Pharmacologic inhibition of acetyl‐CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition ...of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the effect of a liver‐directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet‐induced rodent models of NAFLD. Oral administration of Compound 1 preferentially inhibited ACC enzymatic activity in the liver, reduced hepatic malonyl‐CoA levels, and enhanced hepatic ketogenesis by 50%. Furthermore, administration for 6 days to high‐fructose‐fed rats resulted in a 20% reduction in hepatic de novo lipogenesis. Importantly, long‐term treatment (21 days) significantly reduced high‐fat sucrose diet–induced hepatic steatosis, protein kinase C epsilon activation, and hepatic insulin resistance. ACCi treatment was associated with a significant increase in plasma triglycerides (approximately 30% to 130%, depending on the length of fasting). ACCi‐mediated hypertriglyceridemia could be attributed to approximately a 15% increase in hepatic very low‐density lipoprotein production and approximately a 20% reduction in triglyceride clearance by lipoprotein lipase (P ≤ 0.05). At the molecular level, these changes were associated with increases in liver X receptor/sterol response element‐binding protein‐1 and decreases in peroxisome proliferator–activated receptor‐α target activation and could be reversed with fenofibrate co‐treatment in a high‐fat diet mouse model. Conclusion: Collectively, these studies warrant further investigation into the therapeutic utility of liver‐directed ACC inhibition for the treatment of NAFLD and hepatic insulin resistance.
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. Acetyl-CoA carboxylase (ACC) catalyzes the ...rate-limiting step of de novo lipogenesis and regulates fatty acid β-oxidation in hepatocytes. ACC inhibition reduces hepatic fat content and markers of liver injury in patients with NASH; however, the effect of ACC inhibition on liver fibrosis has not been reported.
A direct role for ACC in fibrosis was evaluated by measuring de novo lipogenesis, procollagen production, gene expression, glycolysis, and mitochondrial respiration in hepatic stellate cells (HSCs) in the absence or presence of small molecule inhibitors of ACC. ACC inhibitors were evaluated in rodent models of liver fibrosis induced by diet or the hepatotoxin, diethylnitrosamine. Fibrosis and hepatic steatosis were evaluated by histological and biochemical assessments.
Inhibition of ACC reduced the activation of TGF-β-stimulated HSCs, as measured by both α-SMA expression and collagen production. ACC inhibition prevented a metabolic switch necessary for induction of glycolysis and oxidative phosphorylation during HSC activation. While the molecular mechanism by which inhibition of de novo lipogenesis blocks glycolysis and oxidative phosphorylation is unknown, we definitively show that HSCs require de novo lipogenesis for activation. Consistent with this direct antifibrotic mechanism in HSCs, ACC inhibition reduced liver fibrosis in a rat choline-deficient, high-fat diet model and in response to chronic diethylnitrosamine-induced liver injury (in the absence of hepatic lipid accumulation).
In addition to reducing lipid accumulation in hepatocytes, ACC inhibition also directly impairs the profibrogenic activity of HSCs. Thus, small molecule inhibitors of ACC may lessen fibrosis by reducing lipotoxicity in hepatocytes and by preventing HSC activation, providing a mechanistic rationale for the treatment of patients with advanced liver fibrosis due to NASH.
Hepatic fibrosis is the most important predictor of liver-related outcomes in patients with non-alcoholic steatohepatitis (NASH). Small molecule inhibitors of acetyl-CoA carboxylase (ACC) reduce hepatic fat content and markers of liver injury in patients with NASH. Herein, we report that inhibition of ACC and de novo lipogenesis also directly suppress the activation of hepatic stellate cells – the primary cell responsible for generating fibrotic scar in the liver – and thus fibrosis. These data provide further evidence for the use of ACC inhibitors to treat patients with NASH and advanced fibrosis.
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•ACC inhibition blocks TGF-β-induced hepatic stellate cell activation.•ACC inhibition blocks tension-mediated activation of primary rat and human hepatic stellate cells.•Inhibiting de novo lipogenesis targets hepatic stellate cells’ reliance on increased glycolysis and oxidative phosphorylation.•ACC inhibition in vivo significantly reduces fibrosis in 4 models of non-alcoholic steatohepatitis.
At present, optimization algorithms are used extensively. One particular type of such algorithms includes random-based heuristic population optimization algorithms, which may be created by modeling ...scientific phenomena, like, for example, physical processes. The present article proposes a novel optimization algorithm based on Hooke’s law, called the spring search algorithm (SSA), which aims to solve single-objective constrained optimization problems. In the SSA, search agents are weights joined through springs, which, as Hooke’s law states, possess a force that corresponds to its length. The mathematics behind the algorithm are presented in the text. In order to test its functionality, it is executed on 38 established benchmark test functions and weighed against eight other optimization algorithms: a genetic algorithm (GA), a gravitational search algorithm (GSA), a grasshopper optimization algorithm (GOA), particle swarm optimization (PSO), teaching–learning-based optimization (TLBO), a grey wolf optimizer (GWO), a spotted hyena optimizer (SHO), as well as an emperor penguin optimizer (EPO). To test the SSA’s usability, it is employed on five engineering optimization problems. The SSA delivered better fitting results than the other algorithms in unimodal objective function, multimodal objective functions, CEC 2015, in addition to the optimization problems in engineering.
Turfgrasses hosts a diverse community of predators that contribute to herbivore suppression. However, there is little evidence that predators directly consume a common turfgrass herbivore, the ...billbug (Sphenophorus sp.) (Coleoptera: Curculionidae). Given low rates of direct consumption by predators, prospects for strong non‐consumptive effects in billbugs were underappreciated. However, this assumed lack of non‐consumptive effects presupposes that herbivorous prey, like billbugs, can identify predators and the level of threat that they pose. Here, we examined this assumption and quantified the extent to which exposure to predators and predator cues altered the behavior (predator avoidance, feeding, and mating) of bluegrass billbug, Sphenophorus parvulus Gyllenhal. First, using a series of behavioral assays within microcosms, we exposed billbugs to predators – Pterostichus melanarius (Illiger) (Coleoptera: Carabidae), Harpalus sp. (Coleoptera: Carabidae), Philonthus sp. (Coleoptera: Staphylinidae), and Hogna sp. (Araneae: Lycosidae) – singly and in combination to measure the effect of contact with predators and potential synergy among predator species pairs. Indirect exposure to predators, predator odor, and non‐predatory arthropods were also used to measure effects of various predator cues on billbug behavior. In subsequent Y‐tube choice assays we determined whether billbugs discriminated between filtered air and predator odor to isolate chemical signaling as a potential mechanism for billbug predator detection. Direct exposure to predators increased billbug predator avoidance (up to 201%), and decreased billbug feeding (down to −78%), though no predation was observed. Similar behavioral changes were observed when billbugs were exposed indirectly to a predator, and to predator odor. In Y‐tube assays billbugs avoided predator odor, further suggesting billbugs use chemical cues to detect predator presence and that these may be a driver in their observed behavior. Our results show that billbugs exhibit strong non‐consumptive effects, even in the absence of strong direct consumptive effects. These results provide the foundation for further research concerning the role of chemical signaling in billbug predator detection.
Given low rates of direct consumption by predators, prospects for strong non‐consumptive effects in the turfgrass herbivore the billbug were underappreciated. However, we found that billbugs respond to predator presence with reduced feeding and mating, and increased predator avoidance behavior. Billbugs displayed similar behavior when exposed to predator odor and avoided predator odor in choice assays, suggesting that chemical signaling contributes to predator detection. Results show that billbugs exhibit strong non‐consumptive effects, even in the absence of strong consumptive effects.
Analyzing data related to the conditions of city streets and avenues could help to make better decisions about public spending on mobility. Generally, streets and avenues are fixed as soon as they ...have a citizen report or when a major incident occurs. However, it is uncommon for cities to have real-time reactive systems that detect the different problems they have to fix on the pavement. This work proposes a solution to detect anomalies in streets through state analysis using sensors within the vehicles that travel daily and connecting them to a fog-computing architecture on a V2I network. The system detects and classifies the main road problems or abnormal conditions in streets and avenues using Machine Learning Algorithms (MLA), comparing roughness against a flat reference. An instrumented vehicle obtained the reference through accelerometry sensors and then sent the data through a mid-range communication system. With these data, the system compared an Artificial Neural Network (supervised MLA) and a K-Nearest Neighbor (Supervised MLA) to select the best option to handle the acquired data. This system makes it desirable to visualize the streets' quality and map the areas with the most significant anomalies.
Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of ...multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX.
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•A panel of 6 FOXP3 mutations from patients with IPEX CRISPRed into the mouse germline•Normal Tregs profoundly alter phenotypes of mutant Tregs by rescue and/or competition•DNA-binding mutation induces a spontaneous multiorgan autoimmunity and high IgE•Perturbations reveal organ-specific autoimmunity from N-terminal IPEX mutations
Leon et al. show that IPEX FoxP3 mutations can split into two. A Forkhead domain mutation induces spontaneous multiorgan inflammation, while inflammatory or genetic challenges reveal organ-specific impacts of mutations outside the DNA-binding domain. IPEX heterogeneity results from the location of FoxP3 mutations as well as from genetic and environmental perturbations.
Spider mite (Acari: Tetranychidae) outbreaks are common on corn grown in the arid West. Hot and dry conditions reduce mite development time, increase fecundity, and accelerate egg hatch. Climate ...change is predicted to increase drought incidents and produce more intense temperature patterns. Together, these environmental shifts may cause more frequent and severe spider mite infestations. Spider mite management is difficult as many commercially available acaricides are ineffective due to the development of resistance traits in field mite populations. Therefore, alternative approaches to suppress outbreaks are critically needed. Drought-tolerant plant hybrids alleviate the challenges of growing crops in water-limited environments; yet, it is unclear if drought-tolerant hybrids exposed to water stress affect mite outbreaks under these conditions. We conducted a greenhouse experiment to evaluate the effect of drought-tolerant corn hybrids on Banks grass mite Oligonychus pratensis Banks (Acari:Tetranychidae), a primary pest of corn, under optimal irrigation and water-stress irrigation. This was followed by a 2-yr field study investigating the effect of drought-tolerant corn hybrids exposed to the same irrigation treatments on Banks grass mite artificially infested on hybrids and resident spider mite populations. Results showed that water-stressed drought-tolerant hybrids had significantly lower Banks grass mite and resident spider mite populations than water-stressed drought-susceptible hybrids. Interestingly, water-stressed drought-tolerant hybrids had equal Banks grass mite populations to drought-susceptible and drought-tolerant hybrids under optimal irrigation. We posit that planting drought-tolerant hybrids may suppress spider mite outbreaks in water-challenged areas.
The aim of this study was to evaluate and compare the efficacy of B-mode, Doppler, contrast-enhanced ultrasonography (CEUS), and Acoustic Radiation Force Impulse (ARFI) elastography in predicting ...malignancy in canine mammary masses. This was a prospective cohort study from 2014 to 2016, which included 153 bitches with one or more mammary masses. A total of 300 masses were evaluated by ultrasonography (B-mode, Doppler, CEUS, and ARFI) and subsequently classified as benign or malignant by histopathology. Each ultrasound parameters studied were compared between benign and malignant masses by Chi-square or Student tests and differences were considered significant when P < 0.01. For the variables that proved significant differences were estimated the cut-off point, sensitivity, specificity, accuracy, and area under curve (AUC) by receiver-operating characteristic curve (ROC) analysis in a logistic regression model using histopathological classification as reference, to assess and compare diagnostic performance of each technique. Out of 300 mammary masses evaluated 246 were classified as malignant and 54 as benign. B-mode measurements showed sensitivity 67.9%, and specificity 67.6% as malignancy predictors on canine mammary masses; Doppler indexes systolic (>21.2 m/s) and diastolic velocity (>4.8 m/s) sensitivity 79.2% and specificity 70.8%; CEUS wash-out time (<80.5 s) sensitivity 80.2% and specificity 16.7%; and ARFI elastography shear velocity (SWV > 2.57 m/s) sensitivity 94.7% and specificity 97.2% In conclusion B-mode and Doppler ultrasound evaluations may assist in malignancy prediction of canine mammary masses with moderate sensitivity and specificity, already the SWV was an great accurate predictor. Therefore, ARFI elastography exam inclusion in veterinary clinic oncology and research is highly recommended, since it allows fast, non-invasive, and complication-free malignancy prediction of canine mammary masses.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Islamic Republic of Iran reported its first COVID-19 cases by 19th February 2020, since then it has become one of the most affected countries, with more than 73,000 cases and 4,585 deaths to this ...date. Spatial modeling could be used to approach an understanding of structural and sociodemographic factors that have impacted COVID-19 spread at a province-level in Iran. Therefore, in the present paper, we developed a spatial statistical approach to describe how COVID-19 cases are spatially distributed and to identify significant spatial clusters of cases and how socioeconomic and climatic features of Iranian provinces might predict the number of cases. The analyses are applied to cumulative cases of the disease from February 19th to March 18th. They correspond to obtaining maps associated with quartiles for rates of COVID-19 cases smoothed through a Bayesian technique and relative risks, the calculation of global (Moran's I) and local indicators of spatial autocorrelation (LISA), both univariate and bivariate, to derive significant clustering, and the fit of a multivariate spatial lag model considering a set of variables potentially affecting the presence of the disease. We identified a cluster of provinces with significantly higher rates of COVID-19 cases around Tehran (p-value< 0.05), indicating that the COVID-19 spread within Iran was spatially correlated. Urbanized, highly connected provinces with older population structures and higher average temperatures were the most susceptible to present a higher number of COVID-19 cases (p-value < 0.05). Interestingly, literacy is a factor that is associated with a decrease in the number of cases (p-value < 0.05), which might be directly related to health literacy and compliance with public health measures. These features indicate that social distancing, protecting older adults, and vulnerable populations, as well as promoting health literacy, might be useful to reduce SARS-CoV-2 spread in Iran. One limitation of our analysis is that the most updated information we found concerning socioeconomic and climatic features is not for 2020, or even for a same year, so that the obtained associations should be interpreted with caution. Our approach could be applied to model COVID-19 outbreaks in other countries with similar characteristics or in case of an upturn in COVID-19 within Iran.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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