The sexual preference of female rats is influenced by males' adolescent social stress history and social status

Ongoing development of brain systems for social behaviour renders these systems susceptible to the influence of stressors in adolescence. We previously found that adult male rats that underwent social instability stress (SS) in mid-adolescence had decreased sexual performance compared with control males (CTL). Here, we test the hypotheses that SS in adolescence decreases the “attractiveness” of male rats as sexual partners compared with CTL rats and that dominance status is a protective factor against the effects of SS. The main prediction was that females would spend more time with CTL males than SS males, and that this bias would be greater for submissive than for dominant rats. Among dominant pairs (n = 16), females preferred SS males, spending more time with and visiting more often SS than CTL males (each pair tested 5 ×), and SS males had shorter latencies to ejaculation, shorter inter-ejaculation intervals, and made more ejaculations compared with CTL males. Among submissive pairs (n = 16), females spent more time with, visited more often, and displayed more paracopulatory behaviour with CTL than with SS males, and differences in sexual performance between SS and CTL males were modest and in the opposite direction from that in dominant pairs. The heightened motivation of SS males relative to CTL males for natural rewards may have attenuated differences in sexual performance in a paced mating context. In sum, the experience of stress in adolescence leads to long-lasting changes in males that are perceptible to females, are moderated by social status, and influence sexual behaviour.     

Like-with-like preference and sexual mixing models

Two new general methods for incorporating like-with-like preference into one-sex mixing models in epidemiology are presented. The first is a generalization of the preferred mixing equation, while the second comprises a transformation of a general preference function for partners of similar sexual activity levels. Both methods satisfy the constraints implicit in a mixing model. The behavior of the transformation preference method is illustrated, and it is compared with the standard proportionate mixing model.     

Autophagy-mediated longevity is modulated by lipoprotein biogenesis

Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.     

Methylphenidate sensitization is modulated by valproate.

Repeated administration of the stimulant methylphenidate (MPD) produces sensitization to its own effects. Glutamate, dopamine, and GABA have been implicated in the underlying mechanism of sensitization to stimulants such as amphetamine and cocaine. We have investigated effects of the GABAergic agent sodium valproate (VAL) on the locomotor response to MPD. Activities of male Sprague-Dawley rats were continuously recorded by a computerized activity monitoring system for 15 days. We studied the dose effect of valproate 1) at 50, 100, and 200 mg/kg (i.p.) on motor activities, 2) on the acute response of motor activities to 2.5 mg/kg MPD, and 3) on behavioral sensitization to subsequent repeated injections of MPD. Valproate alone did not significantly affect motor activities. All three doses of valproate attenuated the acute locomotor effects of MPD, while only the 50 mg/kg dose blocked the development of sensitization to subsequent administration. Possible mechanisms involving substrates for the effect of GABA agonists on sensitization are discussed.     

Face perception: broken into parts

A recent study has shown that, using transcranial magnetic stimulation to stimulate an area of the visual cortex, the perception of face parts can be selectively and reversibly disrupted, while the perception of their arrangement is spared.     

Conditioned place preference induced by sexual interaction in female rats.

The present study was undertaken to establish whether the conditioned place preference paradigm can be utilized to investigate and elucidate the neuroendocrine basis of the appetitive elements of female sexual behavior. Females were exposed to a male with which copulation occurred in a distinctive compartment of the place preference apparatus and did not receive an incentive in the alternative compartment. After six pairings to each compartment a place preference test was conducted. Both estradiol benzoate and estradiol benzoate plus progesterone treated, ovariectomized females showed a preference for the compartment associated with sexual interaction. A second group of estradiol plus progesterone treated females was exposed to a male with which copulation occurred in one compartment of the place preference apparatus and to a sexually active, but caged, male in the other. The females tended to prefer the compartment paired with the caged male. After noncontingent intromissions, immediately preceding an additional test, the females showed a place preference for the compartment paired with sexual interaction. The presented observations indicate the potential use of the place preference procedure in studying opposing motivational processes associated with the unconditioned sequence of responses that characterize the species-specific pattern of sexual behavior.     

Evolution of mating preference and sexual dimorphism

A quantitative genetic model of the joint evolution of female mating preferences and sexual dimorphism in homologous characters of the sexes is described for polygamous species with no male parental effort, such that mating preferences are selectively neutral and evolve only by indirect selection on genetically correlated characters. The male character and the homologous female character are each under stabilizing natural selection toward an optimum phenotype. At an evolutionary equilibrium the female character under natural selection is at its optimum, whereas there is a line of possible equilibria between female mating preferences and the male character. The line of equilibria may be stable or unstable, depending on the intensity of natural selection, the type of mating preferences, and the inheritance of the characters. Various mechanisms for maladaptive evolution of mating preferences and sexual dimorphism are discussed.     

Cell migration is negatively modulated by ABCA1

Temporal and spatial changes of membrane lipid distribution in the plasma membrane are thought to be important for various cellular functions. ATP-Binding Cassette A1 (ABCA1) is a key lipid transporter for the generation of high density lipoprotein. Recently, we reported that ABCA1 maintains an asymmetric distribution of cholesterol in the plasma membrane. Here we report that ABCA1 suppresses cell migration by modulating signal pathways. ABCA1 knockdown in mouse embryonic fibroblasts accelerated cell migration and increased activation of Rac1 and its localization to detergent-resistant membranes. Phosphorylation of MEK and ERK also increased. Inhibition of Rac1 or MEK-ERK signals suppressed cell migration in ABCA1 knockdown cells. Because our experimental conditions for cell migration did not contain cholesterol or lipid acceptors for ABCA1, cellular cholesterol content was not changed. These data suggest that ABCA1 modulates cell migration via Rac1 and MEK-ERK signaling by altering lipid distribution in the plasma membrane.     

Drosophila male courtship behavior is modulated by ecdysteroids

Temperature-dependent induction of ecdysteroid deficiency in the ecdysoneless mutant ecd¹ adult Drosophilamelanogaster results in altered courtship behavior in males. Ecdysteroid deficiency brings about significantly elevated male-male courtship behavior including song production resembling that directed toward females. Supplementation with dietary 20-hydroxyecdysone reduces male-male attraction, but does not change motor activity, courtship patterns or attraction to females. These observations support the hypothesis that reduced levels of ecdysteroids increase the probability that male fruit flies will display courtship behaviors to male stimuli.     

Drosophila female precopulatory behavior is modulated by ecdysteroids

The effect of ecdysteroid signaling on Drosophila female precopulatory behavior was investigated using two types of mutants with either globally reduced ecdysteroid availability or reduced expression of ecdysone receptors in fruitless neurons, known to control sexual behavior. While being courted by males, mutant females performed significantly less full ovipositor extrusion behavior to reject male copulation attempts. Ecdysteroid depleted females (ecdysoneless(1)) performed male-like courtship behaviors, including unilateral wing extension and song production with patterns very similar to male courtship song. These results support the hypothesis that ecdysteroids modulate female sexual behavior, perhaps acting as a regulator of sexual motivation, and as a component affecting the performance of sex specific behavior patterns.     

Postnatal differentiation of sexual preference in male pigs

Attraction to sexually mature males and the immobilization response were evaluated after postpubertal estrogen treatment of ovariectomized females and of males castrated within 48 hr after birth or at 4 or 8 months of age. The time spent in the end of an evaluation pen which housed a mature intact male, the proportion of animals that showed the immobilization response, and the latency to onset and the duration of this response were similar in ovariectomized females and males castrated within 48 hr after birth. These two groups spent more time in the male end of the evaluation pen as opposed to the opposite end which housed an ovariectomized female, showed a shorter latency to the onset of the immobilization response, and expressed this response for a greater number of days than males castrated either at 4 or 8 months of age. Males castrated at 4 or 8 months did not show a strong preference for either a mature male or an ovariectomized female. The immobilization response in estrogen-treated males castrated at 4 or 8 months of age diminished as these animals became older. On the basis of the observations made in this study, attraction to a mature, intact male is a sexually dimorphic behavioral trait in pigs, and defeminization of this trait in male pigs is associated with the pubertal increase in testicular steroid secretion. Presently, pigs are the only mammalian species in which a role has been identified for pubertal, testicular steroid secretion in the defeminization process.     

Phosphorylation of SRSF1 is modulated by replicational stress

DNA ligase I-deficient 46BR.1G1 cells show a delay in the maturation of replicative intermediates resulting in the accumulation of single- and double-stranded DNA breaks. As a consequence the ataxia telangiectasia mutated protein kinase (ATM) is constitutively phosphorylated at a basal level. Here, we use 46BR.1G1 cells as a model system to study the cell response to chronic replication-dependent DNA damage. Starting from a proteomic approach, we demonstrate that the phosphorylation level of factors controlling constitutive and alternative splicing is affected by the damage elicited by DNA ligase I deficiency. In particular, we show that SRSF1 is hyperphosphorylated in 46BR.1G1 cells compared to control fibroblasts. This hyperphosphorylation can be partially prevented by inhibiting ATM activity with caffeine. Notably, hyperphosphorylation of SRSF1 affects the subnuclear distribution of the protein and the alternative splicing pattern of target genes. We also unveil a modulation of SRSF1 phosphorylation after exposure of MRC-5V1 control fibroblasts to different exogenous sources of DNA damage. Altogether, our observations indicate that a relevant aspect of the cell response to DNA damage involves the post-translational regulation of splicing factor SRSF1 which is associated with a shift in the alternative splicing program of target genes to control cell survival or cell death.     

Antibody blood-brain barrier efflux is modulated by glycan modification

BackgroundDrug delivery to the brain is a major roadblock to treatment of Alzheimer's disease. Recent results of the PRIME study indicate that increasing brain penetration of antibody drugs improves Alzheimer's treatment outcomes. New approaches are needed to better accomplish this goal. Based on prior evidence, the hypothesis that glycan modification alters antibody blood-brain barrier permeability was tested here.MethodsThe blood-brain barrier permeability coefficient Pe of different glycosylated states of anti-amyloid IgG was measured using in vitro models of brain microvascular endothelial cells. Monoclonal antibodies 4G8, with sialic acid, and 6E10, lacking sialic acid, were studied. The amount of sialic acid was determined using quantitative and semi-quantitative surface plasmon resonance methods.ResultsInflux of IgG was not saturable and was largely insensitive to IgG species and glycosylation state. By contrast, efflux of 4G8 efflux was significantly lower than both albumin controls and 6E10. Removal of α2,6-linked sialic acid group present on 12% of 4G8 completely restored efflux to that of 6E10 but increasing the α2,6-sialylated fraction to 15% resulted in no change. Removal of the Fc glycan from 4G8 partially restored efflux. Alternate sialic acid groups with α2,3 and α2,8 linkages, nor on the Fc glycan, were not detected at significant levels on either 4G8 or 6E10.ConclusionsThese results support a model in which surface-sialylated 4G8 inhibits its own efflux and that of asialylated 4G8.General significanceGlycan modification has the potential to increase antibody drug penetration into the brain through efflux inhibition.     

MUC1 membrane trafficking is modulated by multiple interactions

MUC1 is a mucin-like transmembrane protein found on the apical surface of many epithelia. Because aberrant intracellular localization of MUC1 in tumor cells correlates with an aggressive tumor and a poor prognosis for the patient, experiments were designed to characterize the features that modulate MUC1 membrane trafficking. By following [(35)S]Met/Cys-labeled MUC1 in glycosylation-defective Chinese hamster ovary cells, we found previously that truncation of O-glycans on MUC1 inhibited its surface expression and stimulated its internalization by clathrin-mediated endocytosis. To identify signals for MUC1 internalization that are independent of its glycosylation state, the ectodomain of MUC1 was replaced with that of Tac, and chimera endocytosis was measured by the same protocol. Endocytosis of the chimera was significantly faster than for MUC1, indicating that features of the highly extended ectodomain inhibit MUC1 internalization. Analysis of truncation mutants and tyrosine mutants showed that Tyr(20) and Tyr(60) were both required for efficient endocytosis. Mutation of Tyr(20) significantly blocked coimmunoprecipitation of the chimera with AP-2, indicating that Y(20)HPM is recognized as a YXXphi motif by the mu2 subunit. The tyrosine-phosphorylated Y(60)TNP was previously identified as an SH2 site for Grb2 binding, and we found that mutation of Tyr(60) blocked coimmunoprecipitation of the chimera with Grb2. This is the first indication that Grb2 plays a significant role in the endocytosis of MUC1.     

Nitrophorin synthesis is modulated by protein kinase CK2

Rhodnius prolixus is a blood-sucking bug whose saliva contains a family of nitric oxide-carrying proteins named nitrophorins (NPs). Saliva is injected into the host bloodstream during insect feeding. Nitric oxide is then released from NPs and will act on vascular smooth muscle, promoting vasodilation. Epithelial cells of salivary glands then undergo a massive synthesis of antihemostatics including NPs which produces saliva for the next blood meal. Here, we demonstrate the transient activation of a protein kinase in the salivary glands of R. prolixus after a blood meal. Biochemical, immunological, and pharmacological assays were used to identify this enzyme as protein kinase CK2. CK2 is activated after a blood meal and decreases to basal levels when salivary gland refilling is resumed. Inhibition of CK2 blocked [(35)S]methionine incorporation into newly synthesized salivary gland proteins in cultured tissue. Dissected salivary glands were then incubated with the heme fluorescent analog palladium (II) mesoporphyrin IX (Pd-MP) in the presence of a selective cell-permeable CK2 inhibitor, TBB (4,5,6,7-tetrabromobenzotriazole). NP synthesis was quantified based on fluorescence of the Pd-MP group bound to the NP heme pocket. TBB dramatically blocked NP synthesis. Altogether, these data are the first demonstration to show that antihemostatic synthesis in a blood-sucking arthropods is under protein phosphorylation control.     

Endoplasmic reticulum calcium release is modulated by actin polymerization

Intracellular calcium ions regulate the structure and functions of cytoskeletal proteins. On the other hand, recent studies have shown that the cytoskeleton, and actin filaments in particular, can modulate calcium influx through plasma membrane ligand- and voltage-gated channels. We now report that calcium release from inositol trisphosphate (IP3) and ryanodine-sensitive endoplasmic reticulum (ER) stores is modulated by polymerization and depolymerization of actin filaments in cultured hippocampal neurons. Depolymerization of actin filaments with cytochalasin D attenuates calcium release induced by carbamylcholine (CCh; a muscarinic agonist for IP3 pathway), caffeine (a ryanodine receptor agonist) and thapsigargin (an inhibitor of the ER calcium- ATPase) in both the presence and absence of extracellular calcium. Conversely, the actin polymerizing agent jasplakinolide potentiates calcium release induced by CCh, caffeine and thapsigargin. Cytochalasin D attenuated, while jasplakinolide augmented, thapsigargin-induced JNK activation and neuronal cell death. Our data show that the actin cytoskeleton regulates ER calcium release, suggesting roles for actin in the various physiological and pathological processes that involve calcium release.     

Disclosure of sexual preference to physicians by black lesbian and bisexual women.

Physicians'' ability to diagnose and treat health care problems, particularly those with a psychosocial component, is facilitated by accurate information concerning the life-styles of their patients. White lesbians have been shown to be generally reluctant to disclose sexual orientation to their physicians, but little, if anything, is known about black lesbians. Black women, self-identified as bisexuals (N = 65) and lesbians (N = 529), were asked whether they had disclosed their homosexual behavior to their physicians. In the sample, only a third of the women had. Previous sexual experiences, both heterosexual and homosexual, were also queried to illuminate patterns of gynecologic health risk factors. Nearly all of the women reported previous heterosexual experiences.