Roles of estrogen receptor-alpha in mediating life span: the hypothalamic deregulation hypothesis.

In several species caloric restriction (CR) extends life span. In this paper we integrate data from studies on CR and other sources to articulate the hypothalamic deregulation hypothesis by which estrogen receptor-alpha (ER-α) signaling in the hypothalamus and limbic system affects life span under the stress of CR in mammals. ER-α is one of two principal estrogen-binding receptors differentially expressed in the amygdala, hippocampus, and several key hypothalamic nuclei: the arcuate nucleus (ARN), preoptic area (POA), ventromedial nucleus (VMN), antero ventral periventricular nucleus (AVPV), paraventricular nucleus (PVN), supraoptic nucleus (SON), and suprachiasmatic nucleus (SCN). Estradiol signaling via ER-α is essential in basal level functioning of reproductive cycle, sexually receptive behaviors, physiological stress responses, as well as sleep cycle, and other nonsexual behaviors. When an organism is placed under long-term CR, which introduces an external stress to this ER-α signaling, the reduction of ER-α expression is attenuated over time in the hypothalamus. This review paper seeks to characterize the downstream effects of ER-α in the hypothalamus and limbic system that affect normal endocrine functioning.

A Mathematical Model of the Dynamics of Cytokine Expression and Human Immune Cell Activation in Response to the Pathogen Staphylococcus aureus.

Cell-based mathematical models have previously been developed to simulate the immune system in response to pathogens. Mathematical modeling papers which study the human immune response to pathogens have predicted concentrations of a variety of cells, including activated and resting macrophages, plasma cells, and antibodies. This study aims to create a comprehensive mathematical model that can predict cytokine levels in response to a gram-positive bacterium, S. aureus by coupling previous models. To accomplish this, the cytokines Tumor Necrosis Factor Alpha (TNF-α), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and Interleukin 10 (IL-10) are included to quantify the relationship between cytokine release from macrophages and the concentration of the pathogen, S. aureus, ex vivo. Partial differential equations (PDEs) are used to model cellular response and ordinary differential equations (ODEs) are used to model cytokine response, and interactions between both components produce a more robust and more complete systems-level understanding of immune activation. In the coupled cellular and cytokine model outlined in this paper, a low concentration of S. aureus is used to stimulate the measured cellular response and cytokine expression. Results show that our cellular activation and cytokine expression model characterizing septic conditions can predict ex vivo mechanisms in response to gram-negative and gram-positive bacteria. Our simulations provide new insights into how the human immune system responds to infections from different pathogens. Novel applications of these insights help in the development of more powerful tools and protocols in infection biology.

Estrogen receptor-alpha immunoreactivity in the arcuate hypothalamus of young and middle-aged female mice.

BACKGROUND: Changes in the neuroendocrine regulation of gonadal function, via altered hypothalamic sensitivity to peripheral hormones, are known to schedule reproductive maturation in the young and influence reproductive senescence. Estrogen (E) is a key hormone in this process. While changes in circulating levels of E over the life span are well documented, less is known about the corresponding changes in E sensitivity over the lifespan, especially during middle-age, when the initial signs of reproductive senescence emerge. OBJECTIVE: Taking Estrogen Receptor (ER)-alpha-immunoreactive cells as an index of hypothalamic sensitivity to E, this investigation aims to quantify alterations occurring at middle age in comparison to young age. METHODS: We counted ER-alpha-immunoreactive (IR) cells in the Arcuate hypothalamus of 6-week-old (young) and 18-month-old (middle-aged) C57BL/6J female mice, sacrificed at vaginal opening and diestrous, respectively. An automated imaging microscopy system (AIMS) was employed to generate counts of ER-alpha-IR cells for each sampled section of the Arcuate nucleus (ARC). RESULTS: This study shows a 21% reduction in the number of ER-alpha-IR cells and an 18% reduction in total ARC cell populations with aging. However, the calculated percentage of ER-alpha IR cells is similar in both young and middle aged mice, 30% and 29%, respectively. CONCLUSIONS: Both ER-alpha IR cell populations and total cell populations within the ARC hypothalamus decline by middle age in comparison to young age. Despite such a significant decrease in ER-alpha immunoreactive and total cells, both young and middle age mice maintain a similar ratio of ER-alpha IR cells to total cells in the ARC hypothalamus.

Human Brain/Cloud Interface.

The Internet comprises a decentralized global system that serves humanity's collective effort to generate, process, and store data, most of which is handled by the rapidly expanding cloud. A stable, secure, real-time system may allow for interfacing the cloud with the human brain. One promising strategy for enabling such a system, denoted here as a "human brain/cloud interface" ("B/CI"), would be based on technologies referred to here as "neuralnanorobotics." Future neuralnanorobotics technologies are anticipated to facilitate accurate diagnoses and eventual cures for the ∼400 conditions that affect the human brain. Neuralnanorobotics may also enable a B/CI with controlled connectivity between neural activity and external data storage and processing, via the direct monitoring of the brain's ∼86 × 109 neurons and ∼2 × 1014 synapses. Subsequent to navigating the human vasculature, three species of neuralnanorobots (endoneurobots, gliabots, and synaptobots) could traverse the blood-brain barrier (BBB), enter the brain parenchyma, ingress into individual human brain cells, and autoposition themselves at the axon initial segments of neurons (endoneurobots), within glial cells (gliabots), and in intimate proximity to synapses (synaptobots). They would then wirelessly transmit up to ∼6 × 1016 bits per second of synaptically processed and encoded human-brain electrical information via auxiliary nanorobotic fiber optics (30 cm3) with the capacity to handle up to 1018 bits/sec and provide rapid data transfer to a cloud based supercomputer for real-time brain-state monitoring and data extraction. A neuralnanorobotically enabled human B/CI might serve as a personalized conduit, allowing persons to obtain direct, instantaneous access to virtually any facet of cumulative human knowledge. Other anticipated applications include myriad opportunities to improve education, intelligence, entertainment, traveling, and other interactive experiences. A specialized application might be the capacity to engage in fully immersive experiential/sensory experiences, including what is referred to here as "transparent shadowing" (TS). Through TS, individuals might experience episodic segments of the lives of other willing participants (locally or remote) to, hopefully, encourage and inspire improved understanding and tolerance among all members of the human family.

Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice.

Life-long calorie restriction (CR) remains the most robust and reliable means of extending life span in mammals. Among the several theories to explain CR actions, one variant of the neuroendocrine theories of aging postulates that changing hypothalamic sensitivity to endocrine feedback is the clock that times phenotypic change over the life span. If the feedback sensitivity hypothesis is correct, CR animals should display a significantly different pattern of hormone-sensitive cell density and distribution in the hypothalamus. Of the many endocrine signal receptors that may be involved in maintaining hypothalamic feedback sensitivity, our study has selected to begin mapping those for estrogen (E). Altered hypothalamic sensitivity to E is known to schedule reproductive maturation and influence reproductive senescence. Taking estrogen receptor-alpha (ERalpha) immunoreactivity as an index of sensitivity to E, we counted ERalpha immunoreactive and non-immunoreactive cells in the pre-optic hypothalamus of young (6 weeks), ad-libitum (Old-AL) fed old (22 months), and calorie restricted (Old-CR) old (22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each sampled section of pre-optic hypothalamus. Results show a 38% reduction in ERalpha immunoreactive cells and an 18% reduction in total cell numbers in AL-old mice in comparison to young mice. However, CR mice only show a 19% reduction in ERalpha immunoreactive cells and a 13% reduction in total cell numbers in comparison to young mice. This indicates CR prevents age-related cell loss and maintains estrogen sensitivity in the pre-optic hypothalamus of old female B6D2F1 mice.