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In the context of global warming, extreme drought has seriously endangered the safety of human lives and assets, indicating an urgent need for its accurate monitoring and early detection. Since various types of drought monitoring indices are calculated from the variable of potential evapotranspiration (PET), thus the selection of models to derive PET has attracted broad attention in recent decades. Generally, the common-used Thornthwaite (TH) model possesses the features of calculation simplicity and great universality, however, its accuracy and temporal resolution (monthly) are relatively low, which greatly hinders the further uses of this model. Considering these restrictions, a novel method for estimating diurnal-provided PET values (DTH-PET) using the TH model was first proposed, in which a 31-day sliding window was adopted to improve its temporal resolution. The new method takes both the diurnal and "monthly" variation features into account. Verification results showed that, compared with the monthly TH model, the improvements in the mean root mean square (RMS) errors made by the new method was 3.1 mm. In addition, to further improve the accuracy of the DTH-PETs, a new high-order calibration function with the use of GNSS and meteorological measurements including ZTD, temperature and pressure was then constructed and fully validated. In comparison with the 29.95 mm mean RMS from the conventional TH model without calibration, the new method led to a 4.37 mm result, i.e., a 25.57 mm improvement (over 85%) was made after a thorough calibration process. In addition, the comparison of the newly-proposed method with the common-used first-order equation also further illustrates its superiority during the whole calibration process. Therefore, all these results suggest that, by using the new strategies proposed in this study, DTH-PET can be easily estimated with high accuracy using limited meteorological variables. • A method for estimating diurnal-provided potential evapotranspiration was proposed. • The PET value takes both the diurnal and monthly variation features into account. • A new calibration function was constructed to further improve the accuracy of PET. • This innovation practice extends the applications of the Thornthwaite equations. [ABSTRACT FROM AUTHOR]

Nowadays, tropospheric products obtained from the Global Navigation Satellite Systems (GNSS) observations, e.g., precipitable water vapor (PWV), have heralded a new era of GNSS meteorological applications, especially for the detection of heavy rainfall. In meteorological studies, the anomaly temporal series of an atmospheric variable is widely used to investigate the deviations of its raw series from a certain "normal" cycle, which is defined based on a specific purpose, e.g., its responses to a specific weather event. In this study, a new model for detecting heavy rainfall using anomaly-based percentile thresholds of seven predictors derived from PWV was established. The seven predictors, which can effectively reflect the complete picture of the variations in the PWV series prior to heavy rainfall events, include hourly PWV value and its six types of derivatives. The diurnal mean values and anomaly-based percentile thresholds for these predictors were obtained based on their raw time series over the 8-year period 2010–2017 at the co-located HKSC-KP stations. Then these values were applied to the sample data over the period 2018–2019 for determining their anomalies and series of abnormality. Finally, the detection results were compared with the hourly rainfall records for evaluation. Results showed that 97.6% of heavy rainfalls were correctly detected with an average lead time of 4.13 h. The seasonal false alarm rate of 13.4% from the new model was reduced in comparison to existing models. By conducting the verification experiments of the new model at another two pair of stations in the Hong Kong region, similar results were also obtained. These results all indicate that the anomaly-based percentile thresholds of predictors derived from PWV can be effectively applied to the detection of heavy rainfall events. • Nowadays, GNSS-derived atmospheric products have heralded a new era of meteorological applications. • The anomaly series of a variable is widely used to investigate the deviations of its raw series from a certain normal cycle. • A new model for detecting heavy rainfall using anomaly-based percentile thresholds of predictors was first established. • These predictors can effectively reflect the complete picture of the variations in the PWV series prior to heavy rainfall. • Results showed that 97.6% of heavy rainfalls were correctly detected and the seasonal false alarm rate was 13.4 %. [ABSTRACT FROM AUTHOR]

The OMI NO 2 standard product, OMNO2d, has been widely used in estimating surface NO 2 concentrations. The Peking University Ozone Monitoring Instrument NO 2 product (POMINO) is claimed to provide an improved quality over east-central China. This study estimated one year (Dec.2016–Nov.2017) of surface NO 2 concentrations at satellite overpass time based on OMNO2d data and POMINO data, respectively. We used an extra-trees (ET) regression model to convey the non-linear relationship between surface NO 2 and predictors, and compared the prediction accuracy with that of random forests (RF) regression model. The ET model showed a better estimation performance than the RF model, with the cross-validation R2 of 0.72 (RMSE = 9.20 μg/m3) and R2 of 0.70 (RMSE = 9.42 μg/m3) based on POMINO and OMNO2d data, respectively. The POMINO-derived monthly mean surface NO 2 concentrations were closer to ground NO 2 measurements than that OMNO2d-derived. Although the estimations from both satellite products were underestimated in polluted situations, the use of POMINO reduced the underestimation as compared to the use of OMNO2d data. • POMINO data with extra-trees model produces highest cross-validation R2 of 0.72 • POMINO increases surface NO 2 concentration compared with OMNO2d in polluted situation. • Monthly NO 2 from POMINO are consistent with ground sites, but OMNO2d underestimates in Jan and Oct. [ABSTRACT FROM AUTHOR]

The ionospheric delay is of paramount importance to radio communication, satellite navigation and positioning. It is necessary to predict high-accuracy ionospheric peak parameters for single frequency receivers. In this study, the state-of-the-art artificial neural network (ANN) technique optimized by the genetic algorithm is used to develop global ionospheric models for predicting foF2 and hmF2. The models are based on long-term multiple measurements including ionospheric peak frequency model (GIPFM) and global ionospheric peak height model (GIPHM). Predictions of the GIPFM and GIPHM are compared with the International Reference Ionosphere (IRI) model in 2009 and 2013 respectively. This comparison shows that the root-mean-square errors (RMSEs) of GIPFM are 0.82 MHz and 0.71 MHz in 2013 and 2009, respectively. This result is about 20%–35% lower than that of IRI. Additionally, the corresponding hmF2 median errors of GIPHM are 20% to 30% smaller than that of IRI. Furthermore, the ANN models present a good capability to capture the global or regional ionospheric spatial-temporal characteristics, e.g., the equatorial ionization anomaly and Weddell Sea anomaly. The study shows that the ANN-based model has a better agreement to reference value than the IRI model, not only along the Greenwich meridian, but also on a global scale. The approach proposed in this study has the potential to be a new three-dimensional electron density model combined with the inclusion of the upcoming Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC-2) data. [ABSTRACT FROM AUTHOR]

In this paper, a design of reconfigurable optical add-drop multiplexer (ROADM) is proposed, which consists of magnetically-coupled switches, bus waveguide, drop waveguide, add waveguide, and reflection cavity based on a photonic crystal (PC). The ferrite materials are introduced to form microcavities in a two-dimensional PC. Then, the magnetic permeability of ferrite rods is changed by adjusting the magnetic field strength, and a scheme for magnetic permeability distribution of magnetically-coupled switches is proposed. The simulation results indicate that the incident wave with wavelength 1550 nm can be downloaded and uploaded successfully, and the transmissivity of wave is both above 90% when the add function and drop function are conducted. The quality (Q) factor is approximately 103. Moreover, the overall size of the device is 13.5 μ m × 10.5 μ m , which is highly suitable for wavelength division multiplexing (WDM) system in the photonic integrated circuits. [ABSTRACT FROM AUTHOR]

Aerosol haze pollution has had a significant impact on both global climate and the regional air quality of Eastern China, which has a high proportion of high level pollution days. Statistical analyses of aerosol optical properties and direct radiative forcing at two AERONET sites (Beijing and Xuzhou) were conducted from 2013 to 2016. Results indicate: (1) Haze pollution days accounted for 26% and 20% of days from 2013 to 2016 in Beijing and Xuzhou, respectively, with the highest proportions in winter; (2) The averaged aerosol optical depth (AOD) at 550 nm on haze days were about 3.7 and 1.6 times greater than those on clean days in Beijing and Xuzhou, respectively. At both sites, the maximum AOD occurred in summer; (3) Hazes were dominated by fine particles at both sites. However, as compared to Xuzhou, Beijing had larger coarse mode AOD and higher percentage of small α. This data, together with an analysis of size distribution, suggests that the hazes in Beijing were more susceptible to coarse dust particles than Xuzhou; (4) During hazes in Beijing, the single scattering albedo (SSA) is significantly higher when compared to clean conditions (0.874 vs. 0.843 in SSA440 nm), an increase much less evident in Xuzhou. The most noticeable differences in both SSA and the imaginary part of the complex refractive index between Beijing and Xuzhou were found in winter; (5) In Beijing, the haze radiative forcing produced an averaged cooling effect of −113.6 ± 63.7 W/m2 at the surface, whereas the averaged heating effect of 77.5 ± 49.7 W/m2 within the atmosphere was at least twice as strong as clean days. In Xuzhou, such a radiative forcing effect appeared to be much smaller and the difference between haze and clean days was insignificant. Derived from long-term observation, these findings are more significant for the improvement of our understanding of haze formation in China and the assessment of its impacts on radiative forcing of climate change than previous short-term case studies. [ABSTRACT FROM AUTHOR]

Mitochondrial (MITO) dysfunction occurs in the failing heart and contributes to worsening of heart failure (HF). Reduced aldehyde dehydrogenase 2 (ALDH2) in left ventricular (LV) myocardium of diabetic hearts has been implicated in MITO dysfunction through accumulation of toxic aldehydes including and elevated levels of 4-hydroxy-2-nonenal (4HNE). This study examined whether dysregulation of MITO ALDH2 (mALDH2) occurs in mitochondria of the failing LV and is associated with increased levels of 4HNE. LV tissue from 7 HF and 7 normal (NL) dogs was obtained. Protein quantification of total mitochondrial ALDH2 (t-mALDH2), phosphorylated mALDH2 (p-mALDH2), total MITO protein kinase c epsilon (t-mPKCε), phosphorylated mPKCε (p-mPKCε) was performed by Western blotting, and total mALDH2 enzymatic activity was measured. Protein adducts of 4HNE-MITO and 4HNE-mALDH2 were also measured in MITO fraction by Western Blotting. Protein level of t-mALDH2 was decreased in HF compared with NL dogs (0.63 ± 0.07 vs 1.17 ± 0.08, p < 0.05) as did mALDH2 enzymatic activity (51.39 ± 3 vs. 107.66 ± 4 nmol NADH/min/mg, p < 0.05). Phosphorylated-mALDH2 and p-mPKCε were unchanged. 4HNE-MITO proteins adduct levels increased in HF compared with NL (2.45 ± 0.08 vs 1.30 ± 0.03 du, p < 0.05) as did adduct levels of 4HNE-mALDH2 (1.60 ± 0.20 vs 0.39 ± 0.08, p < 0.05). In isolated failing cardiomyocytes (CM) exposure to 4HNE decreased mALDH2 activity, increased ROS and 4HNE-ALDH2 adducts, and worsened MITO function. Stimulation of mALDH2 activity with ALDA-1 in isolated HF CMs compared to NL CMs improved ADP-stimulated respiration and maximal ATP synthesis to a greater extant (+47 % and +89 %, respectively). Down-regulation of mALDH2 protein levels and activity occurs in HF and contributes to MITO dysfunction and is likely caused by accumulation of 4HNE-mALDH2 adduct. Increasing mALDH2 activity (via ALDA-1) improved MITO function in failing CMs.

Deoxynivalenol (DON) is the one of the most common mycotoxins, widely detected in various original foods and processed foods. Tanshinone IIA (Tan IIA) is a fat-soluble diterpene quinone extracted from Salvia miltiorrhiza Bunge, which has multi-biological functions and pharmacological effects. However, whether Tan IIA has a protective effect against DON-induced intestinal toxicity is unknown. In this study, the results showed Tan IIA treatment could attenuate DON-induced IPEC-J2 cell death. DON increased oxidation product accumulation, decreased antioxidant ability and disrupted barrier function, while Tan IIA reversed DON-induced barrier function impairment and oxidative stress. Furthermore, Tan IIA dramatically improved mitochondrial function via mitochondrial quality control. Tan IIA could upregulate mitochondrial biogenesis and mitochondrial fusion as well as downregulate mitochondrial fission and mitochondrial unfolded protein response. In addition, Tan IIA significantly attenuated mitophagy caused by DON. Collectively, Tan IIA presented a potential protective effect against DON toxicity and the underlying mechanisms were involved in mitochondrial quality control-mediated mitophagy.

Deoxynivalenol (DON) is the most common mycotoxin in food and feed, which can cause undesirable effects, including diarrhea, emesis, weight loss, and growth delay in livestock. Intestinal epithelial cells were the main target of DON, which can cause oxidative stress and inflammatory injury. Tanshinone IIA (Tan IIA) is fat-soluble diterpene quinone, which is the most abundant active ingredient in salvia miltiorrhiza plant with antioxidant and anti-inflammatory characteristics. However, it is not clear whether Tan IIA can protect against or inhibit intestinal oxidative stress and inflammatory injury under DON exposure. This study aimed to explore the protective effect of Tan IIA on DON-induced toxicity in porcine jejunum epithelial cells (IPEC-J2). Cells were exposed to 0, 0.5, 1.0, 2.0 µM DON and/or 45 µg/mL TAN ⅡA to detect oxidative stress indicators. inflammatory cytokines, NF-κB expression, NLRP3 inflammasome and pyroptosis-related factors. In this study, DON exposure caused IPEC-J2 cells oxidative stress by elevating ROS and 8-OHdG content, inhibited GSH-Px activity. Furthermore, DON increased pro-inflammatory factor (TNF-α, IL-1β, IL-18 and IL-6) expression and decreased the anti-inflammatory factor (IL-10) expression, causing inflammatory response via triggering NF-κB pathway. Interestingly, above changes were alleviated after Tan IIA treatment. In addition, Tan IIA relieved DON-induced pyroptosis by suppressing the expression of pyroptosis-related factors (NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18). In general, our data suggested that Tan IIA can ameliorate DON-induced intestinal epithelial cells injury associated with suppressing the pyroptosis signaling pathway. Our findings pointed that Tan IIA could be used as the potential therapeutic drugs on DON-induced enterotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

T-2 toxin is an unavoidable food and feed contaminant that seriously threatens human and animal health. Exposure to T-2 toxin can cause testosterone synthesis disorder in male animals, but the molecular mechanism is still not completely clear. The MAPK pathway participates in the regulation of testosterone synthesis by Leydig cells, but it is unclear whether the MAPK pathway participates in T-2 toxin-induced testosterone synthesis disorders. In this research, testosterone synthesis capacity, testosterone synthase expression and MAPK pathway activation were examined in male mice and TM3 cells exposed to T-2 toxin. The results showed that T-2 toxin exposure decreased testicular volume and caused pathological changes in the microstructure and ultrastructure of testicular Leydig cells. T-2 toxin exposure also decreased testicular testosterone content and the protein expression of testosterone synthase. In vitro, T-2 toxin inhibited cell viability and decreased the expression of testosterone synthase in TM3 cells, and it decreased the testosterone contents in cell culture supernatants. Moreover, T-2 toxin activated the MAPK pathway by increasing the expression of p38, JNK and ERK as well as the expression of p-p38, p-JNK and p-ERK in testis and TM3 cells. The p38 molecular inhibitor (SB203580) significantly alleviated the T-2 toxin-induced decrease in testosterone synthase expression in TM3 cells and the T-2 toxin-induced reduction in testosterone content in TM3 cell culture supernatants. In summary, p38 mediates T-2 toxin-induced Leydig cell testosterone synthesis disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Accurate and reliable forecasting of PM 2.5 and PM 10 concentrations is important to the public to reasonably avoid air pollution and for the governmental policy responses. However, the prediction of PM 2.5 and PM 10 concentrations has great uncertainty and instability because of the dynamics of atmospheric flows, making it difficult for a single model to efficiently extract the spatial-temporal dependences. This paper reports a robust forecasting system to achieve accurate multi-step ahead forecasting of PM 2.5 and PM 10 concentrations. First, correlation analysis is adopted to screen the spatial information on pollution and meteorology that may facilitate the prediction of concentrations in a target city. Then, a spatial-temporal attention mechanism is used to assign weights to original inputs from both space and time dimensions to enhance the essential information. Subsequently, the residual-based convolutional neural network with feature extraction capabilities is employed to model the refined inputs. Finally, five accuracy metrics and two additional statistical tests are applied to comprehensively assess the performance of the proposed forecasting system. In addition, experimental studies of three major cities in the Yangtze River Delta urban agglomeration region indicate that the forecasting system outperforms various prevalent baseline models in terms of accuracy and stability. Quantitatively, the proposed STA-ResCNN model reduces root mean square error by 5.595 %-15.247 % and 6.827 %-16.906 % for the average of 1-4 h ahead predictions in three major cities of PM 2.5 and PM 10 , respectively, compared to baseline models. The applicability and generalization of the proposed forecasting system are further verified by the extended applications in the other 23 cities in the entire region. The results prove that the forecasting system is promising in the early warning, regional prevention, and control of air pollution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Plant microbiota are of great importance for host nutrition and health. As a C 4 plant species with a high carbon fixation capacity, sugarcane also associates with beneficial microbes, though mechanisms underlying sugarcane root-associated community development remain unclear. Here, we identify microbes that are specifically enriched around sugarcane roots and report results of functional testing of potentially beneficial microbes propagating with sugarcane plants. First, we analyzed recruitment of microbes through analysis of 16S rDNA enrichment in greenhouse cultured sugarcane seedlings growing in field soil. Then, plant-associated microbes were isolated and assayed for beneficial activity, first in greenhouse experiments, followed by field trials for selected microbial strains. The promising beneficial microbe SRB-109, which quickly colonized both roots and shoots of sugarcane plants, significantly promoted sugarcane growth in field trials, nitrogen and potassium acquisition increasing by 35.68 and 28.35%, respectively. Taken together, this report demonstrates successful identification and utilization of beneficial plant-associated microbes in sugarcane production. Further development might facilitate incorporation of such growth-promoting microbial applications in large-scale sugarcane production, which may not only increase yields but also reduce fertilizer costs and runoff., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Li, Wang, Ma, Zheng, Zhang, Fu, Li, Su, Huang, Zhong and Liao.)

Root-associated microbes are critical for plant growth and nutrient acquisition. However, scant information exists on optimizing communities of beneficial root-associated microbes or the mechanisms underlying their interactions with host plants. In this report, we demonstrate that root-associated microbes are critical influencers of host plant growth and nutrient acquisition. Three synthetic communities (SynComs) were constructed based on functional screening of 1,893 microbial strains isolated from root-associated compartments of soybean plants. Functional assemblage of SynComs promoted significant plant growth and nutrient acquisition under both N/P nutrient deficiency and sufficiency conditions. Field trials further revealed that application of SynComs stably and significantly promoted plant growth, facilitated N and P acquisition, and subsequently increased soybean yield. Among the tested communities, SynCom1 exhibited the greatest promotion effect, with yield increases of up to 36.1% observed in two field sites. Further RNA-seq implied that SynCom application systemically regulates N and P signaling networks at the transcriptional level, which leads to increased representation of important growth pathways, especially those related to auxin responses. Overall, this study details a promising strategy for constructing SynComs based on functional screening, which are capable of enhancing nutrient acquisition and crop yield through the activities of beneficial root-associated microbes., (© 2021 Institute of Botany, Chinese Academy of Sciences.)

Legume crops contribute a great portion of clean nitrogen (N) to agro-ecosystems through symbiotic N 2 fixation in the nodule; however, the nodulation is always inhibited by high N availability which is known as the N inhibitory effect through largely unknown mechanisms. We functionally investigated miR169c-GmNFYA-C-GmENOD40 under multiple N conditions in soybean (Glycine max) (ENOD, Early Nodulin; NFYA, Nuclear Factor-Y Subunit A). We elucidated their regulatory roles in soybean nodulation through analyzing expression patterns, micro-messenger RNA (miRNA-mRNA) interactions, phenotypes of transgenic soybean plants and genetic interactions. We found that miR169c expression was induced by high N, whereas its target GmNFYA-C was preferentially expressed in nodules and induced by rhizobium inoculation. Overexpression of miR169c inhibited nodulation through targeting 3'-UTR of GmNFYA-C, whereas knockout miR169c through CRISPR-cas9 promoted nodulation. However, overexpression of GmNFYA-C promoted soybean nodulation through facilitating rhizobium infection and increasing the expression of symbiotic signaling gene GmENOD40. Besides, GmNFYA-C directly induced the expression of GmENOD40. In addition, overexpression of GmNFYA-C without the target site of miR169c partially attenuated the inhibitory effect of high N on soybean nodulation. We discovered a new regulatory pathway involving the miR169c-NFYA-C-ENOD40 module that regulates soybean nodulation in response to N availability. This pathway provides substantial new insights into the mechanisms underlying the N inhibitory effect on nodulation., (© 2020 The Authors New Phytologist © 2020 New Phytologist Foundation.)

Background: Unlike β 1 - and β 2 -adrenergic receptors (ARs), β 3 -AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β 3 -ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous infusions of the β 3 -AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF)., Methods and Results: Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure., Conclusions: Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Sacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome., Methods and Results: Fourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P < .002, whereas change in troponin I decreased, -0.16 ± 0.03 vs -0.03 ± 0.02 ng/mL, P < .001. Urinary change in kidney injury molecule 1 decreased in Sac/Val-treated dogs compared with controls, -17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P < .007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P < .05., Conclusions: In dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Vepoloxamer (VEPO), a rheologic agent, repairs damaged cell membranes, thus inhibiting unregulated Ca 2+ entry into cardiomyocytes. This study examined the effects of i.v. infusion of VEPO on LV function in dogs with coronary microembolization-induced heart failure (HF) (LV ejection fraction, EF ~ 30%)., Methods: Thirty-five HF dogs were studied. Study 1: 21 of 35 dogs were randomized to 2-h infusion of VEPO at dose of 450 mg/kg (n = 7) or VEPO at 225 mg/kg (n = 7) or normal saline (control, n = 7). Hemodynamics were measured at 2 h, 24 h, 1 week, and 2 weeks after infusion. Study 2: 14 HF dogs were randomized to 2-h infusions of VEPO (450 mg/kg, n = 7) or normal saline (control, n = 7). Each dog received 2 infusions of VEPO or saline (pulsed therapy) 3 weeks apart and hemodynamics measured at 24 h, and 1, 2, and 3 weeks after each infusion. In both studies, the change between pre-infusion measures and measures at other time points (treatment effect, Δ) was calculated., Results: Study 1: compared to pre-infusion, high dose VEPO increased LVEF by 11 ± 2% at 2 h, 8 ± 2% at 24 h (p < 0.05), 8 ± 2% at 1 week (p < 0.05), and 4 ± 2% at 2 weeks. LV EF also increased with low-dose VEPO but not with saline. Study 2: VEPO but not saline significantly increased LVEF by 6.0 ± 0.7% at 2 h (p < 0.05); 7.0 ± 0.7%% at 1 week (p < 0.05); 1.0 ± 0.6% at 3 weeks; 6.0 ± 1.3% at 4 weeks (p < 0.05); and 5.9 ± 1.3% at 6 weeks (p < 0.05)., Conclusions: Intravenous VEPO improves LV function for at least 1 week after infusion. The benefits can be extended with pulsed VEPO therapy. The results support development of VEPO for treating patients with acute on chronic HF.

Aims: Elamipretide (ELAM), an aromatic-cationic tetrapeptide, interacts with cardiolipin and normalizes dysfunctional mitochondria of cardiomyocytes. This study examined the effects of ELAM on skeletal muscle mitochondria function in dogs with chronic heart failure (HF)., Methods and Results: Studies were performed in skeletal muscle biopsy specimens obtained from normal dogs (n = 7) and dogs with chronic intracoronary microembolization-induced HF (n = 14) treated with subcutaneous ELAM 0.5 mg/kg (HF + ELAM, n = 7) or vehicle (normal saline control, HF-CON, n = 7). After 3 months of therapy, triceps skeletal muscle samples were obtained from all dogs, and the proportion of type 1 and type 2 fibres was assessed. Mitochondria isolated from myofibrils of the vastus lateralis skeletal muscle exposed in vitro to ELAM for 1 h were used to assess mitochondrial function. The proportion of skeletal muscle type 1 fibres was lower in HF-CON dogs compared with normal dogs (23 ± 4 vs. 32 ± 5%, P < 0.05). Treatment with ELAM restored a near-normal fibre-type composition (31 ± 7%, P < 0.05 vs. HF-CON). Skeletal muscle mitochondria showed significantly lower levels of adenosine diphosphate-dependent mitochondrial respiration (100 ± 9 vs. 164 ± 15 natom O/min/mg protein, P < 0.05), mitochondrial membrane potential (0.17 ± 0.03 vs. 0.53 ± 0.03 red/green fluorescence ratio, P < 0.05), mitochondrial permeability transition pore (38 ± 3 vs. 62 ± 2 relative light units, P < 0.05), maximum rate of adenosine triphosphate synthesis (3284 ± 418 vs. 8835 ± 423 RLU/μg protein, P < 0.05), and cytochrome c oxidase activity (1390 ± 108 vs. 2459 ± 210 natom O/min/mg protein, P < 0.05) compared with normal dogs. Exposure of skeletal muscle myofibrillar mitochondria from HF dogs to ELAM showed a dose-dependent improvement/normalization of all measures of mitochondrial function. In mitochondria from skeletal muscle of HF dogs exposed to 0.10 μM ELAM, adenosine diphosphate-dependent mitochondrial respiration increased to 183 ± 18 natom O/min/mg protein, membrane potential increased to 0.30 ± 0.03 red/green fluorescence ratio, mitochondrial permeability transition pore increased to 54 ± 4 RLU, maximum rate of adenosine triphosphate synthesis increased to 4423 ± 414, and cytochrome c oxidase activity increased to 2033 ± 191 natom O/min/mg protein. Exposure of skeletal muscle myofibrillar mitochondria from normal dogs to ELAM had no effect on mitochondrial function parameters., Conclusions: The results indicate that ELAM, previously shown to positively influence mitochondrial function of the failing heart, can also positively impact mitochondrial function of skeletal muscle and potentially help restore skeletal muscle function and improve exercise tolerance., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

A bstract: The objective of the study was to put forth an interpolation method (the LZ method) for refining the GNSS-derived precipitable water vapor (PWV) map. We established a regional weighted mean temperature ( T m ) model for this experiment, which introduced a minor difference into the resultant GNSS-derived PWV compared to the previous T m models. The kernel of the LZ method consists of increasing the sample density via the virtual sample points. These virtual sample points originated from the digital elevation model (DEM) were constructed on the basis of the statistically significant correlation between PWV and geographical location (i.e., geographical coordinates and elevation). The LZ method was validated and compared to the conventional interpolation approach only accounting for the original sample points. The results reflect that the PWV maps generated by the LZ method showed more details than through conventional one. In addition, the prediction performance of the LZ method was better than that of the conventional method by using cross-validation., Competing Interests: The authors declare no conflicts of interest.

The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and pro-arrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, pre-load-recruitable stroke work, ejection fraction, stroke volume, cardiac output, ratio of early-to-late filling time integrals, and early mitral valve inflow velocity deceleration time. BMS-986231 significantly decreased LV filling pressures, end-diastolic stiffness, the time-constant of relaxation, end-diastolic wall stress, systemic vascular resistance, and myocardial oxygen consumption. BMS-986231 had little effect on heart rate and did not induce de novo arrhythmias. Thus, BMS-986231 has beneficial inotropic, lusitropic, and vasodilatory effects.

Purpose: Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities., Methods: Studies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1., Results: The study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM., Conclusions: Critical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF.

Background: Elamipretide (MTP-131), a novel mitochondria-targeting peptide, was shown to reduce infarct size in animals with myocardial infarction and improve renal function in pigs with acute and chronic kidney injury. This study examined the effects of chronic therapy with elamipretide on left ventricular (LV) and mitochondrial function in dogs with heart failure (HF)., Methods and Results: Fourteen dogs with microembolization-induced HF were randomized to 3 months monotherapy with subcutaneous injections of elamipretide (0.5 mg/kg once daily, HF+ELA, n=7) or saline (control, HF-CON, n=7). LV ejection fraction, plasma n-terminal pro-brain natriuretic peptide, tumor necrosis factor-α, and C-reactive protein were measured before (pretreatment) and 3 months after initiating therapy (post-treatment). Mitochondrial respiration, membrane potential (Δψm), maximum rate of ATP synthesis, and ATP/ADP ratio were measured in isolated LV cardiomyocytes obtained at post-treatment. In HF-CON dogs, ejection fraction decreased at post-treatment compared with pretreatment (29 ± 1% versus 31 ± 2%), whereas in HF+ELA dogs, ejection fraction significantly increased at post-treatment compared with pretreatment (36 ± 2% versus 30 ± 2%; P<0.05). In HF-CON, n-terminal pro-brain natriuretic peptide increased by 88 ± 120 pg/mL during follow-up but decreased significantly by 774 ± 85 pg/mL in HF+ELA dogs (P<0.001). Treatment with elamipretide also normalized plasma tumor necrosis factor-α and C-reactive protein and restored mitochondrial state-3 respiration, Δψm, rate of ATP synthesis, and ATP/ADP ratio (ATP/ADP: 0.38 ± 0.04 HF-CON versus 1.16 ± 0.15 HF+ELA; P<0.001)., Conclusions: Long-term therapy with elamipretide improves LV systolic function, normalizes plasma biomarkers, and reverses mitochondrial abnormalities in LV myocardium of dogs with advanced HF. The results support the development of elamipretide for the treatment of HF., (© 2016 American Heart Association, Inc.)

Purpose: We tested the hypothesis that heart rate (HR) reduction with ivabradine (IVA) leads to reversal of structural, biochemical, and molecular maladaptations characteristic of the heart failure (HF) state. HR reduction with IVA has been shown to improve left ventricular (LV) systolic function and clinical outcome in patients with HF., Methods: Studies were performed in 16 HF dogs produced by intracoronary microembolizations [LV ejection fraction (EF) ~35%]. Dogs were randomized to 3-month oral therapy with IVA (30 mg Bid, n = 8) or to no therapy (Control, n = 8). LV tissue was obtained from all dogs at the end of therapy and used for molecular, biochemical, and histological studies., Results: Average 24-h ambulatory Holter monitoring showed a significant decrease of HR in IVA-treated dogs compared with controls. Compared with pre-therapy, LV EF decreased at 3 months in controls (36 ± 1 vs. 32 ± 2%, P < 0.05) but increased significantly with IVA (40 ± 3 vs. 35 ± 3%, P < 0.05). Treatment with IVA was associated with (i) improved LV diastolic function; (ii) increased sarcoplasmic reticulum Ca 2+ uptake and ATPase activity; (iii) decreased plasma levels of vasoactive neurohormones, natriuretic peptides, and pro-inflammatory cytokines; (iv) normalization of messenger RNA gene expression of multiple signalling pathways; and (v) reduced cardiomyocyte apoptosis and hypertrophy., Conclusion: In dogs with HF, HR reduction with IVA reversed many of the structural, biochemical, and molecular maladaptations characteristic of HF. The findings support the concept that HR reduction in HF can elicit benefits, albeit indirect, on a host of maladaptations implicated in the progressive worsening of the HF state., (© 2014 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Purpose: GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30 %)., Methods: Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10 μg/kg/min) or vehicle (normal saline) for 6 h in random order 1 week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6 h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6 h. LV pressure-volume relationship (PVR) was measured at baseline and 6 h., Results: Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27 ± 1 at baseline to 34 ± 1 after 6 h of drug infusion, p < 0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO2., Conclusions: Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA's for the treatment of acute HF syndromes.

Rhesus putative epidermal stem cells are being investigated for their potential use in regenerative corneal epithelium-like cells, which may provide a practical source of autologous seed cells for the construction of bioengineered corneas. The goal of this study was to investigate the potential of epidermal stem cells for trans-differentiation into corneal epithelium-like cells. Rhesus putative epidermal stem cells were isolated by type IV collagen attachment method. Flow cytometry analysis, immunohistology and RT-PCR were conducted to identify the expression of specific markers (beta1, alpha6 integrin, K15, K1/K10, K3/K12 and CD71) on the isolated rapid attaching cells. The isolated cells were cocultured with human corneal limbal stroma and corneal epithelial cells. After coculture, the expression of the same specific markers was evaluated in order to identify expression difference caused by the coculture conditions. K3/K12 expression was analyzed in coculture cells on day 2, 4, 6, 8 and 10. Putative epidermal stem cells in conditioned culture media were used as control. Putative epidermal stem cells were predominant in rapid attaching cells by type IV collagen attachment isolation. Before being cocultured, the rhesus putative epidermal stem cells expressed K15, alpha6 and beta1 integrin, but no CD71, K1/K10 and K3/K12. After coculture, these cells expressed K3/K12 (a marker of corneal epithelial cells), K15 and beta1 integrin, but no K1/K10. Cells being not coculture converted into terminally differentiated cells expressing K1/K10. These results indicate that rhesus putative epidermal stem cells can trans-differentiate into corneal epithelium-like cells and, therefore, may have potential therapeutic application as autologous seed cells for the construction of bioengineered corneas.

Liver cancers, the majority of which are hepatocellular carcinomas (HCCs), rank as the fourth in cancer mortality worldwide and are the most rapidly increasing type of cancer in the United States. However, the molecular mechanisms underlying HCC development are not well understood. Activation of the hedgehog pathway is shown to be involved in several types of gastrointestinal cancers. Here, we provide evidence to indicate that hedgehog signaling activation occurs frequently in HCC. We detect expression of Shh, PTCH1 and Gli1 in 115 cases of HCC and in 44 liver tissues adjacent to the tumor. Expression of Shh is detectable in about 60% of HCCs examined. Consistent with this, hedgehog target genes PTCH1 and Gli1 are expressed in over 50% of the tumors, suggesting that the hedgehog pathway is frequently activated in HCCs. Of five cell lines screened, we found Hep3B, Huh7 and PLC/PRF/5 cells with detectable hedgehog target genes. Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis. In contrast, no effects are observed after these treatments in HCC36 and HepG2 cells, which do not have detectable hedgehog signaling. Thus, our data indicate that hedgehog signaling activation is an important event for development of human HCCs.