The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease

Digging Deeper Than LC/EC50: Nontraditional Endpoints and Non-Model Species in Oil Spill Technology

The response to the 2010 Deepwater Horizon (DWH) oil spill lead to a number of peer-reviewed publications examining the effects of the released oil and dispersant on fish species found in the northern Gulf of Mexico (GoM). Many of these papers, for very good reasons, focused on assessing toxicity by defining lethality through identification of dose-response curves that were specific to a given species, age class, exposure type, oil preparation method, and many other factors. Often those dose-response curves were used to predict LC or EC50 concentrations – amounts of oil that produced an effect on 50% of the exposed organisms. The advantage of this approach is obvious, in that it provides a single point estimate and variance of a concentration required to produce a given effect. This point estimate can then be compared across different exposure regimes to compare susceptibilities. Relevant LC/EC50 data is summarized and discussed in A synthesis of DWH oil, chemical dispersant and chemically dispersed oil aquatic standard laboratory acute and chronic toxicity studies (see Mitchelmore et al. A synthesis of Deepwater Horizon oil, chemical dispersant and chemically dispersed oil aquatic standard laboratory acute and chronic toxicity studies (Chap. 28). In: Murawski SA, Ainsworth C, Gilbert S, Hollander D, Paris CB, Schlüter M, Wetzel D (Eds.) Deep oil spills – facts, fate and effects. Springer; 2020). By constraining toxicity to this point estimate (often of lethality), however, researchers run the risk of missing effects that evince more subtle effects that do not manifest themselves as overt mortality in the short term. In the present chapter, we focus exclusively on fish and explore some of these endpoints, many of which were successfully used in recent years to assess sublethal health impacts on marine fish as part of the response to the DWH spill. We compare what is known about differences in sensitivity, among species, and between age classes within species, examining both organismal and molecular endpoints. Developmental impacts on cardiac health, swim performance, and sensory systems have been widely studied. We discuss what is known about effects on fish immune and endocrine function, the microbiome of the intestine and gill, and intracellular effects such as altered gene expression, oxidative stress, and DNA damage. In conclusion, we attempt to compare the endpoints, assess the sensitivity and utility, and link molecular- and individual-level impacts to larger population and community-level effects

Neurotrophins and B-cell malignancies

Neurotrophins and their receptors act as important proliferative and pro-survival factors in a variety of cell types. Neurotrophins are produced by multiple cell types in both pro and mature forms, and can act in an autocrine or paracrine fashion. The p75NTR and Trk receptors can elicit signalling in response to the presence or absence of their corresponding neurotrophin ligands. This signalling, along with neurotrophin and receptor expression, varies between different cell types. Neurotrophins and their receptors have been shown to be expressed by and elicit signalling in B lymphocytes. In general, most neurotrophins are expressed by activated B cells and memory B cells. Likewise, the TrkB95 receptor is seen on activated B cells, while TrkA and p75NTR are expressed by both resting and active B cells as well as memory B cells. Nerve growth factor stimulates B cell proliferation, memory B cell survival, antibody production and CD40 expression. Brain derived neurotrophic factor is involved in B cell maturation in the bone marrow through TrkB95. Overall neurotrophins and their receptors have been shown to be involved in B cell proliferation, development, differentiation, antibody secretion and survival. As well as expression and activity in healthy B cells, the neurotrophins and their receptors can contribute to B cell malignancies including acute lymphoblastic leukaemia, diffuse large B cell lymphoma, Burkitt’s lymphoma and multiple myeloma. They are involved in B cell malignancy survival and potentially in drug resistance.Molecular Medicine Ireland as part of the Clinical & Translational Research Scholars Programme2016-09-2