Search

The soil-borne yellow mosaic virus disease, which is caused by the bymoviruses barley yellow mosaic virus (BaYMV) and/or barley mild mosaic virus (BaMMV), seriously threatens winter barley production in Europe and East Asia. Both viruses are transmitted by the soil-borne plasmodiophorid

JMJD6 is a member of the JmjC domain-containing family and has been identified as a promising therapeutic target for treating estrogen-induced and triple-negative breast cancer. To develop novel anti-breast cancer agents, we synthesized a class of N-(1-(6-(substituted phenyl)-pyridazine-3-yl)-piperidine-3-yl)-amine derivatives as potential JMJD6 inhibitors. Among them, the anti-cancer compound A29 was an excellent JMJD6 binder (KsubD/sub = 0.75 ± 0.08 μM). It could upregulate the mRNA and protein levels of p53 and its downstream effectors p21 and PUMA by inhibiting JMJD6. Besides, A29 displayed potent anti-proliferative activities against tested breast cancer cells by the induction of cell apoptosis and cell cycle arrest. Significantly, A29 also promoted a remarkable reduction in tumor growth, with a TGI value of 66.6% (50 mg/kg, i.p.). Taken together, our findings suggest that A29 is a potent JMJD6 inhibitor bearing a new scaffold acting as a promising drug candidate for the treatment of breast cancer.

This study aimed to explore the phytoremediation potential of Salvia tiliifolia for cadmium (Cd)-contaminated soils and to understand the interactions in soil-Cd-plant systems. We assessed the Cd tolerance and accumulation characteristics of S. tiliifolia grown in soils with 0, 5, 25, and 50 mg kg− 1 Cd for 3 months. We also analysed the changes in physicochemical properties, enzyme activities, and bacterial community composition in the rhizosphere soils of S. tiliifolia. S. tiliifolia could tolerate all Cd concentrations with unchanged biomass. Cd concentrations (21.50–189.50 mg kg− 1) in roots of S. tiliifolia and corresponding bioconcentration factors (3.79–4.30) were much higher than those in shoots, and Cd translocation factors (0.03–0.23) were thereby very low. Rhizosphere pH decreased with increasing concentrations of Cd. Soil pH and rich organic matter may jointly affect the soil available Cd. Ultimately, soil enzyme activities involved in carbon, nitrogen, and phosphorus cycles were affected to varying degrees, and bacterial diversity and richness were slightly influenced by Cd stress. Interestingly, bacterial ABC transporters were induced by Cd stress during this process. S. tiliifolia can be designed as a Cd excluder. The induced soil bacterial ABC transporters may contribute to Cd detoxification and accumulation in both soil microbial communities and S. tiliifolia plants.

The outbreak of the novel coronavirus in China (SARS‐CoV‐2) that began in December 2019 presents a significant and urgent threat to global health. This study was conducted to provide the international community with a deeper understanding of this new infectious disease. Epidemiological, clinical features, laboratory findings, radiological characteristics, treatment, and clinical outcomes of 135 patients in northeast Chongqing were collected and analyzed in this study. A total of 135 hospitalized patients with COVID‐19 were enrolled. The median age was 47 years (interquartile range, 36‐55), and there was no significant gender difference (53.3% men). The majority of patients had contact with people from the Wuhan area. Forty‐three (31.9%) patients had underlying disease, primarily hypertension (13 [9.6%]), diabetes (12 [8.9%]), cardiovascular disease (7 [5.2%]), and malignancy (4 [3.0%]). Common symptoms included fever (120 [88.9%]), cough (102 [76.5%]), and fatigue (44 [32.5%]). Chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs of all the patients. All patients received antiviral therapy (135 [100%]) (Kaletra and interferon were both used), antibacterial therapy (59 [43.7%]), and corticosteroids (36 [26.7%]). In addition, many patients received traditional Chinese medicine (TCM) (124 [91.8%]). It is suggested that patients should receive Kaletra early and should be treated by a combination of Western and Chinese medicines. Compared to the mild cases, the severe ones had lower lymphocyte counts and higher plasma levels of Pt, APTT, d‐dimer, lactate dehydrogenase, PCT, ALB, C‐reactive protein, and aspartate aminotransferase. This study demonstrates the clinic features and therapies of 135 COVID‐19 patients. Kaletra and TCM played an important role in the treatment of the viral pneumonia. Further studies are required to explore the role of Kaletra and TCM in the treatment of COVID‐19., Research Highlights 83.7% of the patients had contact history in Wuhan or had been to Wuhan or had contact with people from Wuhan.Common symptoms included fever, cough, and fatigue. Other symptoms include myalgia, fatigue, dyspnea, anorexia, etc.Common complications of the patients include acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, secondary infection and shock. ICU patients were more likely to have these complications than non‐ICU patients.Compared with non‐ICU patients, ICU patients had lower lymphocyte count, and higher plasma levels of the Pt, APTT, D‐dimer, LDH, PCT, ALB, CRP, AST.All patients received antiviral therapy (kaletra or interferon), antibacterial therapy and corticosteroid and many received traditional chinese medicine. It was suggested that patients should use kaletra early.

In continuing our study on discovering new Nur77-targeting anti-inflammatory agents with natural skeletons, we combined adamantyl group and hydroxamic acid moiety with flavonoid nucleus, synthesized three series of flavonoid derivatives with a similar structure like CD437, and evaluated their activities against LPS-induced inflammation. Compound B7 was found to be an excellent Nur77 binder (K

The green soil chelator polyaspartic acid (PASP) can enhance heavy metal phytoextraction efficiency, but the potential mechanisms are not clearly understood from the whole soil-plant system. In this study, we explored the effects and potential mechanisms of PASP addition in soils on plant growth and cadmium (Cd) uptake in the Cd hyperaccumulator Bidens pilosa by analysing variations in chemical elements, rhizospheric microbial community, and plant metabolomics. The results showed that PASP significantly promoted the biomass yield and Cd concentration in B. pilosa, leading to an increase in the total accumulated Cd by 46.4% and 76.4% in shoots and 124.7% and 197.3% in roots under 3 and 6 mg kg

Clarifying the mechanisms of heavy metal (HM) accumulation and translocation from soil-root-leaf is crucial to coping with soil HM pollution. In this study, we analysed copper (Cu), manganese (Mn), zinc (Zn) and cadmium (Cd) accumulation characteristics in Chinese turnips and the effect of soil physicochemical properties on both HM accumulation and translocation. Our results indicate that Chinese turnips absorb and translocate Mn, Zn, and Cd at much higher levels than they do Cu. When we measured bioconcentration factors in Chinese turnips for different HMs in the same soil, we found Chinese turnip capacities for HM accumulation decrease from Zn > Mn > Cd > Cu. In addition, the translocation factor for these HMs decreases from Mn > Cd > Zn > Cu. Correlation analysis indicates that soil pH and various soil components are either negatively or positively correlated with Mn, Zn, and Cd accumulation; also, soil properties are correlated with Mn translocation from root to leaf. These findings may help evaluate HM accumulation and translocation mechanisms as well as artificially regulate HM uptake levels from soils to turnips. Keywords: Turnip, Heavy metal, Bioconcentration, Phytoremediation, Soil composition

Screening or breeding exceptional plant species for heavy metal phytoremediation is as important as adopting feasible measures to enhance phytoremediation efficiency, which are largely based on clarifying the mechanisms of heavy metal tolerance and accumulation by plants. In this study, cadmium (Cd) and lead (Pb) tolerance and accumulation characteristics of Rheum officinale, R. palmatum, and R. tanguticum were analysed to assess their phytoremediation potential. The seed germination test indicated that these three rhubarb species could tolerate 10 mg L

Whale optimization algorithm (WOA), inspired from the natural hunting behavior of humpback whales, is a stochastic searching algorithm for electromagnetic inverse problem and other optimization problems. However, the algorithm may converge very slowly and the exploration reliability of it needs to be improved when dealing with multimodal and complex problems. Thus, some improvements are introduced. Initially, a farthest individual first dynamic topology (FIFDT) is put forward to better balance the exploration and exploitation searches. Additionally, an adaptive fully informed learning mechanism (AFILM) is applied to avoid premature convergence and the decrease of convergence speed. Meanwhile, a gradient descent based accelerated search (GDBAS) is adopted to improve the convergence speed of the algorithm. Finally, a chaotic map based population mutation (CMBPM) is added to enhance the exploration capability in order to find the global optimum solution. Experiments have been conducted on well-known multimodal benchmark test functions and an electromagnetic inverse problem. The numerical results show the merit and efficiency of the proposed modified WOA.

In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10−6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 μM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 μM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.

The quality of the control of looper system can directly affect the width, thickness and other performance of the strip. It is difficult to maintain the speed matching relation between each stand in a finishing mill due to the decrease of the speed of dynamic bite steel of main drive system and external interference in rolling process, so we need to set up hydraulic looper system to maintain constant small tension rolling. Aimed at the characteristics of nonlinear, multi constraint and strong coupling of hydraulic looper system, its mathematical model has been established based on 1700ASP. Then a robust controller is designed using Hinfinity mixed sensitivity method for system uncertainty of dynamic model parameter perturbation and external disturbance to insure the robust stability and robust performance.In this paper, the linear model of hydraulic looper system is established on the basis of practical data. Because of the limitations of conventional PID decoupling control, an intelligent algorithm called robust decoupling control is proposed.The results of decoupling control show that the algorithm is superior to the conventional PID decoupling control in response speed and anti-interference ability.

Neither a vaccine nor specific therapeutic drugs against 2019 novel coronavirus have been developed. Some studies have shown that Xuebijing injection (XBJ) can exert an anti-inflammatory effect by inhibiting the production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and other cytokines. This study aimed to investigate the effect of XBJ on coronavirus disease 2019 (COVID-19) and its effects on IL-6 and tumor necrosis alpha TNF-α.A total of 42 patients, who were diagnosed with COVID-19 and treated with XBJ combined with routine treatment at Chongqing University Three Gorges Hospital between January 20, 2020, and March 11, 2020, were selected as the observation group. A control group comprising 16 patients who received routine treatment was also established, and cases were matched from the observation group on a 1:1 basis according to age, comorbidities, and mild and severe disease. The clinical symptoms, laboratory test indexes, and changes in computed tomography (CT) scans of patients in the two groups were observed at the time of admission and 7 days after treatment, and the time taken for the patients to produce a negative nucleic acid test was also recorded.There were no significant differences in baseline data between the two groups. After treatment, there were significant improvements in IL-6 levels and body temperature in the observation group as compared with the control group. Particularly in severe patients, the reduction in body temperature in the observation group was greater than that in the control group (P0.05). A higher number of patients in the observation group showed improved CT imaging results compared with the control group, and the time taken to produce a negative nucleic acid test was shorter in the observation group than in the control group; however, the differences were not statistically significant (P0.05). Furthermore, there were no significant differences in TNF-α and IL-10 between the two groups.The results of this study suggest that routine treatment combined with XBJ can better improve the clinical outcomes of COVID-19 patients.

Nearly 100,000 ha in the Three Gorges Reservoir Area (TGRA) are in wheat production and the area is a junction where wheat stripe rust overwinters and causes epidemics the next spring; thus the area plays a pivotal role in wheat stripe rust epidemics in China. To better understand wheat resistance levels and the application of Yr genes in this area, 116 wheat cultivars (lines) were collected from the TGRA to investigate stripe rust resistance during the 2014–2016 cropping seasons. Seedling resistance evaluation results indicated that only nine accessions (7.8%) were immune or nearly immune to three predominant races of CYR32, CYR33 and PST-V26. In the field evaluation, 51 accessions (43.9%) showed adult-plant resistance, whereas 56 accessions (48.3%) were susceptible. The application of resistant sources focused on ineffective Yr9 (26.7%) and Yr17 (18.9%), and gradual ineffective Yr26 (34.5%), while effective Yr5, Yr10 and Yr15 were absent. Among them, 21 accessions (18.1%) were combined with two resistance genes. Both low resistance and more concentrated use of Yr genes indicated that this region faces a major risk for a wheat stripe rust epidemic. To improve the wheat resistance level in the TGRA, it is important to discover new all-stage resistance resources and diversify resistance resources for breeding.

Human peroxisome proliferator-activated receptor alpha (hPPARα) is a ligand-dependent transcription factor that mainly controls lipid metabolism in the liver. It has drawn wide attention as a significant target for developing new hypoglycaemic drugs. However, a central and largely unresolved question in finding new drugs targeted on hPPARα concerns ligand action mechanism: what makes certain molecules act as antagonists while others behave as agonists in the same binding site? To understand this, we performed a total of 600 ns all-atom molecular dynamics (MD) simulations to explore how four small molecule ligands bind to the hPPARα and play opposite effects. We characterized and compared the protein backbone fluctuation, and investigated the interaction networks and the movements of helixes and loops near binding site during MD simulations. Moreover, by free energy calculation and phylogenetic tree analysis, 11 key residues favouring binding ligands and some other residues playing important roles in inducing the active conformation changing of hPPARα were discovered. The results could help to understand the activation/deactivation of hPPARα by agonists or antagonists, and provide insightful prospective into hPPARα targeted structure-based drug designs.

Human stimulator of interferon genes protein (hSTING) is an essential signaling adaptor and a cytosolic DNA sensor (CDS) that functions as a homodimer in innate immunity. Natural mutation V155M in hSTING can cause hSTING-associated vasculopathy with onset in infancy (SAVI) which is an autoinflammatory disease. However, the mechanisms between the variant and SAVI are poorly understood. To explore the mechanisms, we performed all-atom molecular dynamics (MD) simulations on the complexes of wild type (WT)/mutated (V155M) hSTING and endogenous agonist 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to investigate whether the interaction between hSTING and 2′3′-cGAMP could be affected by natural mutation V155M, which plays a crucial role in SAVI disease. Based on the MD simulations, the dynamic cross-correlation analysis and principal component analysis indicated that the single point mutation on residue 155 from valine to methionine changed some residues' motions of hSTING. Furthermore, MM/PBSA calculation, hydrogen bond analysis and energy decomposition analysis showed that this single point mutation increased the binding affinity of 2′3′-cGAMP with hSTING. Finally, residual network analysis indicated the way that the V155M mutation around 17 A from the binding site controlled the strength of binding interaction and the conformation change of the substructure. These results will help in the understanding of the mechanism of SAVI disease induced by hSTING mutation at the molecular level, and provide new ideas to design innovative drugs targeted on hSTING.

Human SETD7 methyltransferase (hSETD7) is involved in a wide range of physiological processes, and has been considered as a significant target to develop new drugs. (R)-PFI-2, one hSETD7 inhibitor, could bind to the pocket of substrates with potent (low nanomolar) activity and high selectivity, while its enantiomer (S)-PFI-2 showed 500-fold less activity in IC50 determination. Why do this pair of enantiomers, with nearly identical structures, exert tremendously different inhibitory activity? We performed a total of 900 ns long-timescale molecular dynamics (MD) simulations and 80 ps hybrid quantum mechanics/molecular mechanics (QM/MM) MD simulations to understand the molecular mechanism of the stereoselectivity of hSETD7. For each SAM/hSETD7/PFI-2 system, we characterized and compared the residual fluctuation of hSETD7, and generated molecular interaction fingerprints (IFP) to exemplify the propensities of SAM/hSETD7-inhibitor interactions. Based on the QM/MM MD, we accurately captured the difference of hydrogen bonds between the SAM/hSETD7/(R)-PFI-2 and SAM/hSETD7/(S)-PFI-2 systems. Especially the strength of the hydrogen bond between G336 and two inhibitors, which determines the stability of the post-SET loop. The energy barrier for (S)-PFI-2 was much bigger than (R)-PFI-2 from global minimum to bioactive conformation as the potential energy surface scanning (PES) showed. Moreover, by estimating the binding affinity and phylogenetic tree analysis, we discovered 16 hotspots were essential for binding both enantiomers but the specific mode of interaction between these hotspots and enantiomorphs is different. Our findings reveal the effect of chirality on the inhibition activity of hSETD7 in detail, and provide valuable information for hSETD7 structure-based drug development.

In continuation of our previous work on the investigation of CDK9 inhibitors bearing indole moiety for the discovery of novel anticancer agents, novel methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold were designed, synthesized, and evaluated for the CDK9 inhibitory activity and anticancer activity. Biological activity results demonstrated that most of these derivatives possessed good inhibitory on the kinase activity of CDK9 such as blocking its phosphorylation function and inhibiting HIV-1 transcription. Compound 12i was found to be the most potent CDK9 inhibitor and exhibited excellent anticancer activity against HepG2, A375, MCF-7, and A549, but low toxic on normal cells including HaCaT and MCF-10A. Further studies revealed that as a result of CDK9 inhibition and subsequent inhibition of phosphorylation at Serine 2 of the RNAPII CTD, the representative compound 12i dose-dependently increased cleaved PARP level, exerting its antiproliferative effect through induction of apoptosis in cancer cells. Finally, the molecular docking analysis implied that 12i had a good binding affinity with CDK9. In summary, 12i is a potent CDK9 inhibitor and can be considered as a good lead-candidate for developing potential anticancer drugs.

Discovering the implicit pattern and using it as heuristic information to guide the policy search is one of the core factors to speed up the procedure of robot motor skill acquisition. This paper proposes a compound heuristic information guided reinforcement learning algorithm PI2-CMA-KCCA for policy improvement. Its structure and workflow are similar to a double closed-loop control system. The outer loop realized by Kernel Canonical Correlation Analysis (KCCA) infers the implicit nonlinear heuristic information between the joints of the robot. In addition, the inner loop operated by Covariance Matrix Adaptation (CMA) discovers the hidden linear correlations between the basis functions within the joint of the robot. These patterns which are good for learning the new task can automatically determine the mean and variance of the exploring perturbation for Path Integral Policy Improvement (PI2). Compared with classical PI2, PI2-CMA, and PI2-KCCA, PI2-CMA-KCCA can not only endow the robot with the ability to realize transfer learning from the demonstration trajectory to the new task trajectory, but also complete it more efficiently. The classical via-point experiments based on SCARA and Swayer robots have validated that the proposed method has fast learning convergence and can find a solution for the new task.

The heavy metal ATPase (HMA) subfamily is mainly involved in heavy metal (HM) tolerance and transport in plants, but an understanding of the definite roles and mechanisms of most HMA members are still limited. In the present study, we identified 14 candidate HMA genes named BrrHMA1–BrrHMA8 from the turnip genome and analyzed the phylogeny, gene structure, chromosome distribution, and conserved domains and motifs of HMAs in turnip (Brassica rapa var. rapa). According to our phylogenetic tree, the BrrHMAs are divided into a Zn/Cd/Co/Pb subclass and Cu/Ag subclass. The BrrHMA members show similar structural characteristics within subclasses. To explore the roles of BrrHMAs in turnip, we compared the gene sequences and expression patterns of the BrrHMA genes between a Cd-tolerant landrace and a Cd-sensitive landrace. Most BrrHMA genes showed similar spatial expression patterns in both Cd-tolerant and Cd-sensitive turnip landraces; some BrrHMA genes, however, were differentially expressed in specific tissue in Cd-tolerant and Cd-sensitive turnip. Specifically, BrrHMA genes in the Zn/Cd/Co/Pb subclass shared the same coding sequence but were differentially expressed in Cd-tolerant and Cd-sensitive turnip landraces under Cd stress. Our findings suggest that the stable expression and up-regulated expression of BrrHMA Zn/Cd/Co/Pb subclass genes under Cd stress may contribute to the higher Cd tolerance of turnip landraces. Keywords: Heavy metal ATPase, Cadmium, Turnip, Transmembrane helix, Differential gene expression

We administered foliar applications of 50, 100, and 200 mg L−1 selenium (Se, selenite) on turnip (Brassica rapa var. rapa Linn.) and detected the changes in the main nutrient components in fleshy roots. Results showed that the foliar application of Se (IV) significantly increased the Se content in turnip, and Se (IV) positively affected the uptake of several mineral elements, including magnesium, phosphorus, iron, zinc, manganese, and copper. Se (IV) treatments also improved the synthesis of protein and multiple amino acids instead of crude fat and total carbohydrate in turnip, indicating that the foliar application of Se (IV) could enhance Se biofortification in turnip and promote its nutritional value. We recommended 50–100 mg L−1 Se treatment for foliar application on turnip based on the daily intake of Se for adults (96–139 μg person−1 day−1) and its favorable effects on the nutrient components of turnip.

Selenium (Se) is an essential trace element for humans. About 70% of the regions in China, including most of the Tibetan Plateau, are faced with Se deficiency problems. Turnip is mainly distributed around the Tibetan Plateau and is one of the few local crops. In the present study, we compared the absorption and translocation differences of Se (IV) selenite and Se (VI) selenate in turnip. The results showed that Se treatment, either by soil addition (0.2–2 mg Se kg−1 dry soil) or by foliar spraying (50–200 mg L−1 Se), could significantly increase the Se concentrations in turnips, and 0.5 mg Se (IV) or Se (VI) kg−1 dry matter in soils could improve the biomasses of turnips. Moreover, turnip absorbed significantly more Se (VI) than Se (IV) at the same concentration and also transferred much more Se (VI) from roots to leaves. Based on the Se concentrations, as well as the bioconcentration factors and translocation coefficients, we considered that turnip might be a potential Se indicator plant. Subsequently, we estimated the daily Se intake for adults based on the Se concentrations in turnip roots. The results indicated that Se (IV) should be more suitable as an artificial Se fertilizer for turnips, although the levels found in most samples in this study could cause selenosis to humans. In addition, we also estimated the optimum and maximum Se concentrations for treating turnips based on the linear relations between Se concentrations in turnip roots and Se treatment concentrations. The results provided preliminary and useful information about Se biofortification in turnips.

Phytoextraction is a phytoremediation technique used for remediating polluted soils and it greatly relies on the plants' capacities to accumulate contaminants. Turnip is a high cadmium (Cd)-accumulating plant. We compared the Cd tolerance, growth, and Cd accumulation characteristics of two turnip landraces with three additional commonly known high Cd-accumulating species to systematically estimate its Cd phytoremediation potential. Results showed that the turnips could tolerate relatively lower Cd concentrations than other plants. Growth characteristics analyses indicated that the turnips initially grew rapidly and then gradually slowed down, and their photosynthetic parameters indicated that biomass accumulation was easily affected by light. However, the Cd uptake and translocation capacities of the two turnip landraces were higher than those of Phytolacca americana Linn. and Bidens pilosa Linn. but close to that of Brassica napus Linn.. Ultimately, large amounts of Cd accumulated in turnips during early growth and slightly increased as the fleshy roots increased in size. Based on these findings, the present turnip landraces have potential for soil remediation, but additional research is needed before these landraces can be practically used. Moreover, turnips are good candidates for studying the molecular mechanism of high Cd accumulation in plants.

Constant looper height and small tension control is a basic characteristic of modern hot rolling mill. The control quality of looper system affects directly performances in the width and thickness of a product. A looper system has the features of nonlinearity, strong coupling, uncertainty, and multi-constraints. In this paper, a dynamic mathematical model of looper system is set up based on 1700ASP. In addition, multiple-input multiple-output (MIMO) space model at the vicinity of working point has been deduced. A new control strategy-fuzzy sliding mode control is introduced to decouple the system by using two filters to smooth control signal and to suppress output noise, respectively. Simulation results show that the algorithm is effective and has better control effect in resisting disturbance and weakening chattering after this system is decoupled.