Mechanism of Hsp70 specialised interactions in protein translocation and the unfolded protein response

Hsp70 chaperones interact with substrate proteins in a coordinated fashion that is regulated by nucleotides and enhanced by assisting cochaperones. There are numerous homologues and isoforms of Hsp70 that participate in a wide variety of cellular functions. This diversity can facilitate adaption or specialisation based on particular biological activity and location within the cell. In this review, we highlight two specialised binding partner proteins, Tim44 and IRE1, that interact with Hsp70 at the membrane in order to serve their respective roles in protein translocation and UPR signaling. Recent mechanistic data suggest analogy in the way the two Hsp70 homologues (BiP and mtHsp70) can bind and release from IRE1 and Tim44 upon substrate engagement. These shared mechanistic features may underlie how Hsp70 interacts with specialised binding partners and may extend our understanding of the mechanistic repertoire that Hsp70 chaperones possess

Gathering Real World Evidence Through the Evaluation of Decision History.

Clinical Practice Guidelines (CPGs) gather latest evidence-based results to guide and support clinicians over the decision-making process to provide best care. Nevertheless, clinical cases may be subject to some biases (understood as non-compliance with CPGs) that can lead to adapt care delivery. In this work an experience-based decision support leaning on the structuration of the Decisional Event concept for tracking and storing each clinical decision is presented. Moreover, a visual analytics tool is provided in order to facilitate the visualization of biases from guideline-based decision support and the identification and inclusion of real-world evidence into the reasoning process by augmenting the knowledge formalized in the implemented guidelines

Weighting Experience-Based Decision Support on the Basis of Clinical Outcomes' Assessment.

Technologies such as decision support systems are expected to help clinicians implement clinical practice guidelines (CPGs) with the aim of decreasing practice variations and improving clinical outcomes. However, if CPGs provide recommendations to improve patient care, they may fail to take into account actual clinical outcomes associated to the recommended treatment, such as adverse events or secondary effects. In this paper, we present a novel experience-based decision support approach applied to the management of breast cancer, the most commonly diagnosed cancer among women worldwide. Capitalizing on the clinical know-how of physicians and the modeling of patient's outcomes and toxicities in a computer interpretable way, we are able to discover new knowledge that helps improving patient-centered clinical care. This work is conducted within the EU Horizon 2020 project DESIREE

UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor

BiP is a major ER chaperone and suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains (LD) of UPR proteins, IRE1 and PERK, switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its cochaperones, with loss of ATPase stimulation. Furthermore, misfolded proteindependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as a Hsp70 chaperone and ER stress sensor

Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1

The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. The cellular requirement to synthesize proteins within the ER is matched by its folding capacity. However, the physiological demands or aberrations in folding may result in an imbalance which can lead to the accumulation of misfolded protein, also known as “ER stress.” The unfolded protein response (UPR) is a cell-signaling system that readjusts ER folding capacity to restore protein homeostasis. The key UPR signal activator, IRE1, responds to stress by propagating the UPR signal from the ER to the cytosol. Here, we discuss the structural and molecular basis of IRE1 stress signaling, with particular focus on novel mechanistic advances. We draw a comparison between the recently proposed allosteric model for UPR induction and the role of Hsp70 during polypeptide import to the mitochondrial matrix

In vitro FRET analysis of IRE1 and BiP association and dissociation upon endoplasmic reticulum stress

The unfolded protein response (UPR) is a key signaling system that regulates protein homeostasis within the endoplasmic reticulum (ER). The primary step in UPR activation is the detection of misfolded proteins, the mechanism of which is unclear. We have previously suggested an allosteric mechanism for UPR induction (Carrara et al., 2015) based on qualitative pull-down assays. Here, we develop an in vitro Förster resonance energy transfer (FRET) UPR induction assay that quantifies IRE1 luminal domain and BiP association and dissociation upon addition of misfolded proteins. Using this technique, we reassess our previous observations and extend mechanistic insight to cover other general ER misfolded protein substrates and their folded native state. Moreover, we evaluate the key BiP substrate-binding domain mutant V461F. The new experimental approach significantly enhances the evidence suggesting an allosteric model for UPR induction upon ER stress

Augmenting Guideline-based CDSS with Experts Knowledge.

Over the past years, clinical guidelines have increasingly become part of the clinical daily practice in order to provide best available Evidence-Based-Medicine services. Hence, their formalization as computer interpretable guidelines (CIG) and their implementation in clinical decision support systems (CDSSs) are emerging to support clinicians in their decision making process and potentially improve medical outcomes. However, guideline compliancy in the clinical daily practice is still “low”. Some of the reasons for such low compliance rate are (i) lack of a complete guideline to cover special clinical cases (e.g. oncogeriatric cases), (ii) absence of parameters that current guidelines do not consider (e.g. lifestyle) and (iii) absence of up-to-date guidelines due to lengthy validation procedures. In this paper we present a novel method to build a CDSS that, besides integrating CIGs, stores experts’ knowledge to enrich the CDSS and provide best support to clinicians. The knowledge inc ludes new evidence collected over time by the systematic usage of CDSSs

Ubiquitous healthcare systems and medical rules in COPD Domain

Chronic Obstructive Pulmonary Disease (COPD) is a severe lung illness that causes a progressive deterioration in the function and structure of the respiratory system. Recently, COPD became the fifth cause of mortality and the seventh cause of morbidity in Canada. The advancement of context-aware technology creates a new and important opportunity to transform the standard shape of healthcare services into a more dynamic and interactive form. This research project design and validates a rule-based ontology-reasoning framework that provides a context-aware system for COPD patients. The originality of the proposed approach consists in its methodology to prove the efficiency of this model in simulated examples of real-life scenarios based on collaborative data analysis, recognized by specialized medical experts

Securing Medical Images for Mobile Health Systems Using a Combined Approach of Encryption and Steganography

© 2018, Springer International Publishing AG, part of Springer Nature. In this paper, we propose a medical image encryption scheme which can be used in mobile health systems. The proposed scheme combines RSA algorithm, logistic chaotic encryption algorithm, and steganography technique to secure medical images. In the proposed scheme, we encrypt a medical image based on chaotic sequence and encrypt the initial value of the chaotic sequence using the RSA encryption algorithm. The encrypted information by RSA is hidden in the Image. Only legitimate users can obtain the parameter information and restore the image. In the receiver side, we apply the inverse methods to get the original image after an encrypted image is arrived. We have implemented a simple application on the Android platform and have evaluated its performance. The experimental results show that the proposed image encryption scheme is practical and feasible for mobile health systems