Parallel Reduction Research Articles

Load-Balanced Parallel Implementation on GPUs for Multi-Scalar Multiplication Algorithm

Multi-scalar multiplication (MSM) is an important building block in most of elliptic-curve-based zero-knowledge proof systems, such as Groth16 and PLONK. Recently, Lu et al. proposed cuZK, a new parallel MSM algorithm on GPUs. In this paper, we revisit this scheme and present a new GPU-based implementation to further improve the performance of MSM algorithm. First, we propose a novel method for mapping scalars into Pippenger’s bucket indices, largely reducing the number of buckets compared to the original Pippenger algorithm. Second, in the case that memory is sufficient, we develop a new efficient algorithm based on homogeneous coordinates in the bucket accumulation phase. Moreover, our accumulation phase is load-balanced, which means the parallel speedup ratio is almost linear growth as the number of device threads increases. Finally, we also propose a parallel layered reduction algorithm for the bucket aggregation phase, whose time complexity remains at the logarithmic level of the number of buckets. The implementation results over the BLS12-381 curve on the V100 graphics card show that our proposed algorithm achieves up to 1.998x, 1.821x and 1.818x speedup compared to cuZK at scales of 221, 222, and 223, respectively.

Sufficient Conditions for Topology-Preserving Parallel Reductions on the Face-Centered Cubic Grid

Sufficient Conditions for Topology-Preserving Parallel Reductions on the Face-Centered Cubic Grid

Parallel functional reduction in the mitochondria of apicomplexan parasites

Extreme functional reduction of mitochondria has taken place in parallel in many distantly related lineages of eukaryotes, leading to a number of recurring metabolic states with variously lost electron transport chain (ETC) complexes, loss of the tricarboxylic acid (TCA) cycle, and/or loss of the mitochondrial genome. The resulting mitochondria-related organelles (MROs) are generally structurally reduced and in the most extreme cases barely recognizable features of the cell with no role in energy metabolism whatsoever (e.g., mitosomes, which generally only make iron-sulfur clusters). Recently, a wide diversity of MROs were discovered to be hiding in plain sight: in gregarine apicomplexans. This diverse group of invertebrate parasites has been known and observed for centuries, but until recent applications of culture-free genomics, their mitochondria were unremarkable. The genomics, however, showed that mitochondrial function has reduced in parallel in multiple gregarine lineages to several different endpoints, including the most reduced mitosomes. Here we review this remarkable case of parallel evolution of MROs, and some of the interesting questions this work raises.

Increasing sweep gas flow reduces respiratory drive and dyspnea in non-intubated veno-arterial ECMO patients - a pilot study.

Data on assessment and management of dyspnea in patients on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock are lacking. We hypothesized that increasing sweep gas flow through the VA-ECMO oxygenator may decrease dyspnea in non-intubated VA-ECMO patients exhibiting clinically significant dyspnea, with a parallel reduction in respiratory drive. Non-intubated, spontaneously breathing, supine patients on VA-ECMO for cardiogenic shock who presented with a visual analog dyspnea scale (dyspnea-VAS) ≥ 40/100 mm were included. Sweep gas flow was increased up to +6 L/min by three steps of +2 L/min each. Dyspnea was assessed with dyspnea-VAS and Multidimensional Dyspnea Profile. The respiratory drive was assessed by the electromyographic activity of the alae nasi and parasternal muscles. We included 21 patients. On inclusion, median dyspnea-VAS was 50 ([interquartile range] 45-60) mm and sweep gas flow was 1.0 L/min (0.5-2.0). An increase in sweep gas flow significantly decreased dyspnea-VAS (50[45-60] at baseline vs 20[10-30] at 6L/min; p<0.001). The decrease in dyspnea was greater for the sensory component of dyspnea (-50%[43-75]) than for the affective and emotional components (-17%[0-25] and -12%[0-17], p<0.001). An increase in sweep gas flow significantly decreased electromyographic activity of the alae nasi and parasternal muscles (-23%[36-10] and -20[41-0], p<0.001). There was a significant correlation between the sweep gas flow and the dyspnea-VAS (r=-0.91 95%CI[-0.94, -0.87]), between the respiratory drive and the sensory component of dyspnea (r=0.29 95%CI[0.13, 0.44]), between the respiratory drive and the affective component of dyspnea (r=0.29 95%CI[0.02, 0.54]) and between the sweep gas flow and the alae nasi and parasternal (r=-0.31 95%CI[-0.44, -0.22] and r=-0.25 95%CI[-0.44, -0.16]). In critically ill patients with VA-ECMO, an increase in sweep gas flow through the oxygenation membrane decreases dyspnea, possibly mediated by a decrease in respiratory drive.

Hemoadsorption Combined with Hemodialysis and the “Inflammation Mitigation Hypothesis”

ABSTRACT Clinical outcomes are still unsatisfactory in patients undergoing chronic maintenance dialysis. Signs and symptoms of uremic intoxication are often present even in presence of an adequate dialysis delivery. These along with cardiovascular and skeletal complications, have been correlated to the accumulation of inflammatory chemical mediators, beta-2 microglobulin (β2M), parathyroid hormone (PTH) and other middle to large molecular weight toxins that are insufficiently cleared by current dialysis techniques. Such condition determines a vicious loop where a subclinical status of inflammation causes a disruption of the immunological response affecting outcomes by accelerated atherosclerosis, anemia, and frequent infections. The overall picture can be described as a systemic inflammatory syndrome with simultaneous activation of the innate and the adaptive immunity. In such condition, new options and techniques are required to achieve a more effective blood purification and to correct the altered immuno-homeostasis. New efficient and biocompatible sorbents are today available (HA 130 Cartridge, Jafron Medical, Zhuhai, China) and they can be advantageously coupled in series with the hemodialyzer to perform hemoadsorption combined with hemodialysis (HA-HD). This technique has been already studied in at least two randomized trials demonstrating an effective improvement of clinical and biochemical outcomes. We have calculated the kinetics of β2M in a single session, in a series of three consecutive sessions of a week and in a period of three months using different frequencies of application (first month: Three sessions per week; second month: Two sessions per week; third month: One session per week). In the single session the reduction ratio was superior to other techniques such as hemodialysis (HD), high-flux hemodialysis (HFD) or hemodiafiltration (HDF). In the thrice weekly regime, the time average concentration (TAC) of β2M resulted inferior to HD and HDF. In the long period, a lower concentration of β2M was maintained even with a once-a-week regime. Considering the parallel reduction of inflammatory parameters, we could hypothesize that the enhanced removal of uremic toxins and chemical mediators led to a mitigation of the systemic inflammation with a progressive reduction in the generation of β2M. This “inflammation mitigation hypothesis (IMH)” supports the prescription of HA-HD once a week, possibly after a month of thrice weekly regime.

Effect of Periodontitis and Periodontal Therapy on Oral and Gut Microbiota

Mounting evidence indicates that periodontitis-related oral bacteria may contribute to gut microbial dysbiosis. This clinical study aimed to explore the oral–gut microbial signatures associated with periodontitis and to longitudinally evaluate the effect of periodontal treatment on the oral and gut microbial composition. Stool and saliva samples from generalized stage III/IV periodontitis patients (n = 47) were collected and analyzed by 16S ribosomal RNA gene amplicon sequencing, before and 3 mo after steps I to II of periodontal therapy. Periodontally healthy matched subjects (n = 47) were used as controls. Principal component analysis was carried out to identify oral–gut microbial profiles between periodontitis patients at baseline and healthy subjects; periodontitis samples were longitudinally compared before and after treatment. β-Diversity of gut microbial profiles of periodontitis patients before treatment significantly differed from healthy controls (P < 0.001). Periodontal therapy was associated with a significant change in gut microbiota (P < 0.001), with post-treatment microbial profiles similar to healthy volunteers. A higher abundance of Bacteroides, Faecalibacterium, Fusobacterium, and Lachnospiraceae was noted in fecal samples of periodontitis patients at baseline compared to healthy controls. In contrast, Lactobacillus was the only genus more abundant in the latter. Additionally, periodontal therapy led to a parallel reduction in the salivary carriage of periodontal pathobionts, as well as gut Bacteroides, Lachnoclostridium, Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae, to levels similar to healthy controls. Collectively, discriminating oral–gut microbial signatures of periodontitis were found. Periodontal treatment both mitigated oral dysbiosis and altered gut microbial composition, signifying potential broader implications for gastrointestinal health and disease.

The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis

ObjectiveThe serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hepatic metabolism. A targeted therapeutic strategy for NASH has been investigated, using 1-Piperidine Propionic Acid (1-PPA), since this compound has been recently proposed as both Protease Activated Receptor 2 and SerpinB3 inhibitor. MethodsThe effect of SerpinB3 on inflammation and fibrosis genes was assessed in human macrophage and stellate cell lines. Transgenic mice, either overexpressing SerpinB3 or carrying Serpinb3 deletion and their relative wild type strains, were used in experimental NASH models. Subgroups of SerpinB3 transgenic mice and their controls were also injected with 1-PPA to assess the efficacy of this compound in NASH inhibition. Results1-PPA did not present significant cell and organ toxicity and was able to inhibit SerpinB3 and PAR2 in a dose-dependent manner. This effect was associated to a parallel reduction of the synthesis of the molecules induced by endogenous SerpinB3 or by its paracrine effects both in vitro and in vivo, leading to inhibition of lipid accumulation, inflammation and fibrosis in experimental NASH. At mechanistic level, the antiprotease activity of SerpinB3 was found essential for PAR2 activation, determining upregulation of the CCAAT Enhancer Binding Protein beta (C/EBP-β), another pivotal regulator of metabolism, inflammation and fibrosis, which in turn determined SerpinB3 synthesis. Conclusions1-PPA treatment was able to inhibit the PAR2 - C/EBP-β - SerpinB3 axis and to protect from NASH development and progression, supporting the potential use of a similar approach for a targeted therapy of NASH.

Investigation of DNA damage and inflammatory marker profile in patients after bariatric surgery

Abstract&#x0D; Purpose: Obesity is a significant risk factor in the development of many serious diseases. The most prominent ones among them are diabetes and coronary heart disease. Elevated blood sugar levels in obese individuals lead to increased susceptibility to infections due to the suppression of the immune response. Moreover, fatty skin folds can cause topical infections, ulcers, and delayed/impaired wound healing. Therefore, inflammatory and pro-inflammatory markers in the serum have gained importance in diseases such as diabetes and obesity. Furthermore, in obesity, reactive oxygen species (ROS) lead to DNA damage. 8-oxo-dG, which is the primary product of DNA oxidation, can be detected in the serum, saliva, and urine, making it an ideal biological marker for DNA damage in large population-based studies. The Comet assay analysis is a method used to demonstrate the double-strand breaks in DNA. Induction of γ-H2AX in tissue indicates the initiation of a well-regulated mechanism to reverse double-strand breaks in DNA. Potential benefits of monitoring the genomic health in obesity include creating a sense of urgency for personalized intervention measures and evaluating their progress. DNA damage in obesity is believed to be a reversible condition. Chronic inflammation is an etiological factor known to support DNA damage and neoplastic transformations in cells. Cytokines secreted from adipose tissue, especially TNF-alpha, IL-6, and IL-1β, promote the accumulation of various cells, including neutrophils, macrophages, and dendritic cells, and it indicates the initiation of an inflammatory process. In this project, it was aimed to investigate possible changes in inflammation markers and DNA damage in individuals undergoing bariatric surgery, who were beginning to improve endocrine and metabolic syndrome markers. &#x0D; Materials and methods: For this purpose, blood and urine samples were collected from 45 obese patients, who had undergone bariatric surgery and 45 healthy volunteers matched for age and gender. The levels of inflammatory markers (IL-1β, IL-6, IL-8, and TNF-α) and the DNA damage marker γ-H2AX in serum, as well as the amount of 8-oxo-dG in urine, were determined using ELISA. Additionally, the percentage of DNA damage was determined using the Comet assay analysis. &#x0D; Results: Weight control achieved through bariatric surgery and the subsequent reduction in fat tissue resulted in a significant decrease in the levels of γ-H2AX and 8-oxo-dG, as well as a parallel significant reduction in the percentage of DNA damage in the Comet assay results. The significant decrease in inflammatory markers IL-1β, IL-6, IL-8, and TNF-α levels indicated that bariatric surgery also affects inflammation indirectly. &#x0D; Conclusion: Although there are numerous studies in the literature on individual parameters related to DNA damage in various diseases and obesity, it is believed that the present study determining DNA damage, oxidation, and repair mechanisms simultaneously with inflammatory marker levels serves as a guiding example for comparing genomic health and stability in pre-obese, post-obese, and non-obese individuals.

Sequential co-reduction of nitrate and carbon dioxide enables selective urea electrosynthesis

Despite the recent achievements in urea electrosynthesis from co-reduction of nitrogen wastes (such as NO3−) and CO2, the product selectivity remains fairly mediocre due to the competing nature of the two parallel reduction reactions. Here we report a catalyst design that affords high selectivity to urea by sequentially reducing NO3− and CO2 at a dynamic catalytic centre, which not only alleviates the competition issue but also facilitates C−N coupling. We exemplify this strategy on a nitrogen-doped carbon catalyst, where a spontaneous switch between NO3− and CO2 reduction paths is enabled by reversible hydrogenation on the nitrogen functional groups. A high urea yield rate of 596.1 µg mg−1 h−1 with a promising Faradaic efficiency of 62% is obtained. These findings, rationalized by in situ spectroscopic techniques and theoretical calculations, are rooted in the proton-involved dynamic catalyst evolution that mitigates overwhelming reduction of reactants and thereby minimizes the formation of side products.

Massively Parallel Hybrid TLM-PEEC Solver and Model Order Reduction for 3D Nonlinear Electromagnetic Transient Analysis

Massively Parallel Hybrid TLM-PEEC Solver and Model Order Reduction for 3D Nonlinear Electromagnetic Transient Analysis

Efficient Parallel PAPR Reduction Method Using Null-Constrained Peak Cancellation Signal for Massive MIMO-OFDM Systems

Efficient Parallel PAPR Reduction Method Using Null-Constrained Peak Cancellation Signal for Massive MIMO-OFDM Systems

Adaptive Memory Saving Strategy in Shielding Calculation of RMC

RMC(Reactor Monte Carlo) is a Monte Carlo simulation software used in reactor design and has been verified by different benchmarks. The former data structure and algorithm have been optimized for criticality and burn-up calculation making it inconvenient to be implemented into shielding simulation and variance reduction. In order to expand its availability in shielding calculation, several optimizations have been made in RMC code design to elevate efficiency in variance reduction. Considering parallel computation has been implemented in Monte Carlo simulation for long time, in this paper we proposed an adaptive memory saving strategy specifically designed for boosting parallel variance reduction calculation in RMC. We further found that this strategy can be very effective in certain condition without sacrificing any calculation performance.

Uncovering potential diagnostic and pathophysiological roles of α-synuclein and DJ-1 in melanoma.

Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma. The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein-protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using invitro cellular models and ELISA immunoassays. α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cells induced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability. α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.

Parallelized Inter-Image k-Means Clustering Algorithm for Unsupervised Classification of Series of Satellite Images

As the volume of satellite images increases rapidly, unsupervised classification can be utilized to swiftly investigate land cover distributions without prior knowledge and to generate training data for supervised (or deep learning-based) classification. In this study, an inter-image k-means clustering algorithm (IIkMC), as an improvement of the native k-means clustering algorithm (kMC), was introduced to obtain a single set of class signatures so that the classification results could be compatible among multiple images. Because IIkMC was a computationally intensive algorithm, parallelized approaches were deployed, using multi-cores of a central processing unit (CPU) and a graphics processing unit (GPU), to speed up the process. kMC and IIkMC were applied to a series of images acquired in a PlanetScope mission. In addition to the capability of the inter-image compatibility of the classification results, IIkMC could settle the problem of incomplete segmentation and class canceling revealed in kMC. Based on CPU parallelism, the speed of IIkMC improved, becoming up to 12.83 times better than sequential processing. When using a GPU, the speed improved up to 25.53 times, rising to 39.00 times with parallel reduction. From the results, it was confirmed IIkMC provided more reliable results than kMC, and its parallelism could facilitate the overall inspection of multiple images.

Health economics aspects of kidney transplantation in Sicily: a benchmark analysis on activity and estimated savings.

International and national registries consistently report substantial differences in kidney transplant (KT) activity despite demonstrable clinical and financial benefits. The study aims to estimate the financial resources gained by KT and produce a benchmark analysis that would inform adequate strategies for the growth of the service. We analyzed the KT activity in our region between 2017 and 2019. The benchmark analysis was conducted with programs identified from national and international registries. The estimate of financial resources was obtained by applying the kidney transplant coefficient of value; subsequently, we compared the different activity levels and savings generated by the three KT programs. The KT activity in the region progressively declined in the study years, producing a parallel reduction of the estimated savings. Such savings were substantially inferior when compared to those generated by benchmark programs (range €18-22 million less). The factors influencing the reduced KT activity in the study period with the related "foregone savings" are multiple, as well as interdependent. Organ donation, access to the transplant waiting list, and KT from living donors appear to be the most prominent determinants of the observed different levels of activities. International experience suggests that a comprehensive strategy in the form of a "task force" may successfully address the critical areas of the service reversing the observed trend. The financial impact of a progressively reduced KT activity may be as critical as its clinical implications, jeopardizing the actual sustainability of services for patients with end-stage kidney disease.

Machine learning predictions for optimal cement content in sustainable concrete constructions

The designated concrete compressive strength at 28 days plays an important role in determining the quantity of cement (water to cement ratio) needed in concrete mix designs. Whilst a 28-day target is common, some structural elements receive deferred loads during construction, allowing a reduced cement content and the possibility to optimize the concrete mix to target full strength at 90 days. Machine learning techniques are used in this study to optimize the concrete mix design of structural elements that commonly receive deferred loads, e.g., foundation and pavements, targeting a 90-day full strength. Specifically, the compressive strength of concrete samples cured for 28 and 90 days are considered to estimate the cement content per m3 of concrete using Artificial Neural Network and Regression algorithms. The proposed machine learning and deep learning methods are proved to be capable of predicting the cement content with 94% and 90% accuracy, respectively. The Elastic Net algorithm shows the best performance in cement content optimization to a target 90-days compressive strength. This algorithm is hence employed to assess the carbon reduction benefits in a real case study: a typical mid-sized reinforced concrete structure is considered as a baseline to quantify the environmental benefit of optimizing the cement content for a 90-days target compressive strength. Results of the case study show that the proposed method may result in a reduction of approximately 10% in cement usage, consequently leading to a parallel reduction of about 10% in carbon emissions.

Longer symptom onset-to-door time persists despite reductions in STEMI door-to-balloon time: insights from the victorian cardiac outcomes registry

Abstract Background Prompt revascularisation is central to achieving optimal outcomes for patients presenting with ST-segment elevation myocardial infarction (STEMI). To enable this, health systems have traditionally focused on the ‘door-to-balloon’ (DTB) component of total ischaemic time, while comparatively less attention has been given to symptom ‘onset-to-door’ (OTD) time. Objective To determine the temporal trends, predictors and outcomes among patients with increased OTD time. Methods Consecutive patients with STEMI treated with percutaneous coronary intervention (PCI) across 30 hospitals in the Victorian Cardiac Outcomes Registry were analyzed between 2014 and 2020. Linkage with data from Ambulance Victoria was performed for all patients transported via emergency medical services. Trends in OTD and DTB time were evaluated with Cochrane-Armitage test of trend. Characteristics and outcomes of patients with longer OTD time (&amp;gt;60 mins) were compared to those with shorter OTD time (&amp;lt;60 mins). Multivariable predictors of longer OTD were determined with logistic regression and presented as odds ratio and 95%CI in a forest plot. Results A total of 13,494 patients underwent PCI for STEMI with median OTD time of 150mins (86,328) and median DTB time of 66mins (43,107). DTB time progressively reduced over the study period (p=0.001) while the proportion of patients with longer OTD did not change (90.3%, p=0.91). Patients with longer OTD time were more likely to be older (&amp;gt;65yo = 41% vs. 35%, p&amp;lt;0.001), female (22 vs. 16%, p&amp;lt;0.001), live in a lower-socioeconomic area (36 vs. 28%, p&amp;lt;0.001), be treated for diabetes (17 vs. 13%, p&amp;lt;0.001), have developed their symptoms out-of-hours (65 vs. 60%, p=0.002) and present via ambulance [vs. self-present] (81 vs. 63%, p&amp;lt;0.001). Multivariable predictors of longer OTD time are presented in forest plot below. Higher rates of new renal impairment (6.7 vs. 5.0%, p=0.024) and 30-day MI (1.5 vs. 0.7%, p=0.017) were observed among patients with longer OTD, as were numerical trends in new 30-day heart failure (1.4 vs. 0.9%, p=0.22) and in-hospital shock (5.9 vs. 4.7%, p=0.081). Conclusion No change in the proportion of patients presenting with longer onset-to-door times was observed despite a parallel reduction in door-to-balloon time over the study period. Increased community awareness and education on the symptoms of myocardial infarction, particularly targeted at high risk demographic groups, are needed to further reduce ischaemic times.

Spatiotemporal fishing effort simulations and restriction scenarios in Thermaikos Gulf, Greece (northeastern Mediterranean Sea)

Spatiotemporal simulation modeling is used in the context of ecosystem-based fisheries management to investigate different management options, including the size and allocation of marine protected and fisheries restricted areas. Here, we used ecospace to assess the effectiveness of existing and potential future spatiotemporal fishing restrictions in the heavily exploited Thermaikos Gulf, Greece for the years 2000–2025 (calibration period 2000–2016; projection period 2017–2025). ecospace combines temporal biomass and commercial catch data with spatial habitat and other environmental data, as well as species ecological preferences, feeding, and dispersal rates to depict changes in trophic interactions, biomasses, and commercial catches in time and space. ecospace simulations supported the empirical data demonstrating that fisheries restricted areas are effective tools for rebuilding the biomass of exploited stocks, with their size and location playing a significant role in the way that different organisms respond to protection. Nevertheless, our results suggested that in order to achieve the highest benefits of protection, fisheries restricted areas would need to be accompanied by a parallel reduction in total fishing effort, rather than a redistribution of fishing activities. Such redistribution would just move the pressure on the boundaries of protected areas, causing a local increase of commercial catches owing to the beneficial spillover effects of protection. One of the tested spatiotemporal restriction scenarios (MPA 5) suggests certain additional management measures on top of the existing restrictions for all four fishing fleets operating in the area. This scenario predicted a considerable increase in the biomass of key commercial and vulnerable species groups, including hake, flatfishes, anglerfish, sharks, and rays and skates, by the end of the simulation period in 2025.

A Deterministic Parallel Reduction from Weighted Matroid Intersection Search to Decision

A Deterministic Parallel Reduction from Weighted Matroid Intersection Search to Decision

Parkin depletion prevents the age-related alterations in the FGF21 system and the decline in white adipose tissue thermogenic function in mice.

Parkin is an ubiquitin-E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5month-old) and aged (16month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of β-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality.