Diurnal testosterone variability is differentially associated with parenting quality in mothers and fathers

Previous studies on the relation between testosterone (T) levels and parenting have found ample evidence for the challenge hypothesis, demonstrating that high T levels inhibit parental involvement and that becoming a parent is related to a decrease in T levels in both mothers and fathers. However, less is known about the relation between T levels and more qualitative aspects of parenting. In the current study we examined basal T levels and diurnal variability in T levels in relation to mothers' and fathers' parenting quality. Participants included 217 fathers and 124 mothers with two children (3 and 5 years of age). Evening and morning salivary T samples were analyzed with radio-immunoassays to determine circulating T levels. Parental sensitivity (i.e., child-centered responsiveness) and respect for children's autonomy were observed during free play in the family home. The results showed that higher evening T levels in mothers were associated with more sensitivity to the oldest and youngest child. Diurnal T variability was more consistently associated with parenting behavior towards their children than basal T levels. For fathers, more diurnal variability in T was associated with more sensitivity and more respect for autonomy with their youngest children. For mothers, more diurnal variability in T was associated with less sensitivity to both children and less respect for the youngest child's autonomy. These findings suggest that the T system might act differently in relation to parenting behavior in males and females.     

Hyperlipidemia is associated with altered levels of insulin-like growth factor-I

Previous studies revealed altered levels of the circulating insulin-like growth factor-I (IGF-I) and of its binding protein-3 (IGFBP-3) in subjects with coronary atherosclerosis, metabolic syndrome and premature atherosclerosis. Hyperlipidemia is a powerful risk factor of atherosclerosis. We expected IGF-I and IGFBP-3 alterations in subjects with moderate/severe hyperlipidemia but without any clinical manifestation of atherosclerosis. Total IGF-I and IGFBP-3 were assessed in 56 patients with mixed hyperlipidemia (MHL; cholesterol >6.0 mmol/l, triglycerides >2.0 mmol/l), in 33 patients with isolated hypercholesterolemia (IHC; cholesterol >6.0 mmol/l, triglycerides <2.0 mmol/l), and in 29 healthy controls (cholesterol<6.0 mmol/l, triglycerides<2.0 mmol/l). The molar ratio of IGF-I/IGFBP-3 was used as a measure of free IGF-I. IHC subjects differed from controls by lower total IGF-I (164+/-60 vs. 209+/-73 ng/ml, p=0.01) and IGF-I /IGFBP-3 ratio (0.14+/-0.05 vs. 0.17+/-0.04, p=0.04). Compared to controls, MHL subjects had lower total IGF-I (153+/-54 ng/ml, p=0.0002) and IGFBP-3 (2.8+/-0.6 mg/ml, p<0.0001), but higher IGF-I/IGFBP-3 ratio (0.25+/-0.06, p<0.0001). Differences remained significant after the adjustment for clinical and biochemical covariates, except for triglycerides. Patients with both IHC and MHL have lower total IGF-I compared to controls. The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I.     

Vitellogenin and vitellogenin receptor gene expression is associated with male and female parenting in a subsocial insect

Complex social behaviour in Hymenoptera has been hypothesized to evolve by co-opting reproductive pathways (the ovarian ground plan hypothesis, OGPH) and gene networks (the reproductive ground plan hypothesis, RGPH). In support of these hypotheses, in eusocial Hymenoptera where there is reproductive division of labour, the yolk precursor protein vitellogenin (Vg) influences the expression of worker social behaviour. We suggest that co-opting genes involved in reproduction may occur more generally than just in the evolution of eusociality; i.e. underlie earlier stages of social evolution such as the evolution of parental care, given that reproduction and parental care rarely overlap. We therefore examined vitellogenin (vg) gene expression associated with parental care in the subsocial beetle Nicrophorus vespilloides. We found a significant reduction in the expression of vg and its receptor, vgr, in head tissue during active parental care, and confirmed that the receptor is expressed in the brains of both sexes. Ours is the first study to show that vgr is expressed in the brain of a non-eusocial insect. Given the association between behaviour and gene expression in both sexes, and the presence of vitellogenin receptors in the brain, we suggest that Vg was co-opted early in the evolution of sociality to have a regulatory function. This extends the association of Vg in parenting to subsocial species and outside of the Hymenoptera, and supports the hypothesis that the OGPH is general and that heterochrony in gene expression is important in the evolution of social behaviour and precedes subsequent evolutionary specialization of social roles.     

A flooding-induced xyloglucan endo-transglycosylase homolog in maize is responsive to ethylene and associated with aerenchyma.

Development of aerenchyma (soft cortical tissue with large intercellular air spaces) in flooded plants results from cell-wall hydrolysis and eventual cell lysis and is promoted by endogenous ethylene. Despite its adaptive significance, the molecular mechanisms behind aerenchyma development remain unknown. We recently isolated a flooding-induced maize (Zea mays L.) gene (wusl1005[gfu]; abbreviated as 1005) encoding a homolog of xyloglucan endo-transglycosylase (XET), a putative cell-wall-loosening enzyme active during germination, expansion, and fruit softening. XET and related enzymes may also be involved in cell-wall metabolism during flooding-induced aerenchyma development. Under flooding, 1005 mRNA accumulated in root and mesocotyl locations that subsequently exhibited aerenchyma development and reached maximum levels within 12 h of treatment. Aerenchyma development was observed in the same locations by 48 h of treatment. Treatment with the ethylene synthesis inhibitor (aminooxy) acetic acid (AOA), which prevented cortical air space formation under flooding, almost completely inhibited 1005 mRNA accumulation in both organs. AOA treatment had little effect on the accumulation of mRNA encoded by adh1, indicating that it did not cause general suppression of flooding-responsive genes. Additionally, ethylene treatment under aerobic conditions resulted in aerenchyma development as well as induction of 1005 in both organs. These results indicate that 1005 is responsive to ethylene. Treatment with anoxia, which suppresses ethylene accumulation and aerenchyma development, also resulted in 1005 induction. However, in contrast to flooding, AOA treatment under anoxia did not affect 1005 mRNA accumulation, indicating that 1005 is induced via different mechanisms under flooding (hypoxia) and anoxia.     

Reduced expression of netrin-1 is associated with fetal growth restriction

Two series of fluorescent molecules were synthesized by acylation of dansyl ethylenediamine and phenylalanine dansyl ethylenediamine with one of either acetyl (C(2)), hexanyl (C(6)), cyclohexanecarbonyl (C(7)), myristyl (C(14)), or palmityl (C(16)) groups and examined for entry and localization in Chinese Hamster Ovary (CHO) cells in tissue culture. Gross total fluorescence retention and cellular microscopic fluorescence patterns were analyzed. In both series, molecules with myristyl or palmityl groups entered cells. Only in the phenylalanine series did hexyl and cyclohexanecarbonyl modification enable entry. Consistent with a mechanism of passive diffusion, entry of compounds into cells was neither energy dependent nor endocytosis linked. Acylated molecules were observed to localize in cytoplasm and not enter nuclei or associate with lipophilic plasma membranes.     

Polymorphism in maternal LRP8 gene is associated with fetal growth

Fetal growth restriction (FGR) affects >200,000 pregnancies in the United States annually and is associated with increased perinatal mortality and morbidity, as well as poorer long-term health for infants with FGR compared with infants without FGR. FGR appears to be a complex trait, but the role of genetic factors in the development of FGR is largely unknown. We conducted a candidate-gene association study of birth weight and FGR in two independent study samples obtained at the Boston Medical Center. We first investigated the association between maternal genotypes of 68 single-nucleotide polymorphisms (SNPs) from 41 candidate genes and fetal growth in a sample of 204 black women selected for a previous study of preeclampsia, 92 of whom had preeclampsia (characterized by high blood pressure and the presence of protein in the urine). We found significant association between SNP rs2297660 in the LRP8 gene and birth weight. Subsequently, we replicated the association in a larger independent sample of 1,094 black women; similar association between LRP8 and FGR was observed in this sample. The "A" allele at rs2297660 was associated with a higher standardized birth weight and a lower risk of FGR. Under the additive genetic model, each additional copy of the "A" allele reduced the risk of FGR by 33% (P<.05). In conclusion, results from the two independent samples of black women provide consistent evidence that SNP rs2297660 in LRP8 is associated with fetal growth.     

Insulin-like growth factor-1 is associated with life-history variation across Mammalia

Despite the diversity of mammalian life histories, persistent patterns of covariation have been identified, such as the ‘fast–slow’ axis of life-history covariation. Smaller species generally exhibit ‘faster’ life histories, developing and reproducing rapidly, but dying young. Hormonal mechanisms with pleiotropic effects may mediate such broad patterns of life-history variation. Insulin-like growth factor 1 (IGF-1) is one such mechanism because heightened IGF-1 activity is related to traits associated with faster life histories, such as increased growth and reproduction, but decreased lifespan. Using comparative methods, we show that among 41 mammalian species, increased plasma IGF-1 concentrations are associated with fast life histories and altricial reproductive patterns. Interspecific path analyses show that the effects of IGF-1 on these broad patterns of life-history variation are through its direct effects on some individual life-history traits (adult body size, growth rate, basal metabolic rate) and through its indirect effects on the remaining life-history traits. Our results suggest that the role of IGF-1 as a mechanism mediating life-history variation is conserved over the evolutionary time period defining mammalian diversification, that hormone–trait linkages can evolve as a unit, and that suites of life-history traits could be adjusted in response to selection through changes in plasma IGF-1.     

Labile intracellular zinc is associated with 3T3 cell growth

Increasing evidence shows that labile intracellular zinc is metabolically important. Depletion of labile intracellular zinc using chelators suppresses DNA synthesis. In this study, we tested the hypothesis that labile intracellular zinc could be modulated via varying zinc nutrition. This could result in an altered availability of labile intracellular zinc, which, in turn, could influence zinc-dependent cellular events involved in cell proliferation and ultimately suppress growth. Labile intracellular zinc was detected by using N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ), a membrane-permeable fluorescence probe. After 48 h culture in a zinc-depleted medium, labile intracellular zinc in 3T3 cells was diminished along with a suppressed DNA synthesis and cell proliferation. In contrast, supplementation of zinc to the zinc-depleted medium increased the labile intracellular zinc and promoted DNA synthesis and cell proliferation. Furthermore, growth factor-dependent stimulation of DNA synthesis and cell proliferation was also accompanied by increased labile intracellular zinc. Together, our data showed an association between the labile intracellular zinc, detected using TSQ, and 3T3 cell growth, suggesting that labile intracellular zinc could be an important cellular link between zinc nutrition and growth.     

The epidermal growth factor receptor is associated with actin filaments.

In this paper we describe our investigations on the association of receptors for the epidermal growth factor (EGF) with the cytoskeleton of A431 cells. In order to determine which filamentous system the EGF receptors are associated to, the cytoskeletal fraction to which these receptors bind was isolated. Second, the possible colocalization of EGF receptors with different cytoskeletal elements was examined in A431 cells. By selective extractions of the A431 cytoskeletons, it is shown that more than 90% of the cytoskeleton-associated EGF receptors are removed from the cytoskeletons together with the actin filamentous system. During several cycles of poly- and depolymerization of actin isolated from A431 cells, the EGF receptor precipitates together with the actin containing filaments, indicating that EGF receptors are able to bind in vitro to actin filaments. With immunofluorescence studies we show that EGF receptors especially colocalize with actin filaments. These results demonstrate that the EGF receptor is associated specifically with actin filaments in A431 cells.     

Increased expression of platelet-derived growth factor associated protein-1 is associated with PDGF-B mediated glioma progression

The current treatment therapies available for malignant gliomas are inadequate. There is an urgent need to develop more effective therapies by characterizing the molecular pathogenesis of the disease. Over expression of platelet-derived growth factor (PDGF) ligands and receptors have been reported in malignant gliomas. Platelet-derived growth factor associated protein-1 (PDAP-1) is reported to modulate the mitogenic activity of PDGF ligands, but to date, there is no information concerning its role in PDGF-mediated glioma cell proliferation. This study aimed to characterize the role of PDAP-1 in PDGF-mediated glioma proliferation. The expression of PDAP-1 was observed to be significantly increased (p< 0.05) in grade IV glioma tissue and cell lines compared to grade III. siRNA-mediated knockdown of PDAP-1 reduced the expression of PDGF-B and its downstream genes (Akt1/Protein kinase B (PKB) and phosphoinositide-dependent kinase-1 (PDK1) by up to 50%. In PDAP-1 knockdown glioma cells, more than a twofold reduction was also observed in the level of phosphorylated Akt. Interestingly, knockdown of PDAP-1 in combination with PDGF-B antibody inhibited glioma cell proliferation through activation of Caspase 3/7 and 9. We also demonstrate that PDAP-1 co-localizes with PDGF-B in the cytoplasm of glioma cells, and an interaction between both of the proteins was established. Collectively, these findings suggest that the expression of PDAP-1 is associated with disease malignancy, and its inhibition reduced the proliferation of malignant glioma cells through down-regulation of PDGF-B/Akt/PDK1 signaling. Thus, this study establishes PDAP-1 as an effecter of PDGF signaling in glioma cells and suggests that it could also be a promising therapeutic target.     

Dopamine system genes associated with parenting in the context of daily hassles

The current study examined the molecular genetic foundations of sensitive parenting in humans and is the first to test the interaction between genes and environment in modulating parental sensitive responses to children. In a community sample of 176 Caucasian, middle class mothers with their 23-month-old toddlers at risk for externalizing behavior problems, the association between daily hassles and sensitive parenting was investigated. We tested whether two dopamine-related genes, dopamine D4 receptor ( DRD4 ) and catechol-O-methyltransferase ( COMT ) gene polymorphisms, modulate parents' vulnerability to the negative influence of daily hassles on sensitive parenting behavior to their offspring. Sensitive parenting was observed in structured settings, and parents reported on their daily hassles through a standard questionnaire. In parents with the combination of genes leading to the least efficient dopaminergic system functioning ( COMT val/val or val/met, DRD4 -7Repeat), more daily hassles were associated with less sensitive parenting, and lower levels of daily hassles were associated with more sensitive parenting d  = 1.12. The other combinations of COMT and DRD4 polymorphisms did not show significant associations between daily hassles and maternal sensitivity, suggesting differential susceptibility to hassles depending on parents' dopaminergic system genes. It is concluded that the study of (multiple) gene–environment interactions (in the current case: gene by gene by environment interaction, G × G × E) may explain why some parents are more and others less impacted by daily stresses in responding sensitively to their offspring's signals.     

Proliferative action of erythropoietin is associated with rapid protein tyrosine phosphorylation in responsive B6SUt.EP cells

Erythropoietin is a prime regulator of the growth and terminal differentiation of erythroid blood cells. However, little is understood concerning its molecular mechanism of action. Presently it is shown in the responsive, factor-dependent murine cell line B6SUt.EP that erythropoietin induces the tyrosine phosphorylation of six plasma membrane-associated proteins in a time- and concentration-dependent fashion (i.e. phosphoproteins PY153, PY140, PY100, PY93, PY74, and PY54). Among these, PY153 was prominent. For all proteins, maximal levels of phosphorylation were induced within 3-7 min at low factor concentrations (100-500 pM). These findings establish tyrosine kinase activation as a novel candidate pathway of erythropoietin-induced proliferation. In addition, the tyrosine phosphorylation of six proteins with identical Mr, as well as a Mr 104,000 protein, was induced in B6SUt.EP cells by interleukin 3. In contrast, no induced tyrosine phosphorylation was detectable in the erythropoietin-responsive, leukemic erythroid cell line. Rauscher Red 1, yet proteins of Mr 153,000 and 54,000 were shown to be phosphorylated constitutively at relative levels greater than those observed in B6SUt.EP cells. A possible role for these phosphoproteins in hematopoietic cell transformation is considered.     

GAP-43 mRNA in growth cones is associated with HuD and ribosomes

The neuron-specific ELAV/Hu family member, HuD, interacts with and stabilizes GAP-43 mRNA in developing neurons, and leads to increased levels of GAP-43 protein. As GAP-43 protein is enriched in growth cones, it is of interest to determine if HuD and GAP-43 mRNA are associated in developing growth cones. HuD granules in growth cones are found in the central domain that is rich in microtubules and ribosomes, in the peripheral domain with its actin network, and in filopodia. This distribution of HuD granules in growth cones is dependent on actin filaments but not on microtubules. GAP-43 mRNA is localized in granules found in both the central and peripheral domains, but not in filopodia. Ribosomes were extensively colocalized with HuD and GAP-43 mRNA granules in the central domain, consistent with a role in the control of GAP-43 mRNA stability in the growth cone. Together, these results demonstrate that many of the components necessary for GAP-43 mRNA translation/stabilization are present within growth cones.