Quality Control Network Research Articles

Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions

BackgroundThere is currently no specific therapeutic drug available for heart failure in clinical practice. Numerous studies have validated the efficacy of Ginsenoside Rb1, an active component found in various herbal remedies used for heart failure treatment, in effectively ameliorating myocardial ischemia. However, the precise mechanism of action and molecular targets of Ginsenoside Rb1 remain unclear. PurposeThis study aims to explore the molecular mechanisms through which Ginsenoside Rb1 synergistically modulates the gut flora and mitochondrial quality control network in heart failure by targeting the DUSP-1-TMBIM-6-VDAC1 axis. Study designThis study utilized DUSP-1/VDAC1 knockout (DUSP-1-/-/VDAC1-/-) and DUSP-1/VDAC1 transgenic (DUSP-1+/+/VDAC1+/+) mouse models of heart failure, established through Transverse Aortic Constriction (TAC) surgery and genetic modification techniques. The mice were subsequently subjected to treatment with Ginsenoside Rb1. MethodsA series of follow-up multi-omics analyses were conducted, including assessments of intestinal flora, gene transcription sequencing, single-cell databases, and molecular biology assays of primary cardiomyocytes, to investigate the mechanism of action of Ginsenoside Rb1. ResultsGinsenoside Rb1 was found to have multiple regulatory mechanisms on mitochondria. Notably, DUSP-1 was discovered to be a crucial molecular target of Ginsenoside Rb1, controlling both intestinal flora and mitochondrial function. The regulatory effects of DUSP-1 on inflammation and mitochondrial quality control were mediated by changes in TMBIM-6 and VDAC1. Furthermore, NLRP3-mediated inflammatory responses were found to interact with mitochondrial quality control, exacerbating myocardial injury under stress conditions. Ginsenoside Rb1 modulated the DUSP-1-TMBIM-6-VDAC1 axis, inhibited the release of pro-inflammatory factors, altered the structural composition of the gut flora, and protected impaired heart function. These effects indirectly influenced the crosstalk between inflammation, mitochondria, and gut flora. ConclusionThe DUSP-1-TMBIM-6-VDAC1 axis, an upstream pathway regulated by Ginsenoside Rb1, is a profound mechanism through which Ginsenoside Rb1 improves cardiac function in heart failure by modulating inflammation, mitochondria, and gut flora.

LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome-positive cancer cells

The unfolded protein response pathways (UPR), autophagy, and compartmentalization of misfolded proteins into inclusion bodies are critical components of the protein quality control network. Among inclusion bodies, aggresomes are particularly intriguing due to their association with cellular survival, drug resistance, and cancer-aggressive behavior. Aggresomes are molecular condensates formed when collapsed vimentin cages encircle misfolded proteins before final removal by autophagy. Yet significant gaps persist in the mechanisms governing aggresome formation and elimination in cancer cells. Understanding these mechanisms is crucial, especially considering the involvement of LC3A, a member of the MAP1LC3 family, which plays a unique role in autophagy regulation and has been reported to be epigenetically silenced in many cancers. Herein, we utilized tetracycline-inducible expression of LC3A to investigate its role in choroid plexus carcinoma cells, which inherently exhibit the presence of aggresomes. Live cell imaging was employed to demonstrate the effect of LC3A expression on aggresome-positive cells, while SILAC-based proteomics identified LC3A-induced protein and pathway alterations. Our findings demonstrate that extended expression of LC3A is associated with cellular senescence. However, the obstruction of lysosomal degradation in this context has a deleterious effect on cellular viability. In response to LC3A-induced autophagy, we observed significant alterations in mitochondrial morphology, reflected by mitochondrial dysfunction and increased ROS production. Furthermore, LC3A expression elicited the activation of the PERK-eIF2α-ATF4 axis of the UPR, underscoring a significant change in protein quality control network. In conclusion, our results elucidate that LC3A-mediated autophagy alters the protein quality control network, exposing a vulnerability in aggresome-positive cancer cells.

Enhanced patient-based real-time quality control using the graph-based anomaly detection.

Patient-based real-time quality control (PBRTQC) is an alternative tool for laboratories that has gained increasing attention. Despite the progress made by using various algorithms, the problems of data volume imbalance between in-control and out-of-control results, as well as the issue of variation remain challenges. We propose a novel integrated framework using anomaly detection and graph neural network, combining clinical variables and statistical algorithms, to improve the error detection performance of patient-based quality control. The testing results of three representative analytes (sodium, potassium, and calcium) and eight independent variables of patients (test date, time, gender, age, department, patient type, and reference interval limits) were collected. Graph-based anomaly detection network was modeled and used to generate control limits. Proportional and random errors were simulated for performance evaluation. Five mainstream PBRTQC statistical algorithms were chosen for comparison. The framework of a patient-based graph anomaly detection network for real-time quality control (PGADQC) was established and proven feasible for error detection. Compared with classic PBRTQC, the PGADQC showed a more balanced performance for both positive and negative biases. For different analytes, the average number of patient samples until error detection (ANPed) of PGADQC decreased variably, and reductions could reach up to approximately 95 % at a small bias of 0.02 taking calcium as an example. The PGADQC is an effective framework for patient-based quality control, integrating statistical and artificial intelligence algorithms. It improves error detection in a data-driven fashion and provides a new approach for PBRTQC from the data science perspective.

Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants

Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 ( ~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.

Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy.

This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related mitochondrial fission and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that the damage regulation was positively correlated with the pathological fission and pan-apoptosis of myocardial cell mitochondria. Compared with wild-type mice (WT), NR4A1-knockout mice exhibited resistance to myocardial ischemia-reperfusion injury and mitochondrial pathological fission, characterized by mitophagy activation. Results showed that ischemia-reperfusion injury increased NR4A1 expression level, activating mitochondrial fission mediated by Mff and restoring the mitophagy phenotype mediated by FUNDC1. The inactivation of FUNDC1 phosphorylation could not mediate the normalization of mitophagy in a timely manner, leading to an excessive stress response of unfolded mitochondrial proteins and an imbalance in mitochondrial homeostasis. This process disrupted the normalization of the mitochondrial quality control network, leading to accumulation of damaged mitochondria and the activation of pan-apoptotic programs. Our data indicate that NR4A1 is a novel and critical target in myocardial I/R injury that exertsand negative regulatory effects by activating Mff-mediated mito-fission and inhibiting FUNDC1-mediated mitophagy. Targeting the crosstalk balance between NR4A1-Mff-FUNDC1 is a potential approach for treating I/R.

ECG Modeling for Simulation of Arrhythmias in Time-Varying Conditions.

The present article proposes an ECG simulator that advances modeling of arrhythmias and noise by introducing time-varying signal characteristics. The simulator is built around a discrete-time Markov chain model for simulating atrial and ventricular arrhythmias of particular relevance when analyzing atrial fibrillation (AF). Each state is associated with statistical information on episode duration and heartbeat characteristics. Statistical, time-varying modeling of muscle noise, motion artifacts, and the influence of respiration is introduced to increase the complexity of simulated ECGs, making the simulator well suited for data augmentation in machine learning. Modeling of how the PQ and QT intervals depend on heart rate is also introduced. The realism of simulated ECGs is assessed by three experienced doctors, showing that simulated ECGs are difficult to distinguish from real ECGs. Simulator usefulness is illustrated in terms of AF detection performance when either simulated or real ECGs are used to train a neural network for signal quality control. The results show that both types of training lead to similar performance.

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control

Suppression of premature termination codons (PTCs) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two potent readthrough promoters-NVS1.1 and NVS2.1-that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to other readthrough promoters that affect stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, and activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

Quality control assessment, toxicity profiling, and experimental validation of network pharmacology-predicted anti-inflammatory potential of Natsiatum herpeticum Buch.-Ham. Ex Arn.

Ethnopharmacological relevanceNatsiatum herpticum Buch.-Ham. Ex Arn., a least-explored plant, is being considered a wild edible plant by the Bankariya community of Nepal and the Mishing, Sonowal Kachari, and several ethnic groups in the north-east region of India. It is also used as a traditional remedy for the treatment of pain and inflammation-associated conditions like cuts and wounds, stomach ache, backache, and headache as a practice of a folkloristic system of medicine. In spite of several previous publications suggesting its use by different tribes, no documentation or scientific approaches have been made hitherto to validate its ethnopharmacological claims. Aim of studyThe study aimed at the botanical quality control assessment, toxicity profiling, and network pharmacology-assisted experimental validation of the anti-inflammatory potential of the aqueous extract of N. herpeticum to fill the lacunae in the current knowledge. Material and methodPlant material was authenticated using a classical taxonomical approach and DNA barcoding. The quality control methods, acute toxicity study, and repeated dose 28-day oral toxicity study were performed as per standard guidelines. QToF-MS analysis, drug-likeness properties, network pharmacology-based anti-inflammatory prediction, and in vitro assays were carried out. ResultsQuality control assessment was done for the plant. Toxicity studies revealed the aqueous extract to be non-toxic when consumed for short periods at low doses. Alterations in food and water intake, biochemical parameters, and alterations in liver histology (n = 2 female rats) implicate repeated exposure to high doses (2000 mg/kg) that may possess deleterious effects, particularly in hepatic tissues. 21 representative compounds (14 drug-like molecules) were detected by QToF-MS analysis and then subjected to network pharmacology to predict anti-inflammatory effects. It was found that an anti-inflammatory effect may be exerted by modulating inflammatory pathways involving genes such as TNF, PTGS2, EGFR, STAT3, PPARG, PTGER4, PPARA, NOS2, TRPV1, and JAK2. Further, in vitro studies demonstrated plant extract to possess a good anti-inflammatory effect with IC50 values of 98.76, 85.73, and 96.16 μg/ml in protein denaturation, proteinase inhibition, and haemolysis inhibition assays, respectively. ConclusionThe plant extract was found to be safer at acute dose but may cause potential liver toxicity on prolonged use. The anti-inflammatory property predicted by network pharmacology was further supported by the positive results of in vitro experiments. In summary, to further establish the toxicity profile of this edible plant and its anti-inflammatory properties, chronic toxicity study and in vivo experiments are required.

The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery.

Cellular proteostasis requires a network of molecular chaperones and co-chaperones, which facilitate the correct folding and assembly of other proteins, or the degradation of proteins misfolded beyond repair. The function of the major chaperones, heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90), is regulated by a cohort of co-chaperone proteins. The J domain protein (JDP) family is one of the most diverse co-chaperone families, playing an important role in functionalizing the Hsp70 chaperone system to form a powerful protein quality control network. The intracellular malaria parasite, Plasmodium falciparum, has evolved the capacity to invade and reboot mature human erythrocytes, turning them into a vehicles of pathology. This process appears to involve the harnessing of both the human and parasite chaperone machineries. It is well known that malaria parasite-infected erythrocytes are highly enriched in functional human Hsp70 (HsHsp70) and Hsp90 (HsHsp90), while recent proteomics studies have provided evidence that human JDPs (HsJDPs) may also be enriched, but at lower levels. Interestingly, P. falciparum JDPs (PfJDPs) are the most prominent and diverse family of proteins exported into the infected erythrocyte cytosol. We hypothesize that the exported PfJPDs may be an evolutionary consequence of the need to boost chaperone power for specific protein folding pathways that enable both survival and pathogenesis of the malaria parasite. The evidence suggests that there is an intricate network of PfJDP interactions with the exported malarial Hsp70 (PfHsp70-x) and HsHsp70, which appear to be important for the trafficking of key malarial virulence factors, and the proteostasis of protein complexes of human and parasite proteins associated with pathology. This review will critically evaluate the current understanding of the role of exported PfJDPs in pathological exploitation of the proteostasis machinery by fine-tuning the chaperone properties of both human and malarial Hsp70s.

The Metabolostasis Network and the Cellular Depository of Aggregation-Prone Metabolites.

The vital role of metabolites across all branches of life and their involvement in various disorders have been investigated for decades. Many metabolites are poorly soluble in water or in physiological buffers and tend to form supramolecular aggregates. On the other hand, in the cell, they should be preserved in a pool and be readily available for the execution of biochemical functions. We thus propose that a quality-control network, termed "metabolostasis", has evolved to regulate the storage and retrieval of aggregation-prone metabolites. Such a system should control metabolite concentration, subcellular localization, supramolecular arrangement, and interaction in dynamic environments, thus enabling normal cellular physiology, healthy development, and preventing disease onset. The paradigm-shifting concept of metabolostasis calls for a reevaluation of the traditional view of metabolite storage and dynamics in physiology and pathology and proposes unprecedented directions for therapeutic targets under conditions where metabolostasis is imbalanced.

Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside.

Endoplasmic reticulum (ER) is the largest membrane-bound compartment in all cells and functions as a key regulator in protein biosynthesis, lipid metabolism, and calcium balance. Mammalian endoplasmic reticulum has evolved with an orchestrated protein quality control system to handle defective proteins and ensure endoplasmic reticulum homeostasis. Nevertheless, the accumulation and aggregation of misfolded proteins in the endoplasmic reticulum may occur during pathological conditions. The inability of endoplasmic reticulum quality control system to clear faulty proteins and aggregates from the endoplasmic reticulum results in the development of many human disorders. The efforts to comprehensively understand endoplasmic reticulum quality control network and protein aggregation will benefit the diagnostics and therapeutics of endoplasmic reticulum storage diseases. Herein, we overview recent advances in mammalian endoplasmic reticulum protein quality control system, describe protein phase transition model, and summarize the approaches to monitor protein aggregation. Moreover, we discuss the therapeutic applications of enhancing endoplasmic reticulum protein quality control pathways in endoplasmic reticulum storage diseases.

An integrated strategy of spectrum-effect relationship and near-infrared spectroscopy rapid evaluation based on back propagation neural network for quality control of Paeoniae Radix Alba.

The quantitative analysis of near-infrared spectroscopy in traditional Chinese medicine has still deficiencies in the selection of the measured indexes. Then Paeoniae Radix Alba is one of the famous "Eight Flavors of Zhejiang" herbs, however, it lacks the pharmacodynamic support, and cannot reflect the quality of Paeoniae Radix Alba accurately and reasonably. In this study, the spectrum-effect relationship of the anti-inflammatory activity of Paeoniae Radix Alba was established. Then based on the obtained bioactive component groups, the genetic algorithm, back propagation neural network, was combined with near-infrared spectroscopy to establish calibration models for the content of the bioactive components of Paeoniae Radix Alba. Finally, three bioactive components, paeoniflorin, 1,2,3,4,6-O-pentagalloylglucose, and benzoyl paeoniflorin, were successfully obtained. Their near-infrared spectroscopy content models were also established separately, and the validation sets results showed the coefficient of determination (R2 > 0.85), indicating that good calibration statistics were obtained for the prediction of key pharmacodynamic components. As a result, an integrated analytical method of spectrum-effect relationship combined with near-infrared spectroscopy and deep learning algorithm was first proposed to assess and control the quality of traditional Chinese medicine, which is the future development trend for the rapid inspection of traditional Chinese medicine.

Asperuloside, the bioactive compound in the edible Eucommia ulmoides male flower, delays muscle aging by daf-16 mediated improvement in mitochondrial dysfunction.

Muscle aging is accompanied by a progressive decline in motor performance and mitochondrial function, yet fundamental treatments for this disorder remain sparse. The search for active compounds from natural dietary products that promote muscular health has attracted considerable interest. Although the male flowers of Eucommia ulmoides Oliv., an emerging resource of plant-based food, have healthspan-promoting efficacy, it's still unclear whether they or their main active compounds (iridoids) could improve muscle aging. We compared the effects of three iridoids on motion status during different aging processes in Caenorhabditis elegans (C. elegans). Additionally, we further investigated the roles and mechanisms of the iridoid-rich floral extract (EUFE) and the most active monomer on nematode age-related muscle hypofunction exacerbated by high fat. We found that EUFE and asperuloside (Asp) significantly improved motility and muscular health and reduced lipid accumulation at appropriate concentrations. Compared to normal mitochondria against muscle disorder, Asp delayed the deterioration of mitochondrial function, morphology, or related metabolism during aging. Meanwhile, Asp regulated the mitochondrial quality control (MQC) network, mainly activating mitophagy, which was associated with increased mRNA and protein expression of lgg-1 and dct-1. Mechanistically, Asp promoted the expression and nuclear localization of the DAF-16 protein, an upstream regulator of the above two autophagy-related genes. The defective mutant and RNA interference further suggested that daf-16 mediated the ameliorative effects of Asp on muscle aging and mitochondrial dysfunction. These results provide potential evidence for the preventive application and functional food development of E. ulmoides male flowers and asperuloside against muscle aging.

ЦИФРОВАЯ ПЛАТФОРМА «ГАРАНТИР КАЧЕСТВА»

The paper presents a “Quality Guarantor” digital platform, designed to build intelligent quality gates based on the active use of machine vision technologies. The proposed hardware and software solution implements the modern principles of a rational combination of an algorithmic approach, knowledge bases and artificial intelligence elements to improve the production organization system. The quality guarantor contains components that provide visual control of product compliance with specified parameters, identification of inconsistencies, defects and deviations, collection and processing of information about the current quality of manufactured products within a specialized situational center integrated with PDM and ERP systems of the enterprise. Designing a new visual quality control system consists in planning the control track and designing quality samples in such a way that the key bottlenecks are covered with minimal toolset of machine vision. To build and configure individual control tracks and quality samples, statistical data and the results of video filming of production operations performed by highly professional performers can be used. The implementation of the platform in practice is illustrated by two hardware and software systems for monitoring the results of machining in mechanical engineering and monitoring internal holes using an endoscope video camera. The digital platform “Quality Guarantor” allows you to expand the scope of machine vision systems based on artificial neural networks for quality control of production processes.

High-fat diet causes mitochondrial damage and downregulation of mitofusin-2 and optic atrophy-1 in multiple organs.

High-fat consumption promotes the development of obesity, which is associated with various chronic illnesses. Mitochondria are the energy factories of eukaryotic cells, maintaining self-stability through a fine-tuned quality-control network. In the present study, we evaluated high-fat diet (HFD)-induced changes in mitochondrial ultrastructure and dynamics protein expression in multiple organs. C57BL/6J male mice were fed HFD or normal diet (ND) for 24 weeks. Compared with ND-fed mice, HFD-fed mice exhibited increased body weight, cardiomyocyte enlargement, pulmonary fibrosis, hepatic steatosis, renal and splenic structural abnormalities. The cellular apoptosis of the heart, liver, and kidney increased. Cellular lipid droplet deposition and mitochondrial deformations were observed. The proteins related to mitochondrial biogenesis (TFAM), fission (DRP1), autophagy (LC3 and LC3-II: LC3-I ratio), and mitophagy (PINK1) presented different changes in different organs. The mitochondrial fusion regulators mitofusin-2 (MFN2) and optic atrophy-1 (OPA1) were consistently downregulated in multiple organs, even the spleen. TOMM20 and ATP5A protein were enhanced in the heart, skeletal muscle, and spleen, and attenuated in the kidney. These results indicated that high-fat feeding caused pathological changes in multiple organs, accompanied by mitochondrial ultrastructural damage, and MFN2 and OPA1 downregulation. The mitochondrial fusion proteins may become promising targets and/or markers for treating metabolic disease.

Exploration of the cysteine reactivity of human inducible Hsp70 and cognate Hsc70

Hsp70s are multifunctional proteins and serve as the central hub of the protein quality control network. Hsp70s are also related to a number of diseases and have been established as drug targets. Human HspA1A (hHsp70) and HspA8 (hHsc70) are the major cytosolic Hsp70s, and they have both overlapping and distinct functions. hHsp70 contains five cysteine residues, and hHsc70 contains four cysteine residues. Previous studies have shown these cysteine residues can undergo different cysteine modifications such as oxidation or reaction with electrophiles to regulate their function, and hHsp70 and hHsc70 have different cysteine reactivity. To address the mechanism of the differences in cysteine reactivity between hHsp70 and hHsc70, we studied the factors that determine this reactivity by Ellman assay for the quantification of accessible free thiols and NMR analysis for the assessment of structural dynamics. We found the lower cysteine reactivity of hHsc70 is probably due to its lower structural dynamics and the stronger inhibition effect of interaction between the α-helical lid subdomain of the substrate-binding domain (SBDα) and the β-sheet substrate-binding subdomain (SBDβ) on cysteine reactivity of hHsc70. We determined that Gly557 in hHsp70 contributes significantly to the higher structural dynamics and cysteine reactivity of hHsp70 SBDα. Exploring the cysteine reactivity of hHsp70 and hHsc70 facilitates an understanding of the effects of redox reactions and electrophiles on their chaperone activity and regulation mechanisms, and how these differences allow them to undertake distinct cellular roles.

Gonadotropin-releasing hormone-like receptor 2 inversely regulates somatic proteostasis and reproduction in Caenorhabditis elegans.

The quality control machinery regulates the cellular proteome to ensure proper protein homeostasis (proteostasis). In Caenorhabditis elegans, quality control networks are downregulated cell-nonautonomously by the gonadal longevity pathway or metabolic signaling at the onset of reproduction. However, how signals are mediated between the gonad and the somatic tissues is not known. Gonadotropin-releasing hormone (GnRH)-like signaling functions in the interplay between development and reproduction and have conserved roles in regulating reproduction, metabolism, and stress. We, therefore, asked whether GnRH-like signaling is involved in proteostasis collapse at the onset of reproduction. Here, we examine whether C. elegans orthologues of GnRH receptors modulate heat shock survival. We find that gnrr-2 is required for proteostasis remodeling in different somatic tissues during the transition to adulthood. We show that gnrr-2 likely functions in neurons downstream of the gonad in the gonadal-longevity pathway and modulate the somatic regulation of transcription factors HSF-1, DAF-16, and PQM-1. In parallel, gnrr-2 modulates egg-laying rates, vitellogenin production, and thus reproductive capacity. Taken together, our data suggest that gnrr-2 plays a GnRH-associated role, mediating the cross-talk between the reproduction system and the soma in the decision to commit to reproduction.

Resveratrol Reestablishes Mitochondrial Quality Control in Myocardial Ischemia/Reperfusion Injury through Sirt1/Sirt3-Mfn2-Parkin-PGC-1α Pathway.

Resveratrol is a natural polyphenol found in various plants. It has been widely studied on cardiovascular disorders. It is known that resveratrol can activate Sirtuin proteins and participate in cellular energy metabolism through a Sirtuin-dependent pathway. Here, we hypothesized that resveratrol may protect against myocardial ischemia/reperfusion injury (MIRI) through the target of Sirt1/Sirt3 on mitochondrial dynamics, cardiac autophagy, bioenergetics and oxidative damage in hypoxia/reoxygenation (H/R)-induced neonatal rat cardiomyocytes. We observed that resveratrol could activate the Sirt1/Sirt3-FoxO pathway on myocardial mitochondria in H/R cardiomyocytes. Subsequently, we found that resveratrol repaired the fission–fusion balance, autophagic flux and mitochondrial biosynthesis compared by H/R group. These changes were followed by increased functional mitochondrial number, mitochondrial bioenergetics and a better mitochondrial antioxidant enzyme system. Meanwhile, these effects were antagonized by co-treatment with Selisistat (Ex527), a Sirtuin inhibitor. Together, our findings uncover the potential contribution of resveratrol in reestablishing a mitochondrial quality control network with Parkin, Mfn2 and PGC-1α as the key nodes.

Convolutional neural networks for automatic image quality control and EARL compliance of PET images

BackgroundMachine learning studies require a large number of images often obtained on different PET scanners. When merging these images, the use of harmonized images following EARL-standards is essential. However, when including retrospective images, EARL accreditation might not have been in place. The aim of this study was to develop a convolutional neural network (CNN) that can identify retrospectively if an image is EARL compliant and if it is meeting older or newer EARL-standards.Materials and methods96 PET images acquired on three PET/CT systems were included in the study. All images were reconstructed with the locally clinically preferred, EARL1, and EARL2 compliant reconstruction protocols. After image pre-processing, one CNN was trained to separate clinical and EARL compliant reconstructions. A second CNN was optimized to identify EARL1 and EARL2 compliant images. The accuracy of both CNNs was assessed using fivefold cross-validation. The CNNs were validated on 24 images acquired on a PET scanner not included in the training data. To assess the impact of image noise on the CNN decision, the 24 images were reconstructed with different scan durations.ResultsIn the cross-validation, the first CNN classified all images correctly. When identifying EARL1 and EARL2 compliant images, the second CNN identified 100% EARL1 compliant and 85% EARL2 compliant images correctly. The accuracy in the independent dataset was comparable to the cross-validation accuracy. The scan duration had almost no impact on the results.ConclusionThe two CNNs trained in this study can be used to retrospectively include images in a multi-center setting by, e.g., adding additional smoothing. This method is especially important for machine learning studies where the harmonization of images from different PET systems is essential.

The Role of the Rhomboid Superfamily in ER Protein Quality Control: From Mechanisms and Functions to Diseases.

The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells and is a major site for protein folding, modification, and lipid synthesis. Perturbations within the ER, such as protein misfolding and high demand for protein folding, lead to dysregulation of the ER protein quality control network and ER stress. Recently, the rhomboid superfamily has emerged as a critical player in ER protein quality control because it has diverse cellular functions, including ER-associated degradation (ERAD), endosome Golgi-associated degradation (EGAD), and ER preemptive quality control (ERpQC). This breadth of function both illustrates the importance of the rhomboid superfamily in health and diseases and emphasizes the necessity of understanding their mechanisms of action. Because dysregulation of rhomboid proteins has been implicated in various diseases, such as neurological disorders and cancers, they represent promising potential therapeutic drug targets. This review provides a comprehensive account of the various roles of rhomboid proteins in the context of ER protein quality control and discusses their significance in health and disease.