Mitochondrial degradation by autophagy (mitophagy) in hepatocytes

Mitochondria are the essential site of aerobic energy production in eukaryotic cells. Reactive oxygen species (ROS) are an inevitable by-product of mitochondria metabolism and can cause mitochondrial DNA mutations and dysfunction. Mitochondrial damage can also be the consequence of disease processes. Therefore, maintaining a healthy population of mitochondria is essential to the well-being of cells. Autophagic delivery to lysosomes is the major degradative pathway in mitochondrial turnover. I use the term mitophagy to refer to mitochondrial degradation by autophagy. Although long assumed to be a random process, increasing evidence indicates that mitophagy is a selective process. This study provides a description of a description of the process of mitophagy, the possible role of the mitochondrial permeability transition in mitophagy and the importance of mitophagy in turnover of dysfunctional mitochondria

Molecular Dynamics Simulation to Understand the Ability of Anionic Polymers to Alter the Morphology of Calcite

Molecular dynamics was utilized to investigate the ability of anionic macromolecules to drastically change the morphology of calcite in the presence of magnesium ions. Anionic poly(acrylic acid) and poly(methacrylic acid) were compared with cationic poly(ethylene imine) in their binding behavior on calcite (104) and (110) surfaces. Poly(acrylic acid) and poly(methacrylic acid) showed preferential binding on (110) with strong electrostatic attractions, whereas poly(ethylene imine) was only weakly attracted to (104). The extent of the charge imbalance on the surfaces appeared responsible for the current results, which originated from the deficient number of the coordinating oxygen atoms of carbonate around the surface calcium. The results of the current study were in accordance with the previous experimental observations, where the {hk0} surfaces of calcite were elongated under the coexistence of the anionic polymers and magnesium ions. These results could be generally utilized in the polymer-controlled crystallization with broad implications in the specific interactions with crystal surfaces

Selective degradation of mitochondria by mitophagy

Mitochondria are the essential site of aerobic energy production in eukaryotic cells. Reactive oxygen species (ROS) are an inevitable by-product of mitochondria metabolism and can cause mitochondrial DNA mutations and dysfunction. Mitochondrial damage can also be the consequence of disease processes. Therefore, maintaining a healthy population of mitochondria is essential to the well-being of cells. Autophagic delivery to lysosomes is the major degradative pathway in mitochondrial turnover, and we use the term mitophagy to refer to mitochondrial degradation by autophagy. Although long assumed to be a random process, increasing evidence indicates that mitophagy is a selective process. This review provides an overview of the process of mitophagy, the possible role of the mitochondrial permeability transitionin mitophagy and the importance of mitophagy in turnover of dysfunctional mitochondria

Tracker Dyes to Probe Mitochondrial Autophagy (Mitophagy) in Rat Hepatocytes

Mitochondria become targets for autophagic degradation after nutrient deprivation, a process also termed mitophagy. In this study, we used LysoTracker Red (LTR) and MitoTracker Green to characterize the kinetics of autophagosomal proliferation and mitophagy in cultured rat hepatocytes. Autophagy induced by nutrient deprivation plus glucagon increased LTR uptake assessed with a fluorescence plate reader and the number of LTR-labeled acidic organelles assessed with confocal microscopy in individual hepatocytes both by 4- to 6-fold. Serial imaging of hepatocytes coloaded with MitoTracker Green (MTG) revealed an average mitochondrial digestion time of 7.5 min after autophagic induction. In the presence of protease inhibitors, digestion time more than doubled, and the total number of LTR-labeled organelles increased about 40%, but the proportion of the LTR-labeled acidic organelles containing MTG fluorescence remained constant at about 75%. Autophagy inhibitors, 3-methyladenine, wortmannin and LY204002, suppressed the increase of LTR uptake after nutrient deprivation by up to 85%, confirming that increased LTR uptake reflected autophagy induction. Cyclosporin A and NIM811, specific inhibitors of the mitochondrial permeability transition (MPT), also decreased LTR uptake, whereas tacrolimus, an immunosuppressive reagent that does not inhibit the MPT, was without effect. In addition, the c-Jun N-terminal kinase (JNK) inhibitors, SCP25041 and SP600125, blocked LTR uptake by 47% and 61%, respectively, but ERK1, p38 and caspase inhibitors had no effect. The results show that mitochondria once selected for mitophagy are rapidly digested and support the concept that mitochondrial autophagy involves the MPT and signaling through PI3 kinase and possibly JNK

Validation and Adaptation of the “Modified Transplant Symptom Occurrence and Symptom Distress Scale” for Kidney Transplant Recipients

The aim was to adapt and validate the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) for kidney transplant recipients undergoing immunosuppressive therapy in Korea. The MTSOSD-59R has been used with solid organ transplant recipients globally to assess the adverse effects of immunosuppressive medication. A descriptive cross-sectional design was used. MTSOSD-59R was first translated, and pilot tested. Next, content validity was established with nine organ transplant experts. Then, from October 2017 to October 2018, the Korean MTOSOSD-59R was administered to a convenience sample of 122 kidney transplant recipients recruited from a single center. Ridit analysis was used to measure symptom occurrence and distress. The known-group approach was used to test the construct validity using Mann–Whitney U tests for between-group comparisons. The content validity index for MTSOSD-59R was 0.98, and known-group validity was confirmed. The split-half Spearman–Brown corrected reliability coefficient was 0.902 for symptom occurrence and 0.893 for symptom distress. The four most frequent and distressing symptoms were fatigue, lack of energy, thinning hair, and erectile dysfunction (male). Results suggest this Korean MTSOSD-59R adaptation has adequate language, construct validity, and reliability to gather meaningful information from kidney transplant recipients in Korea

No Movie to Watch: A Design Strategy for Enhancing Content Diversity through Social Recommendation in the Subscription-Video-On-Demand Service

Increasing diversity is becoming crucial in recommender systems to address the “filter bubble” issue caused by accuracy-based algorithms. Diversity-oriented algorithms have been developed to solve this problem. However, this diversification has made it difficult for users to discover what they really want from the variety of information provided by the algorithm. Users spend their time wandering around the recommended content space but fail to find content they want to watch. Therefore, they rely on external services to gather information that does not appear on the recommended list. This could lead to a reduction in the services’ ability to compete with other subscription video on-demand (SVOD) services. To address this problem, this study proposes a human-centered approach to diversification through social recommendations. We conducted an experiment to understand how perceived diversity affects user perceptions and attitudes. Specifically, by incorporating social recommendations into the SVOD service, this experiment was changed to examine the following conditions: (1) influencers vs. online friends, and (2) human recommendation lists vs. algorithmic recommendation lists. The findings indicated that perceived diversity influences the manner in which the users perceive information quality and playfulness, both of which have a positive effect on their intention to use. Additionally, the participants’ perceptions of information quality were greater in the scenario with the human recommendation than in that with the algorithmic recommendation. This study contributes to the development of a theoretical framework based on perceived diversity through social recommendations and the design of an SVOD interface with social recommendations to provide better user experiences

Melting Diagrams of Adefovir Dipivoxil and Dicarboxylic Acids: An Approach to Assess Cocrystal Compositions

Pharmaceutical cocrystallization is a useful method to regulate the physical properties of active pharmaceutical ingredients (APIs). Since the cocrystals may form in various API/coformer ratios, identification of the cocrystal composition is the critical first step of any further analysis. However, the composition identification is not always unambiguous if cocrystallization is performed in solid state with unsuccessful solution crystallization. Single melting point and some new X-ray diffraction peaks are necessary but not sufficient conditions. In the present study, the use of melting diagrams coupled with the X-ray diffraction data was tested to identify cocrystal compositions. Adefovir dipivoxil (AD) was used as a model API, and succinic acid (SUC), suberic acid (SUB), and glutaric acid (GLU) were coformers. Compositions of AD/SUC and AD/SUB had been previously identified as 2:1 and 1:1, but that of AD/GLU was not unambiguously identified because of the difficulty of solution crystallization. Melting diagrams were constructed with differential scanning calorimetry, and their interpretation was assisted by powder X-ray diffraction. The cocrystal formation was exhibited as new compositions with congruent melting in the phase diagrams. This method correctly indicated the previously known cocrystal compositions of AD/SUC and AD/SUB, and it successfully identified the AD/GLU cocrystal composition as 1:1. The current approach is a simple and useful method to assess the cocrystal compositions when the crystallization is only possible in solid state

Ball Milling to Build the Hybrid Mesocrystals of Ibuprofen and Aragonite

Mesocrystal formation is one of the new paradigms of the nonclassical crystallization, where the assembly of crystal domains is observed. Also, it has been recently employed in studies on drug formulation to utilize controlled dissolution of the drug domains. In this report, ibuprofen was attempted to form hybrid mesocrystals with calcium carbonate crystals. Two polymorphs of calcium carbonate (aragonite and calcite) were used during the solid-state process of ball milling. Structural analyses confirmed the mesocrystal formation of ibuprofen with aragonite but not with calcite. The origin of the observed behavior was found from the higher affinity of ibuprofen to aragonite, especially its (0 1 0) surface, compared to calcite. The hybrid mesocrystals of ibuprofen and aragonite showed the environment-responsive release behavior, where the stability of aragonite was the controlling factor for the release kinetics of ibuprofen