Modeling the Critical Activation of Chaperone Machinery in Protein Folding.

Protein homeostasis is a dynamic network that plays a pivotal role in systems' maintenance within a cell. This quality control system involves a number of mechanisms regarding the process of protein folding. Chaperones play a critical role in the folding, refolding, and unfolding of proteins. Aggregation of misfolded proteins is a common characteristic of neurodegenerative diseases. Chaperones act in a variety of pathways in this critical interplay between protein homeostasis network and misfolded protein's load. Moreover, ER stress-induced cell death mechanisms (such as the unfolded protein response) are activated as a response. Therefore, there is a critical balance in the accumulation of misfolded proteins and ER stress response mechanisms which can lead to cell death. Our focus is in understanding the different mechanisms that govern ER stress signaling in health and disease in order to represent the regulation of protein homeostasis and balance of protein synthesis and degradation in the ER. Our proposed model describes, using hybrid modeling, the function of chaperones' machinery for protein folding.

A Hypothesis of Circulating MicroRNAs' Implication in High Incidence of Atrial Fibrillation and Other Electrocardiographic Abnormalities in Cancer Patients.

MicroRNAs are short non-coding RNA molecules that control posttranscriptional gene expression and are present in tissues cells but also circulate in biological fluids in various forms (exosome, connected with proteins, apoptotic bodies, etc.). The roles that circulated extracellular serum microRNAs possess in cancer development, like in the delivery from a recipient cell to distant tissues and the repression of host genes resulting in the impairment of critical functions, are still undetermined. Disturbances, such as the higher incidence of atrial fibrillation in cancer patients, could be analyzed in the frame of suppressive action of circulated microRNAs in genes that control cardiac conduction in atrium. More precisely, mir-21 overexpression in tissues promotes atrium fibrosis and impairs conductibility. A possible hypothesis is that the high levels of circulating microRNA in cancer may exert the same effect. Further experiments are necessary to corroborate the hypothesis.

Particular Biomolecular Processes as Computing Paradigms.

The research on alternative computation paradigms has been initiated mainly because of the apparent limits induced by the nature of the materials and the methods used in current computing technologies. Due to the above observation, various bio-inspired computing methods have already been proposed and studied, both in practice and theory. In this paper, a review of such models is outlined with emphasis on biomolecular forms of computing. In addition, a novel biomolecular model of computation based on P systems is proposed inspired by the structure of mitochondria, namely, the mitochondria P systems and automata.

[MiR-140-3p Downregulation in Association with PDL-1 Overexpression in Many Cancers: A Review from the Literature Using Predictive Bioinformatics Tools].

Programmed death-ligand 1 (PD-L1) has been speculated to play a critical role in suppression of the immune system and it can be upregulated in cancer cells, which may allow cancers to evade the host immune system. MicroRNAs (miRNAs) are small non-coding RNA molecules (containing about 22 nucleotides), that function in RNA silencing and post-transcriptional regulation of gene expression. MiRNAs were found deregulated (upregulated or downregulated) and implicated in cancer development with various roles which depend on their gene target. Using targetscan web server prediction algorithm, we concluded that miR-140-3p is a targeting mirRNA with conserved consequential pairing of target region for PD-L1. Moreover, by reviewing all the available cancer studies in Pub/Medline about miR-140-3p, was found permanently down regulated. Furthermore, in recent immunotherapy related clinical trials in most cancers, evaluated PD-L1, it is found overexpressed. In the near future, in vitro or in vivo studies need to validate whether there is direct correlation between PD-L1 overexpression and miR-140-3p downregulation as targetscan performed algorithm predicted.

Formal Models of Biological Systems.

Recent biomedical research studies are focused in the mechanisms by which misfolded proteins lead to the generation of oxidative stress in the form of reactive oxygen species (ROS), often implicated in neurodegenerative diseases and aging. Moreover, biological experiments are designed to investigate how proteostasis depends on the balance between the folding capacity of chaperone networks and the continuous flux of potentially nonnative proteins. Nevertheless, biological experimental methods can examine the protein folding quality control mechanisms only in individual cells, but not in a multicellular level. Formal models offer a dynamic form of modelling, which allows to explore various parameter values in an integrated time-dependent system. This paper aims to present a formal approach of a mathematical descriptive model using as example a representation of a known molecular chaperone system and its relation to diseases associated to protein misfolding and neurodegeneration.

Molecular Chaperones in Neurodegenerative Diseases: A Short Review.

Stress and misfolded proteins result to dysfunction in the cell, often leading to neurodegenerative diseases and aging. Misfolded proteins form toxic aggregates that threaten cell's stability and normal functions. In order to restore its homeostasis, the cell activates the UPR system. Leading role in the restoration play the molecular chaperones which target the misfolded proteins with the purpose of either helping them to unfold and refold to their natural state or lead them degradation. This paper aims to present some of the most known molecular chaperones and their relation with diseases associated to protein misfolding and neurodegeneration, as well as the role of chaperones in proteostasis.

Modeling protein misfolding in charcot-marie-tooth disease.

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. Recent advancements in molecular biology have elucidated the molecular bases of this genetically heterogeneous neuropathy. Still, the major challenge lies in determining the individual contributions by malfunctions of proteins to the disease's pathology. This paper reviews the identified molecular mechanisms underlying major forms of CMT disease. A growing body of evidence has highlighted the role of protein misfolding in demyelinating peripheral neuropathies and neurodegenerative diseases. Several hypotheses have been proposed to explain how misfolded aggregates induce neuronal damage. Current research focuses on developing novel therapeutic targets which aim to prevent, or even reverse the formation of protein aggregation. Interestingly, the role of the cellular defence mechanisms against accumulation of misfolded proteins may play a key role leading to novel strategies for treatment accelerating the clearance of their toxic early aggregates. Based on these findings we propose a model for describing in terms of a formal computer language, the biomolecular processes involving proteins associated with CMT disease.

The ubiquitous role of mitochondria in Parkinson and other neurodegenerative diseases.

Orderly mitochondrial life cycle, plays a key role in the pathology of neurodegenerative diseases. Mitochondria are ubiquitous in neurons as they respond to an ever-changing demand for energy supply. Mitochondria constantly change in shape and location, feature of their dynamic nature, which facilitates a quality control mechanism. Biological studies in mitochondria dynamics are unveiling the mechanisms of fission and fusion, which essentially arrange morphology and motility of these organelles. Control of mitochondrial network homeostasis is a critical factor for the proper function of neurons. Disease-related genes have been reported to be implicated in mitochondrial dysfunction. Increasing evidence implicate mitochondrial perturbation in neuronal diseases, such as AD, PD, HD, and ALS. The intricacy involved in neurodegenerative diseases and the dynamic nature of mitochondria point to the idea that, despite progress toward detecting the biology underlying mitochondrial disorders, its link to these diseases is difficult to be identified in the laboratory. Considering the need to model signaling pathways, both in spatial and temporal level, there is a challenge to use a multiscale modeling framework, which is essential for understanding the dynamics of a complex biological system. The use of computational models in order to represent both a qualitative and a quantitative structure of mitochondrial homeostasis, allows to perform simulation experiments so as to monitor the conformational changes, as well as the intersection of form and function.