553 research outputs found
Molecular mechanisms of androgen receptor functions
The androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which
are necessary for development and maintenance of the functions of the male sex organs,
including the prostate. Androgens also play an important role in benign abnormalities of the
prostate and in the growth of prostate cancer. Prostate tumors, which are not yet metastatic, are
treated with radiotherapy or by surgical removal of the complete prostate. Therapy of
metastasized prostate cancer aims on inhibition of androgen action, by inhibtion of the
production of T in the testis (chemical castration) and by administration of anti-androgens. T
and DHT exert their function by specific binding as a ligand to the androgen receptor (AR). The
AR is a member of the family of nuclear receptors. It is expressed in androgen target cells, and
functions as a ligand induced transcription factor. In this thesis described research project
focusses on several molecular mechanisms of AR functions.
Chapter 1 gives an overview of the current knowledge on nuclear receptors in general and
different aspects of AR functions in particular. Among the latter are: receptor structure,
interaction with other proteins involved in transcription, the ligand-dependent interaction
between the N-terminal domain (NTD) and the ligand binding C-terminal domain (LBD) of the
AR (N/C interaction), expression of androgen-specific regulated genes, and the role of AR
mutations in prostate cancer
Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcirptional coactivator TIF2 (Transcriptional Intermediary Factor 2)
Hoarding and Emotional Reactivity: The Link Between Negative Emotional Reactions and Hoarding Symptomatology
Hoarding disorder (HD) is characterized by difficulty discarding, clutter, and frequently excessive acquiring. Theories have pointed to intense negative emotional reactions (e.g., sadness) as one factor that may play a critical role in HD\u27s etiology. Preliminary work with an analogue sample indicated that more intense negative emotions following emotional films were linked with greater hoarding symptoms. Symptom provocation imaging studies with HD patients have also found evidence for excessive activation in brain regions implicated in processing emotions. The current study utilized a sample with self-reported serious hoarding difficulties to examine how hoarding symptoms related to both general and hoarding-related emotional reactivity, taking into account the specificity of these relationships. We also examined how two cognitive factors, fear of decision-making and confidence in memory, modified this relationship. 628 participants with self-identified hoarding difficulties completed questionnaires about general emotional reactivity, depression, anxiety, decision-making, and confidence in memory. To assess hoarding-related emotional reactivity, participants reported their emotional reactions when imagining discarding various items. Heightened general emotional reactivity and more intense emotional reactions to imagined discarding were associated with both difficulty discarding and acquisition, but not clutter, controlling for age, gender, and co-occurring mood and anxiety symptoms. Fear of decision-making and confidence in memory interacted with general emotional reactivity to predict hoarding symptoms. These findings provide support for cognitive-behavioral models of hoarding. Experimental research should be conducted to discover whether emotional reactivity increases vulnerability for HD. Future work should also examine whether emotional reactivity should be targeted in interventions for hoarding
Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2)
Previous studies in yeast and mammalian cells showed a functional
interaction between the amino-terminal domain and the carboxy-terminal,
ligand-binding domain (LBD) of the human androgen receptor (AR). In the
present study, the AR subdomains involved in this in vivo interaction were
determined in more detail. Cotransfection experiments in Chinese hamster
ovary (CHO) cells and two-hybrid experiments in yeast revealed that two
regions in the NH2-terminal domain are involved in the functional
interaction with the LBD: an interacting domain at the very NH2 terminus,
located between amino acid residues 3 and 36, and a second domain,
essential for transactivation, located between residues 370 and 494.
Substitution of glutamic acid by glutamine at position 888 (E888Q) in the
AF-2 activation domain (AD) core region in the LBD, markedly decreased the
interaction with the NH2-terminal domain. This mutation neither influenced
hormone binding nor LBD homodimerization, suggesting a role of the AF-2 AD
core region in the functional interaction between the NH2-terminal domain
and the LBD. The AF-2 AD core region was also involved in the interaction
with the coactivator TIF2 (transcriptional intermediary factor 2), as the
E888Q mutation decreased the stimulatory effect of TIF2 on AR AF-2
activity. Cotransfection of TIF2 and the AR NH2-terminal domain expression
vectors did not result in synergy between both factors in the induction of
AR AF-2 activity. TIF2 highly induced AR AF-2 activity on a complex
promoter [mouse mammary tumor virus (MMTV)], but it was hardly active on a
minimal promoter (GRE-TATA). In contrast, the AR NH2-terminal domain
induced AR AF-2 activity on both promoter constructs. These data indicate
that both the AR NH2-terminal domain and the coactivator TIF2 functionally
interact, either directly or indirectly, with the AF-2 AD core region in
the AR-LBD, but the level of transcriptional response induced by TIF2
depends on the promoter context
Viewpoint: Evaluating the impact of malaria control efforts on mortality in sub-Saharan Africa
OBJECTIVE To describe an approach for evaluating the impact of malaria control efforts on malaria-associated mortality in sub-Saharan Africa, where disease-specific mortality trends usually cannot be measured directly and most malaria deaths occur among young children. METHODS Methods for evaluating changes in malaria-associated mortality are examined; advantages and disadvantages are presented. RESULTS All methods require a plausibility argument - i.e., an assumption that mortality reductions can be attributed to programmatic efforts if improvements are found in steps of the causal pathway between intervention scale-up and mortality trends. As different methods provide complementary information, they can be used together. We recommend following trends in the coverage of malaria control interventions, other factors influencing childhood mortality, malaria-associated morbidity (especially anaemia), and all-cause childhood mortality. This approach reflects decreases in malaria's direct and indirect mortality burden and can be examined in nearly all countries. Adding other information can strengthen the plausibility argument: trends in indicators of malaria transmission, information from demographic surveillance systems and sentinel sites where malaria diagnostics are systematically used, and verbal autopsies linked to representative household surveys. Health facility data on malaria deaths have well-recognized limitations; however, in specific circumstances, they could produce reliable trends. Model-based predictions can help describe changes in malaria-specific burden and assist with program management and advocacy. CONCLUSIONS Despite challenges, efforts to reduce malaria-associated mortality in Africa can be evaluated with trends in malaria intervention coverage and all-cause childhood mortality. Where there are resources and interest, complementary data on malaria morbidity and malaria-specific mortality could be added
Caution is required when using health facility-based data to evaluate the health impact of malaria control efforts in Africa
The global health community is interested in the health impact of the billions of dollars invested to fight malaria in Africa. A recent publication used trends in malaria cases and deaths based on health facility records to evaluate the impact of malaria control efforts in Rwanda and Ethiopia. Although the authors demonstrate the use of facility-based data to estimate the impact of malaria control efforts, they also illustrate several pitfalls of such analyses that should be avoided, minimized, or actively acknowledged. A critique of this analysis is presented because many country programmes and donors are interested in evaluating programmatic impact with facility-based data. Key concerns related to: 1) clarifying the objective of the analysis; 2) data validity; 3) data representativeness; 4) the exploration of trends in factors that could influence malaria rates and thus confound the relationship between intervention scale-up and the observed changes in malaria outcomes; 5) the analytic approaches, including small numbers of patient outcomes, selective reporting of results, and choice of statistical and modeling methods; and 6) internal inconsistency on the strength and interpretation of the data. In conclusion, evaluations of malaria burden reduction using facility-based data could be very helpful, but those data should be collected, analysed, and interpreted with care, transparency, and a full recognition of their limitations
Both androgen receptor and glucocorticoid receptor are able to induce prostate-specific antigen expression, but differ in their growth-stimulating properties of LNCaP cells
Androgen receptor-positive LNCaP cells were stably transfected with a rat
glucocorticoid receptor (GR) expression plasmid. Ligand-binding studies in
the generated cell lines revealed high-affinity binding of the cognate
ligands to their receptors. Transfection experiments with the newly
derived cell lines showed that, like androgen receptor, GR can induce
activity of a prostate-specific antigen promoter fragment linked to the
luciferase gene. Similarly, dexamethasone can stimulate expression of
endogenous prostate-specific antigen messenger RNA. Cell proliferation
could be induced by R1881. In contrast, dexamethasone treatment of the
GR-positive sublines had no stimulatory effect on cell growth. Using the
differential display technique, a so far unknown complementary DNA
fragment, designated 21.1, specifically induced by androgens and not by
glucocorticoids, has been identified. In conclusion, the newly generated
cell lines, together with the parental LNCaP cell line, form an attractive
system with which to study the mechanism of specificity of steroid hormone
regulation of gene expression
The impact of cessation or continuation of family violence on children
Children exposed to family violence are at risk for developing long-lasting problems. Family violence is a pervasive problem, however, studies comparing continuation with cessation of family violence are limited. Understanding the cessation or continuation of family violence on child development is a prerequisite to prevent enduring problems and develop interventions. This study compares posttraumatic stress and delinquent behavior of children aged between eight and eighteen years for whom severe violence continues to children for whom violence diminishes or ceases. Children (N = 162, 43% boys, mean age 12 years) and their parents reported to child protection services (CPS) with severe violence were included. Levels of family violence, posttraumatic stress and delinquent behavior were re-assessed after 18 months. Most families (74%) still experienced severe family violence at the second assessment despite involvement of CPS. Structural equation modelling was applied. In the group where violence diminished or stopped, delinquent behavior decreased. A decrease of posttraumatic stress only occurred when violence diminished but surprisingly no decrease was observed when violence stopped completely. The findings demonstrate that overall family violence is persistent. Differing paths can be discerned for delinquent behavior and posttraumatic stress, indicating different developmental and recovery pathways after cessation of family violence. Nonetheless, it is fair to state that specialized and long-term care is crucial
Amino acids 3-13 and amino acids in and flanking the 23FxxLF27 motif modulate the interaction between the N-terminal and ligand-binding domain of the androgen receptor
The N-terminal domain (NTD) and the ligand-binding domain (LBD) of the
androgen receptor (AR) exhibit a ligand-dependent interaction (N/C
interaction). Amino acids 3-36 in the NTD (AR3-36) play a dominant role in
this interaction. Previously, it has been shown that a PhixxPhiPhi motif
in AR3-36, 23FxxLF27, is essential for LBD interaction. We demonstrate in
the current study that AR3-36 can be subdivided into two functionally
distinct fragments: AR3-13 and AR16-36. AR3-13 does not directly interact
with the AR LBD, but rather contributes to the transactivation function of
the AR.NTD-AR.LBD complex. AR16-36, encompassing the 23FxxLF27 motif, is
predicted to fold into a long amphipathic alpha-helix. A second
PhixxPhiPhi candidate protein interaction motif within the helical
structure, 30VREVI34, shows no affinity to the LBD. Within AR16-36, amino
acid residues in and flanking the 23FxxLF27 motif are demonstrated to
modulate N/C interaction. Substitution of Q24 and N25 by alanine residues
enhances N/C interaction. Substitution of amino acids flanking the
23FxxLF27 motif by alanines are inhibitory to LBD interaction
Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcirptional coactivator TIF2 (Transcriptional Intermediary Factor 2)
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