhibitory cyclic nucleotide signaling involving cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI), induces the phosphorylation of serine 216 of RGS18 and the detachment of 14-3-3. Serine 216 phosphorylation is able to block 14-3-3 binding to RGS18 even in the presence of thrombin, thromboxane A2, or ADP. 14-3-3-deficient RGS18 is more active compared with 14-3-3-bound RGS18, leading to a more pronounced inhibition of thrombin-induced release of calcium ions from intracellular stores. Therefore, PKA- and PKGI-mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signaling. These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq. PMID:22234696

  16. MicroRNA-9 regulates survival of chondroblasts and cartilage integrity by targeting protogenin

    PubMed Central

    2013-01-01

    Background Studies have shown the roles of miR-9 and its validated target, protogenin (PRTG) in the differentiation of chondroblasts to chondrocyte and in the pathogenesis of osteoarthritis (OA). We hypothesized that miR-9 plays a distinct role in endochondral ossification and OA pathogenesis and the present study was undertaken to identify this role. In the studies, chondroblasts were isolated from limb bud of chick and mouse embryos and articular chondrocytes were isolated from rabbit and human cartilage. Osteoarthritic chondrocytes were isolated from cartilage from patients undergoing total knee replacement. Using these cells, we analyzed the changes in the expression of genes and proteins, tested the expression level of miR-9, and applied a target validation system. We also performed functional study of miR-9 and PRTG. Results With the progression of chondrogenesis, decreased miR-9 level was observed at the time of numerous apoptotic cell deaths. And chondrocytes isolated from normal human articular cartilage expressed miR-9, and this expression was significantly reduced in OA chondrocytes, especially decreased its expression in parallel with the degree of cartilage degradation. Over-expression of PRTG induced the activation of caspase-3 signaling and increased apoptosis. However, the co-treatment with the miR-9 precursor or PRTG-specific siRNA blocked this apoptotic signaling. Conclusion This study shows that PRTG is regulated by miR-9, plays an inhibitory action on survival of chondroblasts and articular chondrocytes during chondrogenesis and OA pathogenesis. PMID:24007463

  17. The lateral reticular nucleus; integration of descending and ascending systems regulating voluntary forelimb movements

    PubMed Central

    Alstermark, Bror; Ekerot, Carl-Fredrik

    2015-01-01

    Cerebellar control of movements is dependent on mossy fiber input conveying information about sensory and premotor activity in the spinal cord. While much is known about spino-cerebellar systems, which provide the cerebellum with detailed sensory information, much less is known about systems conveying motor information. Individual motoneurones do not have projections to spino-cerebellar neurons. Instead, the fastest route is from last order spinal interneurons. In order to identify the networks that convey ascending premotor information from last order interneurons, we have focused on the lateral reticular nucleus (LRN), which provides the major mossy fiber input to cerebellum from spinal interneuronal systems. Three spinal ascending systems to the LRN have been investigated: the C3-C4 propriospinal neurones (PNs), the ipsilateral forelimb tract (iFT) and the bilateral ventral flexor reflex tract (bVFRT). Voluntary forelimb movements involve reaching and grasping together with necessary postural adjustments and each of these three interneuronal systems likely contribute to specific aspects of forelimb motor control. It has been demonstrated that the command for reaching can be mediated via C3-C4 PNs, while the command for grasping is conveyed via segmental interneurons in the forelimb segments. Our results reveal convergence of ascending projections from all three interneuronal systems in the LRN, producing distinct combinations of excitation and inhibition. We have also identified a separate descending control of LRN neurons exerted via a subgroup of cortico-reticular neurones. The LRN projections to the deep cerebellar nuclei exert a direct excitatory effect on descending motor pathways via the reticulospinal, vestibulospinal, and other supraspinal tracts, and might play a key role in cerebellar motor control. Our results support the hypothesis that the LRN provides the cerebellum with highly integrated information, enabling cerebellar control of complex forelimb

  18. Identification of a Male-Specific RNA Binding Protein That Regulates Sex-Specific Splicing of Bmdsx by Increasing RNA Binding Activity of BmPSI▿ §

    PubMed Central

    Suzuki, Masataka G.; Imanishi, Shigeo; Dohmae, Naoshi; Asanuma, Miwako; Matsumoto, Shogo

    2010-01-01

    Bmdsx is a sex-determining gene in the silkworm and is alternatively spliced in males and females. CE1 is a splicing silencer element responsible for the sex-specific splicing of Bmdsx. To identify sex-specific factors implicated in the sex-specific splicing of Bmdsx, we performed RNA affinity chromatography using CE1 RNA as a ligand. We have identified BmIMP, a Bombyx homolog of IGF-II mRNA binding protein (IMP), as a male-specific factor that specifically binds to CE1. The gene encoding BmIMP is localized on the Z chromosome and is male-specifically expressed in various tissues. Antisense inhibition of BmIMP expression increased female-specific splicing of Bmdsx pre-mRNA. Coimmunoprecipitation and glutathione S-transferase (GST) pulldown analyses demonstrated that BmIMP physically interacts with BmPSI, which has been identified as a factor implicated in the sex-specific splicing of Bmdsx, through the KH domains of BmIMP. The functional consequence of this interaction was examined using RNA mobility shift analysis. BmIMP increased BmPSI-CE1 RNA binding activity by decreasing the rate of BmPSI dissociation from CE1 RNA. Truncation analysis of BmIMP suggested that the KH domains are responsible for enhancing BmPSI-CE1 RNA binding activity. These results suggest that BmIMP may enhance the male-specific splicing of Bmdsx pre-mRNA by increasing RNA binding activity of BmPSI. PMID:20956562

  19. Testosterone selectively increases serum follicle-stimulating hormonal (FSH) but not luteinizing hormone (LH) in gonadotropin-releasing hormone antagonist-treated male rats: evidence for differential regulation of LH and FSH secretion.

    PubMed

    Bhasin, S; Fielder, T J; Swerdloff, R S

    1987-08-01

    Both testosterone (T) and gonadotropin-releasing hormone (GnRH)-antagonist (GnRH-A) when given alone lower serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in intact and castrated rats. However, when graded doses of testosterone enanthate (T.E.) were given to GnRH-A-treated intact male rats, a paradoxical dose-dependent increase in serum FSH occurred; whereas serum LH remained suppressed. This surprising finding led us to ask whether the paradoxical increase in serum FSH in GnRH-A-suppressed animals was a direct stimulatory effect of T on the hypothalamic-pituitary axis or the result of a T effect on a testicular regulator of FSH. To test these hypotheses, we treated adult male castrated rats with GnRH-A and graded doses of T.E. In both intact and castrated rats, serum LH remained undetectable in GnRH-A-treated rats with or without T.E. However, addition of T.E. to GnRH-A led to a dose-dependent increase in serum FSH in castrated animals as well, thus pointing against mediation by a selective testicular regulator of FSH. These data provide evidence that pituitary LH and FSH responses may be differentially regulated under certain conditions. When the action of GnRH is blocked (such as in GnRH-A-treated animals), T directly and selectively increases pituitary FSH secretion.

  20. Difficulties in Emotion Regulation as a Mediator of the Relationship Between Child Sexual Abuse Victimization and Sexual Aggression Perpetration in Male College Students.

    PubMed

    Parkhill, Michele R; Pickett, Scott M

    2016-01-01

    Although numerous studies document a link between child sexual abuse and later sexual assault perpetration in men, little research has examined why this relationship exists. One potential mechanism may be emotional regulation difficulties. The current study utilizes a college sample of 132 men to examine the mediating role of emotion regulation difficulties on the relationship between experiencing child sexual abuse and later sexual aggression. Although emotion regulation difficulties in general was not significantly related to sexual aggression, one facet, impulse control difficulties, emerged as a significant mediator of the relationship between child sexual abuse and sexual aggression. Intervention programs should focus on the care that children receive following sexual abuse, with particular emphasis on how emotion regulation abilities may be impacted. PMID:27561122

  1. Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer.

    PubMed

    Chang, Chia-Ming; Chuang, Chi-Mu; Wang, Mong-Lien; Yang, Yi-Ping; Chuang, Jen-Hua; Yang, Ming-Jie; Yen, Ming-Shyen; Chiou, Shih-Hwa; Chang, Cheng-Chang

    2016-08-05

    Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.

  2. Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells.

    PubMed

    Schmidt, Søren Fisker; Madsen, Jesper Grud Skat; Frafjord, Kari Østerli; Poulsen, Lars la Cour; Salö, Sofia; Boergesen, Michael; Loft, Anne; Larsen, Bjørk Ditlev; Madsen, Maria Stahl; Holst, Jens Juul; Maechler, Pierre; Dalgaard, Louise Torp; Mandrup, Susanne

    2016-08-30

    Glucose is an important inducer of insulin secretion, but it also stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β cells. Here, we have generated time-resolved profiles of enhancer and transcriptional activity in response to glucose in the INS-1E pancreatic β cell line. Our data outline a biphasic response with a first transcriptional wave during which metabolic genes are activated, and a second wave where cell-cycle genes are activated and β cell identity genes are repressed. The glucose-sensing transcription factor ChREBP directly activates first wave enhancers, whereas repression and activation of second wave enhancers are indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we have identified multiple putative regulators of the second wave. These include RORγ, the activity of which is important for glucose-induced proliferation of both INS-1E and primary rat β cells. PMID:27545881

  3. Gene Set−Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer

    PubMed Central

    Chang, Chia-Ming; Chuang, Chi-Mu; Wang, Mong-Lien; Yang, Yi-Ping; Chuang, Jen-Hua; Yang, Ming-Jie; Yen, Ming-Shyen; Chiou, Shih-Hwa; Chang, Cheng-Chang

    2016-01-01

    Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis. PMID:27527159

  4. Evidence-Based Theory for Integrated Genome Regulation of Ontogeny--An Unprecedented Role of Nuclear FGFR1 Signaling.

    PubMed

    Stachowiak, Michal K; Stachowiak, Ewa K

    2016-06-01

    Genetic experiments have positioned the fgfr1 gene at the top of the gene hierarchy that governs gastrulation, as well as the subsequent development of the major body axes, nervous system, muscles, and bones, by affecting downstream genes that control the cell cycle, pluripotency, and differentiation, as well as microRNAs. Studies show that this regulation is executed by a single protein, the nuclear isoform of FGFR1 (nFGFR1), which integrates signals from development-initiating factors, such as retinoic acid (RA), and operates at the interface of genomic and epigenomic information. nFGFR1 cooperates with a multitude of transcriptional factors (TFs), and targets thousands of genes encoding for mRNAs, as well as miRNAs in top ontogenic networks. nFGFR1 binds to the promoters of ancient proto-oncogenes and tumor suppressor genes, in addition to binding to metazoan morphogens that delineate body axes, and construct the nervous system, as well as mesodermal and endodermal tissues. The discovery of pan-ontogenic gene programming by integrative nuclear FGFR1 signaling (INFS) impacts our understanding of ontogeny, as well as developmental pathologies, and holds new promise for reconstructive medicine, and cancer therapy. PMID:26729628

  5. Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

    PubMed Central

    Stachowiak, Ewa K.

    2016-01-01

    Genetic experiments have positioned the fgfr1 gene at the top of the gene hierarchy that governs gastrulation, as well as the subsequent development of the major body axes, nervous system, muscles, and bones, by affecting downstream genes that control the cell cycle, pluripotency, and differentiation, as well as microRNAs. Studies show that this regulation is executed by a single protein, the nuclear isoform of FGFR1 (nFGFR1), which integrates signals from development‐initiating factors, such as retinoic acid (RA), and operates at the interface of genomic and epigenomic information. nFGFR1 cooperates with a multitude of transcriptional factors (TFs), and targets thousands of genes encoding for mRNAs, as well as miRNAs in top ontogenic networks. nFGFR1 binds to the promoters of ancient proto‐oncogenes and tumor suppressor genes, in addition to binding to metazoan morphogens that delineate body axes, and construct the nervous system, as well as mesodermal and endodermal tissues. The discovery of pan‐ontogenic gene programming by integrative nuclear FGFR1 signaling (INFS) impacts our understanding of ontogeny, as well as developmental pathologies, and holds new promise for reconstructive medicine, and cancer therapy. J. Cell. Physiol. 231: 1199–1218, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc. PMID:26729628

  6. The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway.

    PubMed

    Maclaine, Nicola J; Hupp, Ted R

    2009-05-01

    The tumour suppressor p53 is a transcription factor that has evolved the ability to integrate distinct environmental signals including DNA damage, virus infection, and cytokine signaling into a common biological outcome that maintains normal cellular control. Mutations in p53 switch the cellular transcription program resulting in deregulation of the stress responses that normally maintain cell and tissue integrity. Transgenic studies in mice have indicated that changes in the specific activity of p53 can have profound effects not only on cancer development, but also on organism aging. As the specific activity of p53 is regulated at a post-translational level by sets of enzymes that mediate phosphorylation, acetylation, methylation, and ubiquitin-like modifications, it is likely that physiological modifiers of the aging function of p53 would be enzymes that catalyze such covalent modifications. We demonstrate that distinct stress-activated kinases, including ataxia telangiectasia mutated (ATM), casein kinase 1 (CK1) and AMP-activated protein kinase (AMPK), mediate phosphorylation of a key phospho-acceptor site in the p53 transactivation domain in response to diverse stresses including ionizing radiation, DNA virus infection, and elevation in the intracellular AMP/ATP ratio. As diseases linked to aging can involve activation of p53-dependent changes in cellular protective pathways, the development of specific physiological models might further shed light on the role of p53 kinases in modifying age-related diseases. PMID:20157532

  7. Local chromatin structure of heterochromatin regulates repeated DNA stability, nucleolus structure, and genome integrity

    SciTech Connect

    Peng, Jamy C.

    2007-01-01

    Heterochromatin constitutes a significant portion of the genome in higher eukaryotes; approximately 30% in Drosophila and human. Heterochromatin contains a high repeat DNA content and a low density of protein-encoding genes. In contrast, euchromatin is composed mostly of unique sequences and contains the majority of single-copy genes. Genetic and cytological studies demonstrated that heterochromatin exhibits regulatory roles in chromosome organization, centromere function and telomere protection. As an epigenetically regulated structure, heterochromatin formation is not defined by any DNA sequence consensus. Heterochromatin is characterized by its association with nucleosomes containing methylated-lysine 9 of histone H3 (H3K9me), heterochromatin protein 1 (HP1) that binds H3K9me, and Su(var)3-9, which methylates H3K9 and binds HP1. Heterochromatin formation and functions are influenced by HP1, Su(var)3-9, and the RNA interference (RNAi) pathway. My thesis project investigates how heterochromatin formation and function impact nuclear architecture, repeated DNA organization, and genome stability in Drosophila melanogaster. H3K9me-based chromatin reduces extrachromosomal DNA formation; most likely by restricting the access of repair machineries to repeated DNAs. Reducing extrachromosomal ribosomal DNA stabilizes rDNA repeats and the nucleolus structure. H3K9me-based chromatin also inhibits DNA damage in heterochromatin. Cells with compromised heterochromatin structure, due to Su(var)3-9 or dcr-2 (a component of the RNAi pathway) mutations, display severe DNA damage in heterochromatin compared to wild type. In these mutant cells, accumulated DNA damage leads to chromosomal defects such as translocations, defective DNA repair response, and activation of the G2-M DNA repair and mitotic checkpoints that ensure cellular and animal viability. My thesis research suggests that DNA replication, repair, and recombination mechanisms in heterochromatin differ from those in

  8. A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

    PubMed Central

    Stacey, David; Lourdusamy, Anbarasu; Ruggeri, Barbara; Maroteaux, Matthieu; Jia, Tianye; Cattrell, Anna; Nymberg, Charlotte; Banaschewski, Tobias; Bhattacharyya, Sohinee; Band, Hamid; Barker, Gareth; Bokde, Arun; Buchel, Christian; Carvalho, Fabiana; Conrod, Patricia; Desrivieres, Sylvane; Easton, Alanna; Fauth-Buehler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavanh, Hugh; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Rotter, Andrea; Santos, Eugenio; Smolka, Michael; Sommer, Wolfgang; Mameli, Manuel; Spanagel, Rainer; Girault, Jean-Antoine; Mueller, Christian; Schumann, Gunter

    2016-01-01

    Background The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2−/− mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Methods Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2−/− mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). Results The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). Limitations It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2−/− mice by perturbed mesolimbic

  9. Microtubule integrity regulates src-like and extracellular signal-regulated kinase activities in human pro-monocytic cells. Importance for interleukin-1 production.

    PubMed

    Schmid-Alliana, A; Menou, L; Manié, S; Schmid-Antomarchi, H; Millet, M A; Giuriato, S; Ferrua, B; Rossi, B

    1998-02-01

    We have demonstrated previously that microtubule depolymerization by colchicine in human monocytes induces selective production of interleukin-1 (IL-1) (Manié, S., Schmid-Alliana, A., Kubar, J., Ferrua, B., and Rossi, B. (1993) J. Biol. Chem. 268, 13675-13681). Here, we provide evidence that disruption of the microtubule structure rapidly triggers extracellular signal-regulated kinase (ERK) activation, whereas it was without effect on SAPK2 activity, which is commonly acknowledged to control pro-inflammatory cytokine production. This process involves the activation of the entire cascade including Ras, Raf-1, MEK1/2, ERK1, and ERK2. Activation of ERKs is followed by their nuclear translocation. Although other SAPK congeners might be activated upon microtubule depolymerization, the activation of ERK1 and ERK2 is mandatory for IL-1 production as shown by the blocking effect of PD 98059, a specific MEK1/2 inhibitor. Additionally, we provide evidence that microtubule disruption also induces the activation of c-Src and Hck activities. The importance of Src kinases in the mediation of the colchicine effect is underscored by the fact that CP 118556, a specific inhibitor of Src-like kinase, abrogates both the colchicine-induced ERK activation and IL-1 production. This is the first evidence that ERK activation is an absolute prerequisite for induction of this cytokine. Altogether, our data lend support to a model where the status of microtubule integrity controls the level of Src activities that subsequently activate the ERK kinase cascade, thus leading to IL-1 production.

  10. Age dependent differences in the regulation of hippocampal steroid hormones and receptor genes: relations to motivation and cognition in male rats.

    PubMed

    Meyer, K; Korz, V

    2013-02-01

    Estrogen and estrogenic functions are age-dependently involved in the modulation of learning, memory and mood in female humans and animals. However, the investigation of estrogenic effects in males has been largely neglected. Therefore, we investigated the hippocampal gene expression of estrogen receptors α and β (ERα, β) in 8-week-old, 12-week-old and 24-week-old male rats. To control for possible interactions between the expression of the estrogen receptor genes and other learning-related steroid receptors, androgen receptors (AR), corticosterone-binding glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) were also measured. Furthermore, the concentrations of the ligands 17β-estradiol, testosterone and corticosterone were measured. The spatial training was conducted in a hole-board. The 8-week-old rats exhibited higher levels of general activity and exploration during the training and performed best with respect to spatial learning and memory, whereas no difference was found between the 12-week-old and 24-week-old rats. The trained 8-week-old rats exhibited increased gene expression of ERα compared with the untrained rats in this age group as well as the trained 12-week-old and 24-week-old rats. The concentrations of estradiol and testosterone, however, were generally higher in the 24-week-old rats than in the 8-week-old and 12-week-old rats. The ERα mRNA concentrations correlated positively with behavior that indicate general learning motivation. These results suggest a specific role of ERα in the age-related differences in motivation and subsequent success in the task. Thus, estrogen and estrogenic functions may play a more prominent role in young male behavior and development than has been previously assumed.

  11. Cocaine exposure prior to pregnancy alters the psychomotor response to cocaine and transcriptional regulation of the dopamine D1 receptor in adult male offspring.

    PubMed

    Sasaki, Aya; Constantinof, Andrea; Pan, Pauline; Kupferschmidt, Dave A; McGowan, Patrick O; Erb, Suzanne

    2014-05-15

    There is evidence that maternal experience prior to pregnancy can play an important role in behavioral, physiological, and genetic programming of offspring. Likewise, exposure to cocaine in utero can result in marked changes in central nervous system function of offspring. In this study, we examined whether exposure of rat dams to cocaine prior to pregnancy subsequently alters indices of behavior, physiology, and gene expression in offspring. Multiple outcome measures were examined in adult male offspring: (1) behavioral expression of cocaine-induced psychomotor activation; (2) levels of corticosterone in response to immobilization stress; and (3) expression of multiple genes, including dopamine receptor D1 (DRD1) and D2 (DRD2), glucocorticoid receptor (GR), and corticotropin-releasing factor (CRF), in functionally relevant brain regions. Adult Sprague-Dawley females were exposed to cocaine (15-30 mg/kg, i.p.) or saline for 10 days, and were then mated to drug naïve males of the same strain. Separate groups of adult male offspring were tested for their acute psychomotor response to cocaine (0, 15, 30 mg/kg, i.p.), corticosterone responsivity to 20 min of immobilization stress, and expression of multiple genes using quantitative PCR. Offspring of dams exposed to cocaine prior to conception exhibited increased psychomotor sensitivity to cocaine, and upregulated gene expression of DRD1 in the medial prefrontal cortex (mPFC). Neither stress-induced corticosterone levels nor gene expression of GR or CRF genes were altered. These data suggest that cocaine exposure before pregnancy can serve to enhance psychomotor sensitivity to cocaine in offspring, possibly via alterations in dopamine function that include upregulation of the DRD1. PMID:24583058

  12. The male sterility 8 mutation of maize disrupts the temporal progression of the transcriptome and results in mis-regulation of metabolic functions

    PubMed Central

    Wang, Dongxue; Oses-Prieto, Juan A.; Li, Kathy H.; Fernandes, John F.; Burlingame, Alma L.; Walbot, Virginia

    2010-01-01

    SUMMARY Maize anther ontogeny is complex with expression of more than 30,000 genes over four days of cell proliferation, cell fate acquisition, and the start of meiosis. Although many male-sterile mutants disrupt these key steps, few have been investigated in detail. The terminal phenotypes of maize male-sterile 8 (ms8) are small anthers exhibiting meiotic failure. Here we document much earlier defects: ms8 epidermal cells are normal in number but fail to elongate, and there are fewer, larger tapetal cells that retain rather than secrete their contents. ms8 meiocytes separate early, have extra space between them occupied by excess callose, and the meiotic dyads abort. Thousands of transcriptome changes occur in ms8 including ectopic activation of genes not expressed in fertile siblings, failure to express some genes, differential expression compared to fertile siblings and about 40% of the differentially expressed transcripts appear precociously. There is a high correlation between mRNA accumulation assessed by microarray hybridization and qRT-PCR. Sixty-three differentially expressed proteins were identified after 2-D gel electrophoresis followed by LC/MS/MS (liquid chromatography tandem mass spectroscopy), including those involved in metabolism, plasmodesmatal remodeling, and cell division. The majority of these were not identified by differential RNA expression demonstrating the importance of proteomics to define developmental mutants. PMID:20626649

  13. Type IV Collagen Controls the Axogenesis of Cerebellar Granule Cells by Regulating Basement Membrane Integrity in Zebrafish

    PubMed Central

    Takeuchi, Miki; Yamaguchi, Shingo; Yonemura, Shigenobu; Kakiguchi, Kisa; Sato, Yoshikatsu; Higashiyama, Tetsuya; Shimizu, Takashi; Hibi, Masahiko

    2015-01-01

    Granule cells (GCs) are the major glutamatergic neurons in the cerebellum, and GC axon formation is an initial step in establishing functional cerebellar circuits. In the zebrafish cerebellum, GCs can be classified into rostromedial and caudolateral groups, according to the locations of their somata in the corresponding cerebellar lobes. The axons of the GCs in the caudolateral lobes terminate on crest cells in the dorsal hindbrain, as well as forming en passant synapses with Purkinje cells in the cerebellum. In the zebrafish mutant shiomaneki, the caudolateral GCs extend aberrant axons. Positional cloning revealed that the shiomaneki (sio) gene locus encodes Col4a6, a subunit of type IV collagen, which, in a complex with Col4a5, is a basement membrane (BM) component. Both col4a5 and col4a6 mutants displayed similar abnormalities in the axogenesis of GCs and retinal ganglion cells (RGCs). Although type IV collagen is reported to control axon targeting by regulating the concentration gradient of an axonal guidance molecule Slit, Slit overexpression did not affect the GC axons. The structure of the BM surrounding the tectum and dorsal hindbrain was disorganized in the col4a5 and col4a6 mutants. Moreover, the abnormal axogenesis of the caudolateral GCs and the RGCs was coupled with aberrant BM structures in the type IV collagen mutants. The regrowth of GC axons after experimental ablation revealed that the original and newly formed axons displayed similar branching and extension abnormalities in the col4a6 mutants. These results collectively suggest that type IV collagen controls GC axon formation by regulating the integrity of the BM, which provides axons with the correct path to their targets. PMID:26451951

  14. An integrated genomic approach for rapid delineation of candidate genes regulating agro-morphological traits in chickpea.

    PubMed

    Saxena, Maneesha S; Bajaj, Deepak; Das, Shouvik; Kujur, Alice; Kumar, Vinod; Singh, Mohar; Bansal, Kailash C; Tyagi, Akhilesh K; Parida, Swarup K

    2014-12-01

    The identification and fine mapping of robust quantitative trait loci (QTLs)/genes governing important agro-morphological traits in chickpea still lacks systematic efforts at a genome-wide scale involving wild Cicer accessions. In this context, an 834 simple sequence repeat and single-nucleotide polymorphism marker-based high-density genetic linkage map between cultivated and wild parental accessions (Cicer arietinum desi cv. ICC 4958 and Cicer reticulatum wild cv. ICC 17160) was constructed. This inter-specific genetic map comprising eight linkage groups spanned a map length of 949.4 cM with an average inter-marker distance of 1.14 cM. Eleven novel major genomic regions harbouring 15 robust QTLs (15.6-39.8% R(2) at 4.2-15.7 logarithm of odds) associated with four agro-morphological traits (100-seed weight, pod and branch number/plant and plant hairiness) were identified and mapped on chickpea chromosomes. Most of these QTLs showed positive additive gene effects with effective allelic contribution from ICC 4958, particularly for increasing seed weight (SW) and pod and branch number. One robust SW-influencing major QTL region (qSW4.2) has been narrowed down by combining QTL mapping with high-resolution QTL region-specific association analysis, differential expression profiling and gene haplotype-based association/LD mapping. This enabled to delineate a strong SW-regulating ABI3VP1 transcription factor (TF) gene at trait-specific QTL interval and consequently identified favourable natural allelic variants and superior high seed weight-specific haplotypes in the upstream regulatory region of this gene showing increased transcript expression during seed development. The genes (TFs) harbouring diverse trait-regulating QTLs, once validated and fine-mapped by our developed rapid integrated genomic approach and through gene/QTL map-based cloning, can be utilized as potential candidates for marker-assisted genetic enhancement of chickpea.

  15. Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes

    PubMed Central

    2011-01-01

    Background Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Little is known about small regulatory RNAs and how they contribute to pathogenesis, progression and transcriptome changes in MDS. Methods Patients' primary marrow cells were screened for short RNAs (RNA-seq) using next generation sequencing. Exon arrays from the same cells were used to profile gene expression and additional measures on 98 patients obtained. Integrative bioinformatics algorithms were proposed, and pathway and ontology analysis performed. Results In low-grade MDS, observations implied extensive post-transcriptional regulation via microRNAs (miRNA) and the recently discovered Piwi interacting RNAs (piRNA). Large expression differences were found for MDS-associated and novel miRNAs, including 48 sequences matching to miRNA star (miRNA*) motifs. The detected species were predicted to regulate disease stage specific molecular functions and pathways, including apoptosis and response to DNA damage. In high-grade MDS, results suggested extensive post-translation editing via transfer RNAs (tRNAs), providing a potential link for reduced apoptosis, a hallmark for this disease stage. Bioinformatics analysis confirmed important regulatory roles for MDS linked miRNAs and TFs, and strengthened the biological significance of miRNA*. The "RNA polymerase II promoters" were identified as the tightest controlled biological function. We suggest their control by a miRNA dominated feedback loop, which might be linked to the dramatically different miRNA amounts seen between low and high-grade MDS. Discussion The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis. PMID:21342535

  16. HRGRN: A Graph Search-Empowered Integrative Database of Arabidopsis Signaling Transduction, Metabolism and Gene Regulation Networks

    PubMed Central

    Dai, Xinbin; Li, Jun; Liu, Tingsong; Zhao, Patrick Xuechun

    2016-01-01

    The biological networks controlling plant signal transduction, metabolism and gene regulation are composed of not only tens of thousands of genes, compounds, proteins and RNAs but also the complicated interactions and co-ordination among them. These networks play critical roles in many fundamental mechanisms, such as plant growth, development and environmental response. Although much is known about these complex interactions, the knowledge and data are currently scattered throughout the published literature, publicly available high-throughput data sets and third-party databases. Many ‘unknown’ yet important interactions among genes need to be mined and established through extensive computational analysis. However, exploring these complex biological interactions at the network level from existing heterogeneous resources remains challenging and time-consuming for biologists. Here, we introduce HRGRN, a graph search-empowered integrative database of Arabidopsis signal transduction, metabolism and gene regulatory networks. HRGRN utilizes Neo4j, which is a highly scalable graph database management system, to host large-scale biological interactions among genes, proteins, compounds and small RNAs that were either validated experimentally or predicted computationally. The associated biological pathway information was also specially marked for the interactions that are involved in the pathway to facilitate the investigation of cross-talk between pathways. Furthermore, HRGRN integrates a series of graph path search algorithms to discover novel relationships among genes, compounds, RNAs and even pathways from heterogeneous biological interaction data that could be missed by traditional SQL database search methods. Users can also build subnetworks based on known interactions. The outcomes are visualized with rich text, figures and interactive network graphs on web pages. The HRGRN database is freely available at http://plantgrn.noble.org/hrgrn/. PMID:26657893

  17. HRGRN: A Graph Search-Empowered Integrative Database of Arabidopsis Signaling Transduction, Metabolism and Gene Regulation Networks.

    PubMed

    Dai, Xinbin; Li, Jun; Liu, Tingsong; Zhao, Patrick Xuechun

    2016-01-01

    The biological networks controlling plant signal transduction, metabolism and gene regulation are composed of not only tens of thousands of genes, compounds, proteins and RNAs but also the complicated interactions and co-ordination among them. These networks play critical roles in many fundamental mechanisms, such as plant growth, development and environmental response. Although much is known about these complex interactions, the knowledge and data are currently scattered throughout the published literature, publicly available high-throughput data sets and third-party databases. Many 'unknown' yet important interactions among genes need to be mined and established through extensive computational analysis. However, exploring these complex biological interactions at the network level from existing heterogeneous resources remains challenging and time-consuming for biologists. Here, we introduce HRGRN, a graph search-empowered integrative database of Arabidopsis signal transduction, metabolism and gene regulatory networks. HRGRN utilizes Neo4j, which is a highly scalable graph database management system, to host large-scale biological interactions among genes, proteins, compounds and small RNAs that were either validated experimentally or predicted computationally. The associated biological pathway information was also specially marked for the interactions that are involved in the pathway to facilitate the investigation of cross-talk between pathways. Furthermore, HRGRN integrates a series of graph path search algorithms to discover novel relationships among genes, compounds, RNAs and even pathways from heterogeneous biological interaction data that could be missed by traditional SQL database search methods. Users can also build subnetworks based on known interactions. The outcomes are visualized with rich text, figures and interactive network graphs on web pages. The HRGRN database is freely available at http://plantgrn.noble.org/hrgrn/. PMID:26657893

  18. HRGRN: A Graph Search-Empowered Integrative Database of Arabidopsis Signaling Transduction, Metabolism and Gene Regulation Networks.

    PubMed

    Dai, Xinbin; Li, Jun; Liu, Tingsong; Zhao, Patrick Xuechun

    2016-01-01

    The biological networks controlling plant signal transduction, metabolism and gene regulation are composed of not only tens of thousands of genes, compounds, proteins and RNAs but also the complicated interactions and co-ordination among them. These networks play critical roles in many fundamental mechanisms, such as plant growth, development and environmental response. Although much is known about these complex interactions, the knowledge and data are currently scattered throughout the published literature, publicly available high-throughput data sets and third-party databases. Many 'unknown' yet important interactions among genes need to be mined and established through extensive computational analysis. However, exploring these complex biological interactions at the network level from existing heterogeneous resources remains challenging and time-consuming for biologists. Here, we introduce HRGRN, a graph search-empowered integrative database of Arabidopsis signal transduction, metabolism and gene regulatory networks. HRGRN utilizes Neo4j, which is a highly scalable graph database management system, to host large-scale biological interactions among genes, proteins, compounds and small RNAs that were either validated experimentally or predicted computationally. The associated biological pathway information was also specially marked for the interactions that are involved in the pathway to facilitate the investigation of cross-talk between pathways. Furthermore, HRGRN integrates a series of graph path search algorithms to discover novel relationships among genes, compounds, RNAs and even pathways from heterogeneous biological interaction data that could be missed by traditional SQL database search methods. Users can also build subnetworks based on known interactions. The outcomes are visualized with rich text, figures and interactive network graphs on web pages. The HRGRN database is freely available at http://plantgrn.noble.org/hrgrn/.

  19. Male Puberty Rites: A Path Analytic Model.

    ERIC Educational Resources Information Center

    Kitahara, Michio

    1982-01-01

    Studies two determinants of male puberty rites: communitywide exclusive male work groups and polygyny which act as an extension of male subculture; and sexual integration in the division of labor and distant father-child relationship which act to reduce the distance between the sexes. (Author/RC)

  20. Long-term treadmill exercise improves spatial memory of male APPswe/PS1dE9 mice by regulation of BDNF expression and microglia activation.

    PubMed

    Xiong, J Y; Li, S C; Sun, Y X; Zhang, X S; Dong, Z Z; Zhong, P; Sun, X R

    2015-11-01

    Increasing evidence suggests that physical activity could delay or attenuate the symptoms of Alzheimer's disease (AD). But the underlying mechanisms are still not fully understood. To investigate the effect of long-term treadmill exercise on the spatial memory of AD mice and the possible role of β-amyloid, brain-derived neurotrophic factor (BDNF) and microglia in the effect, male APPswe/PS1dE9 AD mice aged 4 months were subjected to treadmill exercise for 5 months with 6 sessions per week and gradually increased load. A Morris water maze was used to evaluate the spatial memory. Expression levels of β-amyloid, BDNF and Iba-1 (a microglia marker) in brain tissue were detected by immunohistochemistry. Sedentary AD mice and wildtype C57BL/6J mice served as controls. The results showed that 5-month treadmill exercise significantly decreased the escape latencies (P < 0.01 on the 4th day) and improved the spatial memory of the AD mice in the water maze test. Meanwhile, treadmill exercise significantly increased the number of BDNF-positive cells and decreased the ratios of activated microglia in both the cerebral cortex and the hippocampus. However, treadmill exercise did not significantly alleviate the accumulation of β-amyloid in either the cerebral cortex or the hippocampus of the AD mice (P > 0.05). The study suggested that long-term treadmill exercise could improve the spatial memory of the male APPswe/PS1dE9 AD mice. The increase in BDNF-positive cells and decrease in activated microglia might underpin the beneficial effect.

  1. An overview of anorexia nervosa in males.

    PubMed

    Wooldridge, Tom; Lytle, Pauline Polly

    2012-01-01

    This article presents an integrative overview of existing research on anorexia nervosa (AN) in adolescent males. AN is commonly thought of as a female disorder. Even though as much as 25% of the clinical population is male, research on AN in males is limited. Additionally, most conceptualizations of male AN emphasize a single etiological factor and, therefore, produce treatments that fail to address it as a global phenomenon. In contrast, an integrative understanding that incorporates research on the familial, biological, cultural, and psychodynamic elements involved in male AN encourages treatment that comprehensively addresses the disorder.

  2. Male contraception.

    PubMed

    Chao, Jing; Page, Stephanie T; Anderson, Richard A

    2014-08-01

    Clear evidence shows that many men and women would welcome new male methods of contraception, but none have become available. The hormonal approach is based on suppression of gonadotropins and thus of testicular function and spermatogenesis, and has been investigated for several decades. This approach can achieve sufficient suppression of spermatogenesis for effective contraception in most men, but not all; the basis for these men responding insufficiently is unclear. Alternatively, the non-hormonal approach is based on identifying specific processes in sperm development, maturation and function. A range of targets has been identified in animal models, and targeted effectively. This approach, however, remains in the pre-clinical domain at present. There are, therefore, grounds for considering that safe, effective and reversible methods of contraception for men can be developed. PMID:24947599

  3. Male contraception

    PubMed Central

    Chao, Jing; Page, Stephanie T.; Anderson, Richard A.

    2015-01-01

    Clear evidence shows that many men and women would welcome new male methods of contraception, but none have become available. The hormonal approach is based on suppression of gonadotropins and thus of testicular function and spermatogenesis, and has been investigated for several decades. This approach can achieve sufficient suppression of spermatogenesis for effective contraception in most men, but not all; the basis for these men responding insufficiently is unclear. Alternatively, the nonhormonal approach is based on identifying specific processes in sperm development, maturation and function. A range of targets has been identified in animal models, and targeted effectively. This approach, however, remains in the pre-clinical domain at present. There are, therefore, grounds for considering that safe, effective and reversible methods of contraception for men can be developed. PMID:24947599

  4. Male hypogonadism.

    PubMed

    Basaria, Shehzad

    2014-04-01

    Male hypogonadism is a clinical syndrome that results from failure to produce physiological concentrations of testosterone, normal amounts of sperm, or both. Hypogonadism may arise from testicular disease (primary hypogonadism) or dysfunction of the hypothalamic-pituitary unit (secondary hypogonadism). Clinical presentations vary dependent on the time of onset of androgen deficiency, whether the defect is in testosterone production or spermatogenesis, associated genetic factors, or history of androgen therapy. The clinical diagnosis of hypogonadism is made on the basis of signs and symptoms consistent with androgen deficiency and low morning testosterone concentrations in serum on multiple occasions. Several testosterone-replacement therapies are approved for treatment and should be selected according to the patient's preference, cost, availability, and formulation-specific properties. Contraindications to testosterone-replacement therapy include prostate and breast cancers, uncontrolled congestive heart failure, severe lower-urinary-tract symptoms, and erythrocytosis. Treatment should be monitored for benefits and adverse effects. PMID:24119423

  5. Effects of an Obesity Intervention Integrating Physical Activity and Psychological Strategy on BMI, Physical Activity, and Psychological Variables in Male Obese Adolescents.

    PubMed

    Lee, HakGweon; Kim, YoungHo

    2015-01-01

    The current study investigated the effect of an obesity intervention incorporating physical activity and behavior-based motivational enhancement intervention on BMI, physical activity levels, and psychological variables toward physical activity in male obese adolescents. Single group study without having a control group was carried out in Korea. Sixty-eight obese male adolescents who had BMI greater than 25 kg/m(2) participated in the 16-week obesity intervention. During this period, the study participants' BMI, physical activity levels, self-efficacy, and perceived benefits and barriers were measured at the three time point (baseline, after week 8, and after week 16). Results indicated that obese adolescents' BMI significantly decreased (F = 3.51, p = .03) and physical activity (F = 4.01, p = .02) significantly increased over the 16-week obesity intervention. In addition, Exercise self-efficacy (F = 5.02) and perceived benefits toward physical activity (F = 5.34) significantly increased but perceived barriers of physical activity (F = 5.10) gradually decreased over the intervention. This study suggests that an obesity intervention combining physical activity and behavior-based motivational enhancement intervention significantly contributed to decreased BMI, increased physical activity, and positively changed psychological variables related to physical activity. This first application has resulted in preliminary support for this intervention modality within non-western obese adolescents.

  6. The PHD Finger Protein MMD1/DUET Ensures the Progression of Male Meiotic Chromosome Condensation and Directly Regulates the Expression of the Condensin Gene CAP-D3.

    PubMed

    Wang, Jun; Niu, Baixiao; Huang, Jiyue; Wang, Hongkuan; Yang, Xiaohui; Dong, Aiwu; Makaroff, Christopher; Ma, Hong; Wang, Yingxiang

    2016-08-01

    Chromosome condensation, a process mediated by the condensin complex, is essential for proper chromosome segregation during cell division. Unlike rapid mitotic chromosome condensation, meiotic chromosome condensation occurs over a relatively long prophase I and is unusually complex due to the coordination with chromosome axis formation and homolog interaction. The molecular mechanisms that regulate meiotic chromosome condensation progression from prophase I to metaphase I are unclear. Here, we show that the Arabidopsis thaliana meiotic PHD-finger protein MMD1/DUET is required for progressive compaction of prophase I chromosomes to metaphase I bivalents. The MMD1 PHD domain is required for its function in chromosome condensation and binds to methylated histone tails. Transcriptome analysis and qRT-PCR showed that several condensin genes exhibit significantly reduced expression in mmd1 meiocytes. Furthermore, MMD1 specifically binds to the promoter region of the condensin subunit gene CAP-D3 to enhance its expression. Moreover, cap-d3 mutants exhibit similar chromosome condensation defects, revealing an MMD1-dependent mechanism for regulating meiotic chromosome condensation, which functions in part by promoting condensin gene expression. Together, these discoveries provide strong evidence that the histone reader MMD1/DUET defines an important step for regulating the progression of meiotic prophase I chromosome condensation.

  7. The PHD Finger Protein MMD1/DUET Ensures the Progression of Male Meiotic Chromosome Condensation and Directly Regulates the Expression of the Condensin Gene CAP-D3.

    PubMed

    Wang, Jun; Niu, Baixiao; Huang, Jiyue; Wang, Hongkuan; Yang, Xiaohui; Dong, Aiwu; Makaroff, Christopher; Ma, Hong; Wang, Yingxiang

    2016-08-01

    Chromosome condensation, a process mediated by the condensin complex, is essential for proper chromosome segregation during cell division. Unlike rapid mitotic chromosome condensation, meiotic chromosome condensation occurs over a relatively long prophase I and is unusually complex due to the coordination with chromosome axis formation and homolog interaction. The molecular mechanisms that regulate meiotic chromosome condensation progression from prophase I to metaphase I are unclear. Here, we show that the Arabidopsis thaliana meiotic PHD-finger protein MMD1/DUET is required for progressive compaction of prophase I chromosomes to metaphase I bivalents. The MMD1 PHD domain is required for its function in chromosome condensation and binds to methylated histone tails. Transcriptome analysis and qRT-PCR showed that several condensin genes exhibit significantly reduced expression in mmd1 meiocytes. Furthermore, MMD1 specifically binds to the promoter region of the condensin subunit gene CAP-D3 to enhance its expression. Moreover, cap-d3 mutants exhibit similar chromosome condensation defects, revealing an MMD1-dependent mechanism for regulating meiotic chromosome condensation, which functions in part by promoting condensin gene expression. Together, these discoveries provide strong evidence that the histone reader MMD1/DUET defines an important step for regulating the progression of meiotic prophase I chromosome condensation. PMID:27385818

  8. Lycopene and male infertility.

    PubMed

    Durairajanayagam, Damayanthi; Agarwal, Ashok; Ong, Chloe; Prashast, Pallavi

    2014-01-01

    Excessive amounts of reactive oxygen species (ROS) cause a state of oxidative stress, which result in sperm membrane lipid peroxidation, DNA damage and apoptosis, leading to decreased sperm viability and motility. Elevated levels of ROS are a major cause of idiopathic male factor infertility, which is an increasingly common problem today. Lycopene, the most potent singlet oxygen quencher of all carotenoids, is a possible treatment option for male infertility because of its antioxidant properties. By reacting with and neutralizing free radicals, lycopene could reduce the incidence of oxidative stress and thus, lessen the damage that would otherwise be inflicted on spermatozoa. It is postulated that lycopene may have other beneficial effects via nonoxidative mechanisms in the testis, such as gap junction communication, modulation of gene expression, regulation of the cell cycle and immunoenhancement. Various lycopene supplementation studies conducted on both humans and animals have shown promising results in alleviating male infertility-lipid peroxidation and DNA damage were decreased, while sperm count and viability, and general immunity were increased. Improvement of these parameters indicates a reduction in oxidative stress, and thus the spermatozoa is less vulnerable to oxidative damage, which increases the chances of a normal sperm fertilizing the egg. Human trials have reported improvement in sperm parameters and pregnancy rates with supplementation of 4-8 mg of lycopene daily for 3-12 months. However, further detailed and extensive research is still required to determine the dosage and the usefulness of lycopene as a treatment for male infertility.

  9. An Analysis of the Effects of Integrated Instruction of Metacognitive and Study Skills upon the Self-Efficacy and Achievement of Male and Female Students.

    ERIC Educational Resources Information Center

    Higgins, Barbara Ann

    The impact of using integrated metacognitive instruction on high school students' achievement, self-efficacy, and test anxiety was studied. Forty students in 2 advanced geography classes in a large suburban high school participated. The level of metacognitive strategies students used at the beginning of the semester was assessed and compared to…

  10. Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells

    PubMed Central

    Latos, Paulina A.; Goncalves, Angela; Oxley, David; Mohammed, Hisham; Turro, Ernest; Hemberger, Myriam

    2015-01-01

    Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors. PMID:26206133

  11. An integrative analysis of TFBS-clustered regions reveals new transcriptional regulation models on the accessible chromatin landscape.

    PubMed

    Chen, Hebing; Li, Hao; Liu, Feng; Zheng, Xiaofei; Wang, Shengqi; Bo, Xiaochen; Shu, Wenjie

    2015-01-01

    DNase I hypersensitive sites (DHSs) define the accessible chromatin landscape and have revolutionised the discovery of distinct cis-regulatory elements in diverse organisms. Here, we report the first comprehensive map of human transcription factor binding site (TFBS)-clustered regions using Gaussian kernel density estimation based on genome-wide mapping of the TFBSs in 133 human cell and tissue types. Approximately 1.6 million distinct TFBS-clustered regions, collectively spanning 27.7% of the human genome, were discovered. The TFBS complexity assigned to each TFBS-clustered region was highly correlated with genomic location, cell selectivity, evolutionary conservation, sequence features, and functional roles. An integrative analysis of these regions using ENCODE data revealed transcription factor occupancy, transcriptional activity, histone modification, DNA methylation, and chromatin structures that varied based on TFBS complexity. Furthermore, we found that we could recreate lineage-branching relationships by simple clustering of the TFBS-clustered regions from terminally differentiated cells. Based on these findings, a model of transcriptional regulation determined by TFBS complexity is proposed. PMID:25682954

  12. Extracytoplasmic Function (ECF) Sigma Factor Gene Regulation in Pseudomonas syringae: Integrated Molecular and Computational Characterization of PvdS-Regulated Promoters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The extracytoplasmic function (ECF) sigma factor PvdS regulates the expression of genes required for the biosynthesis and transport of pyoverdine, a siderophore that functions in iron acquisition. The production of pyoverdine is a distinctive trait of the fluorescent pseudomonads and the regulation ...

  13. An integrated genetic, genomic and systems approach defines gene networks regulated by the interaction of light and carbon signaling pathways in Arabidopsis

    PubMed Central

    Thum, Karen E; Shin, Michael J; Gutiérrez, Rodrigo A; Mukherjee, Indrani; Katari, Manpreet S; Nero, Damion; Shasha, Dennis; Coruzzi, Gloria M

    2008-01-01

    Background Light and carbon are two important interacting signals affecting plant growth and development. The mechanism(s) and/or genes involved in sensing and/or mediating the signaling pathways involving these interactions are unknown. This study integrates genetic, genomic and systems approaches to identify a genetically perturbed gene network that is regulated by the interaction of carbon and light signaling in Arabidopsis. Results Carbon and light insensitive (cli) mutants were isolated. Microarray data from cli186 is analyzed to identify the genes, biological processes and gene networks affected by the integration of light and carbon pathways. Analysis of this data reveals 966 genes regulated by light and/or carbon signaling in wild-type. In cli186, 216 of these light/carbon regulated genes are misregulated in response to light and/or carbon treatments where 78% are misregulated in response to light and carbon interactions. Analysis of the gene lists show that genes in the biological processes "energy" and "metabolism" are over-represented among the 966 genes regulated by carbon and/or light in wild-type, and the 216 misregulated genes in cli186. To understand connections among carbon and/or light regulated genes in wild-type and the misregulated genes in cli186, the microarray data is interpreted in the context of metabolic and regulatory networks. The network created from the 966 light/carbon regulated genes in wild-type, reveals that cli186 is affected in the light and/or carbon regulation of a network of 60 connected genes, including six transcription factors. One transcription factor, HAT22 appears to be a regulatory "hub" in the cli186 network as it shows regulatory connections linking a metabolic network of genes involved in "amino acid metabolism", "C-compound/carbohydrate metabolism" and "glycolysis/gluconeogenesis". Conclusion The glob