Neuroendocrine Modulation of Complex Behavior and Physiology in C. elegans

To survive, animals must adapt to a complex and challenging world in a way that is flexible and responsive, while maintaining internal homeostasis. Neuromodulators provide a means to systemically alter behavioral or physiological state based on intrinsic or extrinsic cues, however dysregulated neuroendocrine signaling has negative consequences for fitness and survival. Here I examine neuroendocrine function and dysfunction using the escape response in Caenorhabditis elegans. The RFamide neuropeptide FLP-18 is a co-transmitter with the monoamine tyramine and functions both synergistically and antagonistically to tyramine in coordinating escape behavior. Using behavioral analysis and calcium imaging, I show that FLP-18 functions primarily through the G-protein coupled receptor (GPCR) NPR-5 to increase calcium levels in muscle, enhancing locomotion rate, bending and reversal behavior during the escape response. Furthermore, I examine the relationship between persistent acute stress and resilience using repeated activation of the escape response as a model of neuroendocrine dysregulation. Repeated activation of the escape response shortens lifespan and renders animals more susceptible to thermal, oxidative, and nutritional stress. Tyramine release is necessary and sufficient for this effect and activity of the tyraminergic RIM neurons is differentially regulated by acute versus long-term stressors. Impaired stress resistance requires both the GPCR TYRA-3 in the intestine and intestinal neuropeptide release. Activation of the insulin receptor DAF-2 is downstream of TYRA-3 and inhibits the transcription factors DAF-16/FOXO, SKN-1/Nrf2 and HSF-1, linking monoamine signaling in acute stress to the insulin signaling pathway and impaired resilience to long-term stressors

Geographic Mobility in the European Union: Optimising its Economic and Social Benefits

One of the founding principles of the European Union is the freedom of movement of workers (Article 39 of the Treaty establishing the European Community). The free movement of workers is essential for the creation of an area without internal frontiers, and for the strength-ening of economic and social cohesion and active citizenship.Taking an economic perspective, geographic mobility can have major positive effects by bringing about economic growth in countries with labour deficits and prosperity in countries with labour surplus. Hence, the diffusion of skills through occupational and geographic mo-bility is a central factor to enhance the productive capacity of firms and put regions or na-tional economies on a higher growth path. Taking a social perspective, geographical mobility has the potential of fostering social-cultural integration in the European Union, and strength-ening European identity and inter-cultural networks

A Primer on Cognitive Errors Illustrated Through the Lens of a Neurosurgical Practice

Problem Statement: Diagnostic error is often attributed to cognitive errors, including biased thinking patterns, rather than knowledge or data limitations, and education on cognitive bias deserves review in all spheres of practice. Background: The cognitive biases of practitioners create an inherent fallibility in recognizing and treating medical conditions. Awareness of cognitive errors is valuable for mitigating risk of diagnostic error. The impact of cognitive error is substantial in the management of neurosurgically relevant disease. Remarkably broad differential diagnoses often accompany neurologic symptoms. Both focal and non-focal symptoms lend themselves to diagnostic inertia that contributes to errors. Further, initial diagnostic direction can be inaccurate in the involved biological system, anatomic localization, and the pathologic process; thus delaying diagnosis and potentially courting severe consequences. The authors present neurosurgical cases to illustrate the major types of unconscious cognitive errors in medicine using clinically relevant vignettes. Strategies to mitigate cognitive error are also reviewed. Application/Recommendations: Awareness of the types of cognitive errors and de-biasing strategies are valuable to avoid faulty estimation of disease likelihood, avoid overlooking all relevant possibilities, and mitigate error in critical thinking. Recognition that all clinicians are vulnerable to cognitive error exposes the importance of strategies to reduce biases. Efforts to reduce error in medicine can be approached strategically by working to reduce bias and increase discipline in clinical reasoning

A critical evaluation of social impact assessment methodologies and a call to measure economic and social impact holistically through the external rate of return platform

Companies, investors, international organisations and non-governmental organisations have designed frameworks and tools for measuring the social impact of business. In this report we evaluate the landscape of existing social impact assessment methods. We first delineate the characteristics, context and development of leading methodologies. We then critically evaluate the strengths and weaknesses of todayʼs leading social impact assessment methodologies. We identify the strengths of existing approaches to be their increasing usability, inclusiveness and ability to demonstrate – and enhance – value; weaknesses are their resource-intensive nature, subjectivity, narrow focus on social outcomes, insufficient transparency, and inaccessibility. In light of the strengths and weaknesses of existing methods, we close the report with a call for a new platform. Building upon the advances of existing methods, we propose the creation of a platform wherein companies, investors and third-parties can comprehensively and transparently report their activities across a range of parameters: (i) Company; (ii) Suppliers; (iii) Customers; (iv) Society; and (v) Environment. Through the radical transparency of the platform, which we call the “External Rate of Return” (ERR) a wide range of users will be able to measure and compare the economic and social impact of all types of business ventures in a holistic and consistent manner. Furthermore, through the ERR platform companies and the public at large can engage in on-going dialogues about the overall impact of business. We close our paper with a call for action as follows: we ask readers of the report to contact us to suggest indicators and metrics to be included in such a comprehensive impact assessment platform. Also, contact us if you would like to help build the platform

Voltage-dependent calcium influx in human sperm assessed by simultaneous optical detection of intracellular calcium and membrane potential

AbstractThere are several physiological and pharmacological evidences indicating that opening of voltage dependent calcium channels play a crucial role in the induction of the acrosome reaction in mammalian sperm. In mature sperm, physiological inductors of the acrosome reaction such as ZP3, a zona pellucida protein, and the steroid hormone progesterone, induce depolarization and calcium influx, which are required for the acrosome reaction. In this paper, we describe a voltage-dependent calcium influx present in human sperm. We report an experimental procedure that allows measurement of intracellular calcium and membrane potential simultaneously using the fluorescent dyes DiSC3(5) and Fura-2. We found that in human uncapacitated sperm, depolarization induces a nifedipine-insensitive calcium influx that, in most cases, was transient. Calcium influx was observed in the range of −60 to −15 mV (the range tested). At resting membrane potential (around −40 mV), potassium addition depolarized and induced calcium influx, but when the depolarization was preceded by a hyperpolarization (induced with valinomycin), calcium influx was remarkably enhanced, suggesting that at −40 mV, channels are in a putative inactivated state. When sperm was incubated in medium without calcium, calcium restoration caused calcium influx that depended on voltage, and decayed between 1 and 2 min after depolarization. Unlike ram, mouse or bovine sperm, in which an alkalinization is required to induce calcium influx with potassium, the voltage-dependent calcium influx observed in human sperm did not require an increase in internal or external pH. However, we observed that ammonium, which increases intracellular pH, enhanced the voltage-dependent calcium influx about 90%. Furthermore, depolarization by itself caused a small increase in intracellular pH suggesting that pH can be regulated by membrane potential in human sperm

pH Regulation in Mouse Sperm: Identification of Na+-, Cl−-, and[formula]Dependent and Arylaminobenzoate-Dependent Regulatory Mechanisms and Characterization of Their Roles in Sperm Capacitation

AbstractIntracellular pH (pHi) regulates several aspects of mammalian sperm function, although the transport mechanisms that control pHiin these cells are not understood. The pHiof mouse cauda epididymal sperm was determined from the fluorescence excitation ratio of 2,7-bis(carboxyethyl)-5(6)-carboxyfluorescein and calibrated with nigericin and elevated external [K+]. Two acid efflux mechanisms were identified following imposition of acid loads. One pathway has many anticipated characteristics of the somatic Na+-dependent Cl−–[formula]exchanger, although sperm and somatic mechanisms can be distinguished by their ion selectivity and inhibitor sensitivity. Sperm may have an isoform of this exchange pathway with novel functional characteristics. The second acid-export pathway does not require extracellular anions or cations and is inhibited by arylaminobenzoates (flufenamic acid, diphenylamine-2-carboxylate). Mouse sperm also recover spontaneously from intracellular alkalinization. Recovery rates inN-methyl-D-glucamine+Cl−or in 0.25Msucrose are not significantly different from that in a complex culture medium. Thus, recovery from alkalinization does not utilize specific, ion-dependent transport mechanisms. Other widely distributed acid-efflux mechanisms, such as the Na+–H+antiport pathway and the Na+-independent Cl−–[formula]exchanger are not major regulators of mouse sperm pHi. Sperm capacitation results in pHiincreases (from 6.54 ± 0.08 to 6.73 ± 0.09) that require a functional Na+-, Cl−-, and[formula]-dependent acid-efflux pathway. Inhibition of this regulatory mechanism attenuates alkaline shifts in pHiduring capacitation as well as the ability of sperm to produce a secretory response to zona pellucida agonists. These data suggest that one aspect of mouse sperm capacitation is the selective activation of one major pHiregulator

Report No. 19: Geographic Mobility in the European Union: Optimising its Economic and Social Benefits

Joint expertise with NIRAS Consultants and AMS for the European Commission, Bonn 2008 (159 pages)