746 research outputs found

    Wired on Steroids: Sexual Differentiation of the Brain and Its Role in the Expression of Sexual Partner Preferences

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    The preference to seek out a sexual partner of the opposite sex is robust and ensures reproduction and survival of the species. Development of female-directed partner preference in the male is dependent on exposure of the developing brain to gonadal steroids synthesized during critical periods of sexual differentiation of the central nervous system. In the absence of androgen exposure, a male-directed partner preference develops. The development and expression of sexual partner preference has been extensively studied in rat, ferret, and sheep model systems. From these models it is clear that gonadal testosterone, often through estrogenic metabolites, cause both masculinization and defeminization of behavior during critical periods of brain development. Changes in the steroid environment during these critical periods result in atypical sexual partner preference. In this manuscript, we review the major findings which support the hypothesis that the organizational actions of sex steroids are responsible for sexual differentiation of sexual partner preferences in select non-human species. We also explore how this information has helped to frame our understanding of the biological influences on human sexual orientation and gender identity

    Influence of Running and Walking on Hormonal Regulators of Appetite in Women

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    Nine female runners and ten walkers completed a 60 min moderate-intensity (70% VO2max) run or walk, or 60 min rest in counterbalanced order. Plasma concentrations of the orexogenic peptide ghrelin, anorexogenic peptides peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and appetite ratings were measured at 30 min interval for 120 min, followed by a free-choice meal. Both orexogenic and anorexogenic peptides were elevated after running, but no changes were observed after walking. Relative energy intake (adjusted for cost of exercise/rest) was negative in the meal following running (−194 ± 206 kcal) versus walking (41 ± 196 kcal) (P = 0.015), although both were suppressed (P < 0.05) compared to rest (299 ± 308 and 284 ± 121 kcal, resp.). The average rate of change in PYY and GLP-1 over time predicted appetite in runners, but only the change in GLP-1 predicted hunger (P = 0.05) in walkers. Results provide evidence that exercise-induced alterations in appetite are likely driven by complex changes in appetite-regulating hormones rather than change in a single gut peptide

    Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

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    Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity

    Dynamic optimal taxation with human capital.

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    This paper revisits the dynamic optimal taxation results of Jones, Manuelli, and Rossi (1993, 1997). They use a growth model with human capital and find that optimal taxes on both capital income and labor income converge to zero in steady state. For one of the models under consideration, I show that the representative household's problem does not have an interior solution. This raises concerns since these corners are inconsistent with aggregate data. Interiority is restored if preferences are modified so that human capital augments the value of leisure time. With this change, the optimal tax problem is analyzed and, reassuringly, the Jones, Manuelli, and Rossi results are confirmed: neither capital income nor labor income should be taxed in steady state

    Myeloid Cell Sirtuin-1 Expression Does Not Alter Host Immune Responses to Gram-Negative Endotoxemia or Gram-Positive Bacterial Infection

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    The role of sirtuin-1 (SIRT1) in innate immunity, and in particular the influence of SIRT1 on antimicrobial defense against infection, has yet to be reported but is important to define since SIRT1 inhibitors are being investigated as therapeutic agents in the treatment of cancer, Huntington’s disease, and autoimmune diseases. Given the therapeutic potential of SIRT1 suppression, we sought to characterize the role of SIRT1 in host defense. Utilizing both pharmacologic methods and a genetic knockout, we demonstrate that SIRT1 expression has little influence on macrophage and neutrophil antimicrobial functions. Myeloid SIRT1 expression does not change mortality in gram-negative toxin-induced shock or gram-positive bacteremia, suggesting that therapeutic suppression of SIRT1 may be done safely without suppression of myeloid cell-specific immune responses to severe bacterial infections.American Asthma Foundation (Stephen Silberstein Senior Fellowship Awards

    When the noise goes on : received sound energy predicts sperm whale responses to both intermittent and continuous navy sonar

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    This work was supported by the UK Defence Science and Technology Laboratory, The Netherlands Ministry of Defence, French Ministry of Defence, and US Navy Living Marine Resources program (contract No. N39430-17-C-1935). Open access funding provided by the University of St Andrews. Deposited in PMC for immediate release.Anthropogenic noise sources range from intermittent to continuous, with seismic and navy sonar technology moving towards near-continuous transmissions. Continuous active sonar (CAS) may be used at a lower amplitude than traditional pulsed active sonar (PAS), but potentially with greater cumulative sound energy. We conducted at-sea experiments to contrast the effects of navy PAS versus CAS on sperm whale behaviour using animal-attached sound- and movement-recording tags (n=16 individuals) in Norway. Changes in foraging effort and proxies for foraging success and cost during sonar and control exposures were assessed while accounting for baseline variation [individual effects, time of day, bathymetry and blackfish (pilot/killer whale) presence] in generalized additive mixed models (GAMMs). We found no reduction in time spent foraging during exposures to medium-level PAS (MPAS) transmitted at the same peak amplitude as CAS. In contrast, we found similar reductions in foraging during CAS (d.f.=1, F=8.0, P=0.005) and higher amplitude PAS (d.f.=1, F=20.8, P<0.001) when received at similar energy levels integrated over signal duration. These results provide clear support for sound energy over amplitude as the response driver. We discuss the importance of exposure context and the need to measure cumulative sound energy to account for intermittent versus more continuous sources in noise impact assessments.Publisher PDFPeer reviewe

    A Phase I/II Study of Chemotherapy Followed by Donor Lymphocyte Infusion plus Interleukin-2 for Relapsed Acute Leukemia after Allogeneic Hematopoietic Cell Transplantation

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    The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 108 CD3/kg for patients with related donors, and 0.1 × 108 CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 106 IU/m2/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 106 IU/m2/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2–related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 106 IU/m2/day. IL-2 administration after DLI might increase the incidence of cGVHD

    Post-Construction Support and Sustainability in Community-Managed Rural Water Supply

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    Executive Summary This volume reports the main findings from a multi-country research project that was designed to develop a better understanding of how rural water supply systems are performing in developing countries. We began the research in 2004 to investigate how the provision of support to communities after the construction of a rural water supply project affected project performance in the medium term. We collected information from households, village water committees, focus groups of village residents, system operators, and key informants in 400 rural communities in Bolivia, Ghana, and Peru; in total, we discussed community water supply issues with approximately 10,000 individuals in these communities. To our surprise, we found the great majority of the village water systems were performing well. Our findings on the factors influencing their sustainability will, we hope, be of use to policy makers, investors, and managers in rural water supply

    Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

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    Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS
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