Regulation of the H<Superscript>+</Superscript>-ATP synthase by IF1: a role in mitohormesis

The mitochondrial H⁺-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H⁺-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H⁺-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H⁺-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H⁺-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases.     

Aptamer and its applications in neurodegenerative diseases

Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, transmissible spongiform encephalopathy, Huntington’s disease and multiple sclerosis.     

Risk reduction in a project portfolio

The positive impacts of managing projects as a portfolio are quantified by comparing the value of the integrated risk of a project portfolio and the aggregation of single project risks implemented separately. Firstly, the integrated risk is defined by proposing risky events based on set theory. Secondly, as projects interact with each other in a project portfolio, the integrated risk is evaluated by using a Bayesian network structure learning algorithm to construct an interdependent network of risks. Finally, the integrated risk of a practical case is assessed using this method, and the results show that the proposed method is an effective tool for calculating the extent of risk reduction of implementing a project portfolio and identifying the most risky project, so as to assist companies in making comprehensive decisions in the phase of portfolio selection and portfolio controlling.     

Optimal bundling and pricing decisions for complementary products in a two-layer supply chain

This article explores bundling and pricing decisions for two complementary products in a two-layer supply chain consisting of a multi-product manufacturer and a retailer. We establish four different pricing models under cases of decentralized decision, while considering different portfolio-bundling strategies of the manufacturer and the retailer. A game-theoretical method is used to characterize the corresponding equilibrium outcomes in each scenario. By further analyzing and comparing the maximum profits of all four possible scenarios, optimal bundling and pricing decisions for the manufacturer and the retailer are obtained, respectively. Model extensions and numerical examples are enriched to highlight the factors affecting optimal decision-making. Finally, valuable and interesting managerial insights are summarized. Results show that the upstream manufacturer always profits more when he sells complementary products separately. However, the optimal bundling decision of the downstream retailer is jointly determined by product complementarity (as a major factor) and the difference of product profitability (as a secondary factor). Market power cannot exert an influence on both optimal bundling decisions, but it can partly affect pricing decisions.     

Which is the use of systems theory in literature analysis?: The discovery of the place in La Mancha in Don Quixote

The use of systems theory to attempt to determine which ''place in La Mancha'' was the one whose name Cervantes could not quite recall in his universal novel, appears to be ordained to change certain attitudes towards science held in Cervantine literature. The reason: after four centuries of literary analysis, systemic methodology has proven able to identify the famous ''place'' with acceptable accuracy. Nonetheless, certain reasonable doubts persist around the suitability of a strictly scientific analysis of literature. In light of those doubts, the present article aims primarily to facilitate critique both of the systemic approach adopted and its outcome.     

The cellular autophagy/apoptosis checkpoint during inflammation

Cell death is a major determinant of inflammatory disease severity. Whether cells live or die during inflammation largely depends on the relative success of the pro-survival process of autophagy versus the pro-death process of apoptosis. These processes interact and influence each other during inflammation and there is a checkpoint at which cells irrevocably commit to either one pathway or another. This review will discuss the concept of the autophagy/apoptosis checkpoint and its importance during inflammation, the mechanisms of inflammation leading up to the checkpoint, and how the checkpoint is regulated. Understanding these concepts is important since manipulation of the autophagy/apoptosis checkpoint represents a novel opportunity for treatment of inflammatory diseases caused by too much or too little cell death.     

Null controllability of some degenerate wave equations

This paper is devoted to a study of the null controllability problems for one-dimensional linear degenerate wave equations through a boundary controller. First, the well-posedness of linear degenerate wave equations is discussed. Then the null controllability of some degenerate wave equations is established, when a control acts on the non-degenerate boundary. Different from the known controllability results in the case that a control acts on the degenerate boundary, any initial value in state space is controllable in this case. Also, an explicit expression for the controllability time is given. Furthermore, a counterexample on the controllability is given for some other degenerate wave equations.     

Single cell biology beyond the era of antibodies: relevance,challenges, and promises in biomedical research

Research of the past two decades has proved the relevance of single cell biology in basic research and translational medicine. Successful detection and isolation of specific subsets is the key to understand their functional heterogeneity. Antibodies are conventionally used for this purpose, but their relevance in certain contexts is limited. In this review, we discuss some of these contexts, posing bottle neck for different fields of biology including biomedical research. With the advancement of chemistry, several methods have been introduced to overcome these problems. Even though microfluidics and microraft array are newer techniques exploited for single cell biology, fluorescence-activated cell sorting (FACS) remains the gold standard technique for isolation of cells for many biomedical applications, like stem cell therapy. Here, we present a comprehensive and comparative account of some of the probes that are useful in FACS. Further, we illustrate how these techniques could be applied in biomedical research. It is postulated that intracellular molecular markers like nucleostemin (GNL3), alkaline phosphatase (ALPL) and HIRA can be used for improving the outcome of cardiac as well as bone regeneration. Another field that could utilize intracellular markers is diagnostics, and we propose the use of specific peptide nucleic acid probes (PNPs) against certain miRNAs for cancer surgical margin prediction. The newer techniques for single cell biology, based on intracellular molecules, will immensely enhance the repertoire of possible markers for the isolation of cell types useful in biomedical research.