The key spatial elements and high-density development of urban peninsula:A discussion on the relationship between core and cape

Urban peninsulas are an important category with distinctive geographical characteristics in the history of human settlements.Despite their time-honored development,abundant cultural accumulation,and developed water transportation,a considerable number of world-famous urban peninsulas demonstrate a remarkable feature of high-density development because of their limited space for expansion.Based on the in-depth analysis of the connotation and features of urban peninsulas,this study summarizes five basic elements concerning the space of urban peninsulas,namely,capes,boundaries,networks,nodes,and cores.On the basis of these five elements,different high-density developmental modes of urban peninsulas are construed to provide a reference model for the location,density control,and urban structure of high-rise building clusters in peninsulas and further reveal the significance and value of high-rise buildings in shaping the special urban form of peninsulas.

Carbamylated lipoproteins in diabetes

Diabetic dyslipidemia is characterized by quantitative and qualitative abnormalities in lipoproteins.In addition to glycation and oxidation,carbamylation is also a post-translational modification affecting lipoproteins in diabetes.Patients with type 2 diabetes(T2D)exhibit higher levels of carbamylated low-density lipoproteins(cLDL)and high-density lipoproteins(cHDL).Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes.cLDL levels have been shown to predict cardiovascular events and all-cause mortality.cLDL facilitates immune cell recruitment in the vascular wall,promotes accumulation of lipids in macrophages,and contributes to endothelial dysf-unction,endothelial nitric oxide-synthase(eNOS)inactivation and endothelial repair defects.Lastly,cLDL induces thrombus formation and platelet aggregation.On the other hand,recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients.This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation.Thus,cHDL loses the ability to remove cholesterol from macrophages,to inhibit monocyte adhesion and recruitment,to induce eNOS activation and to inhibit apoptosis.Taken together,it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes.

Dynamics of hepatic and intestinal cholesterol and bile acid pathways: The impact of the animal model of estrogen deficiency and exercise training

Plasma cholesterol level is determined by a complex dynamics that involves transport lipoproteins which levels are tightly dependent on how the liver and the intestine regulate cholesterol and biliary acid metabolism. Regulation of cholesterol and biliary acids by the liver and the intestine is in turn coupled to a large array of enzymes and transporters that largely influence the inflow and the outflow of cholesterol and biliary acids through these organs. The activity of the key regulators of cholesterol and biliary acids may be influenced by several external factors such as pharmacological drugs and the nutritional status. In recent years, more information has been gathered about the impact of estrogens on regulation of cholesterol in the body. Exposure to high levels of estrogens has been reported to promote cholesterol gallstone formation and women are twice as likely as men to develop cholesterol gallstones. The impact of estrogen withdrawal, such as experienced by menopausal women, is therefore of importance and more information on how the absence of estrogens influence cholesterol regulation is started to come out, especially through the use of animal models. An interesting alternative to metabolic deterioration due to estrogen deficiency is exercise training. The present review is intended to summarize the present information that links key regulators of cholesterol and biliary acid pathways in liver and intestine to the absence of estrogens in an animal model and to discuss the potential role of exercise training as an alternative.

低密度脂蛋白和高密度脂蛋白相对全蛋黄溶液在猕猴精子低温冷冻中的作用

Low-density lipoprotein （LDL） extracted from hen egg yolk has recently been considered to be superior to whole egg yolk in sperm cryopreservation of various animal species. Meanwhile, there was a notion that high-density lipoprotein （HDL） in egg yolk may have a negative effect on post-thaw survival. The role of LDL and HDL in sperm cryopreservation of rhesus monkeys has not been explored. The present study evaluates their effect in comparison with egg yolk with or without the addition of permeable cryoprotectant （glycerol） on sperm cryopreservation of rhesus macaques. In addition, various additives intended to change the lipid composition of LDL-sperm membrane complex have also been tested for their effectiveness in preserving post-thaw viability. Our findings indicated that LDL is the main component in egg yolk that is responsible for its protective role for sperm cryopreservation in rhesus monkeys. Regardless of the presence or absence of glycerol, the protective role of LDL is similar to that of egg yolk and we did not observe any superiority in post-thaw survival with LDL when compared to egg yolk. Modifying the lipid composition of LDL-sperm membrane complex with the addition of cholesterol, cholesterol loaded cyclodextrin and phosphatidylcholine also did not yield any improvements in pest-thaw survival; while addition of methyl-β-cyclodextrin reduced post-thaw motility. HDL plays a neutral role in sperm cryopreservation of rhesus monkeys. The present study suggests that egg yolk may still hold advantages when compared with LDL as effective components in extenders for sperm cryopreservation in rhesus monkeys.

Mechanisms of dysregulation of low-density lipoprotein receptor expression in HepG2 cells induced by inflammatory cytokines

Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated LDL receptor feedback regulation causing intracellular accumulation of unmodified LDL in peripheral cells. Liver is the central organ for lipid homeostasis. The aim of this study was to investigate the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms in human hepatic cell line （HepG2） cells under physiological and inflammatory conditions. Methods Intracellular total cholesterol （TC）, free cholesterol （FC） and cholesterol ester （CE） were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein （SREBP）-2 and SREBP cleavage-activating protein （SCAP） mRNA levels using real-time quantitative PCR. LDL receptor and SREBP-2 protein expression were examined by Western blotting. Confocal microscopy was used to investigate the translocation of SCAP-SREBP complex from the endoplasmic reticulum （ER） to the Golgi by dual staining with anti-human SCAP and anti-Golgin antibodies. Results LDL loading increased intracellular cholesterol level, thereby reduced LDL receptor mRNA and protein expression in HepG2 cells under physiological conditions. However, interleukin 1β （IL-1β） further increased intracellular cholesterol level in the presence of LDL by increasing both LDL receptor mRNA and protein expression in HepG2. LDL also reduced the SREBP and SCAP mRNA level under physiological conditions. Exposure to IL-1β caused over-expression of SREBP-2 and also disrupted normal distribution of SCAP-SREBP complex in HepG2 by enhancing translocation of SCAP-SREBP from the ER to the Golgi despite a high concentration of LDL in the culture medium. Conclusions IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi, thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL. This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.

Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship?

Life expectancy in patients with rheumatoid arthritis(RA)is reduced compared to the general population owing to an increase in cardiovascular diseases(CVD)not fully explained by traditional cardiovascular risk factors.In recent years,interest has been focused on the alterations in lipid metabolism in relation to chronic inflammation as one of the possible mechanisms involvedin the pathogenesis of atherosclerosis of RA patients.Research regarding this issue has revealed quantitative alterations in lipoproteins during the acute-phase reaction,and has also demonstrated structural alterations in these lipoproteins which affect their functional abilities.Although many alterations in lipid metabolism have been described in this regard,these structural changes associated with inflammation are particularly important in high-density lipoproteins as they affect their cardioprotective functions.In this respect,excessive oxidation in low-density lipoprotein(LDL)and increased lipoprotein(a)with a predominance of smaller apolipoprotein(a)isoforms has also been reported.This article will discuss proinflammatory high-density lipoproteins(pi HDL),oxidized LDL and lipoprotein(a).Elevated concentrations of these lipoproteins with marked pro-atherogenic properties have been observed in RA patients,which could help to explain the increased cardiovascular risk of these patients.

Ankle-brachial index and brachial-ankle pulse wave velocity are risk factors for ischemic stroke in patients with type 2 diabetes

The incidence of ischemic stroke in patients with diabetes is increasing. While brachial-ankle pulse wave velocity （BaPWV） and ankle-bra- chial index （ABI） are known to be associated with ischemic cardiovascular and cerebrovascular diseases, whether these measures predict the risk of ischemic cerebrovascular disease in diabetic patients remains unclear. 117 patients with type 2 diabetes were enrolled in this study. According to the results of head magnetic resonance imaging, the patients were divided into a diabetes-only group （n = 55） and a diabetes and ischemic stroke group （n = 62）. We then performed ABI and BaPWV examinations for all patients. Compared with the diabe- tes-only group, we found decreased ABI and increased BaPWV in the diabetes and ischemic stroke group. Multivariate logistic regression analyses revealed that BaPWV and ABI were risk factors for ischemic stroke in patients with type 2 diabetes. Our findings indicate that decreased ABI and increased BaPWV are objective indicators of increased risk of ischemic stroke in patients with type 2 diabetes.

High-density/efficient surface active sites on modified separators to boost Li-S batteries via atomic Co^(3+)-Se termination

Various and critical electrocatalytic processes are involved during the redox reactions in the Li-S batteries,which extremely depend on the surface structure and chemical state.Recently,single-atom concept unlocks a route to maximize the use of surface-active atoms,however,further increasing the density of active site is still strictly limited by the inherent structure that single-atoms are only highly-dispersed on substrate.Herein,we provide a viewpoint that an elaborate facet design with singlecrystalline structure engineering can harvest high-density surface active sites,which can significantly boost the electrocatalyst performance for excellent Li-S batteries.Specifically,the single-crystal CoSe_(2)(scCS)exhibits three-types of terminated(011)facet,efficiently obtaining the surface with a high-rich Co^(3+)–Se bond termination,in contrast with lots of surface grain boundaries and dangling bonds in polycrystalline CoSe_(2).Surprisingly,the surface active sites concentration can reach more than 69%.As anticipated,it can provide high-density and high-efficient active sites,enormously suppressing the shuttle effect and improving the reaction kinetics via accelerating the conversion and deposition of polysulfides and Li2S.This surface lattice strategy with element terminated mode is a promising approach for designing electrocatalyst effect-based energy system,not merely for Li-S batteries.

Prospective randomized clinical trial evaluating the impact of vinegar on lipids in non-diabetics

Background: Heart disease is now considered an inflammatory process targeted primarily by medical therapy on lipid levels. Complementary and alternative medicine searches for novel non-pharmacologic therapy, including pursuing various diets. Animal studies and consumer literature suggest benefits of vinegar on lipid levels and diabetes mellitus. Our nonrandomized pilot study from our group suggested a benefit in raising high-density lipoprotein cholesterol (HDL-C). Based on this data, we conducted a randomized placebo controlled clinical trial to determine the effects of apple cider vinegar intake in those without diabetes mellitus on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides, HDL-C, Hemoglobin A1C(Hgb-A1C) and measurement of inflammation with high sensitivity CRP levels (HS-CRP). Methods: A prospective randomized, double blind, placebo-controlled clinical trial consisting of 114 participants was conducted. Participants consumed 30 mL of either apple cider vinegar or placebo for two months. Measurements were collected at baseline, eight and sixteen weeks. The primary endpoint was the change in HDL-C from baseline to eight weeks between the vinegar and placebo groups. Secondary endpoints were change from baseline to eight weeks in TC, LDL-C, triglycerides, Hgb-A1cand HS-CRP. Results: Change in serum HDL-C concentration was not significantly different between the vinegar and control groups after eight weeks of supplementation. Secondary endpoints including TC, LDL-C, Hgb-A1cand HS-CRP were not statistically different at the Bonferroni corrected significance level of 0.01. No significant difference was found regardless of baseline HDL-C levels. Conclusions: We found no significant difference in HDL-C, LDL-C, triglycerides, total cholesterol, or HS-CRP levels with use of vinegar but a trend down of Hgb-A1cin this group of non-diabetic participants. Further investigation is required to define the impact of vinegar in those with diabetes mellitus.

EXPERIMENTAL STUDY ON THE PREVENTION AND TREATMENT EFFECT OF WARMING-REINFORCING METHOD ON RABBIT'S HYPERLIPEMIA

In this experiment, the contents of serum total cholesterol (TC), triglyceride(TG),low-density lipoprotein(LDL), high-density lipoprotein(HDL) were used as indexes to observe the effects of warming-reinforcing method on rabbit’s lipide, liopoprotein. The results indicated that in the warming-reinforcing group, TC decreased markedly and HDL increased obviously with significant difference as compared with the twirling-reinforcing group:TC and LDL also decreased, but no significant differencte as compared with the twirling-reinforcing group. Warming-reinforcing method can decrease lipids more effectively than twirling-reinforcing method.

Bed type and flow mechanism of deep water sub-lacustrine fan fringe facies:an example from the Middle Permian Lucaogou Formation in Southern Junggar Basin of NW China

Submarine or sub-lacustrine lobe deposits are important reservoirs,but the fan fringe deposits form heterogeneities within deep water fan deposits.Fan fringe facies records the complex sediment gravity flow types.By understanding of the bed types and flow mechanisms,we can identify the fan fringe deposit,which aids in the reconstruction of deep water fan and reservoir evaluations.The Jiucaiyuanzi and Dalongkou sections in the West Bogda Mountains preserve well-exposed 536-m and 171-m thick successions,respectively,of a deep water lacustrine depositional system from the Middle Permian Lucaogou Formation.Bed types of the Lucaogou Formation include high-density turbidite,low-density turbidite,incomplete Bouma-type turbidite,hybrid event beds,and slump deposits.The Lucaogou Formation is interpreted here as a fan fringe facies due to the thin bed thickness that characterize turbidites and hybrid event beds,as well as the predominance of the isolated sheet architecture.Previous studies suggest that these deposits were considered as deposited in a deep water setting due to the absence of wave-related structures.The presence of abundant mud clasts in massive medium-coarse grained sandstone beds reflects the significant erosional capability and interactions between high-density turbidity currents and lake floor.The fan fringe facies here contains amalgamated and thick-bedded homolithic facies(~30%)and thin-bedded heterolithic facies(~70%).The examination of the bed type is of wider significance for facies prediction and reservoir heterogeneity in the sub-lacustrine fan fringe facies.

Recent Advances on the Corrosion Resistance of Low-Density Steel:A Review

This paper reviews the previous literature on the alloy composition design of low-density steel(LDS),focusing on the eff ect of Al,Mn,Ni,and other alloy elements on the formation of the steel matrix and second phase,and provides classifi cation.The microstructure of LDS after processing includes the matrix structure,к-carbide,and B2(FeAl,NiAl,or MnAl)phase of ferritic LDS,austenitic LDS,and dual-phase LDS.The infl uence of alloy elements on the corrosion resistance of LDS is derived from the addition of Al and Mn for metallurgy.Additionally,the infl uence of Cr and Mo addition on the corrosion resistance improvement was studied.The electrochemical properties of the corrosion process in LDS are discussed.Further,the microstructure of LDS aff ects the corrosion resistance properties including pitting corrosion,hydrogen embrittlement,and SCC(stress corrosion cracking).Finally,future research directions are proposed.

Lipoprotein in cholesterol transport: Highlights and recent insights into its structural basis and functional mechanism

Lipoproteins are protein-lipid macromolecular assemblies which are used to transport lipids in circulation and are key targets in cardiovascular disease （CVD）. The highly dynamic lipoprotein molecules are capable of adopting an array of conformations that is crucial to lipid transport along the cholesterol transport pathway, among which high-density lipopro- tein （HDL） and low-density lipoprotein （LDL） are major players in plasma cholesterol metabolism. For a more detailed illustration of cholesterol transport process, as well as the development of therapies to prevent CVD, here we review the functional mechanism and structural basis of lipoproteins in cholesterol transport, as well as their structural dynamics in the plasma lipoprotein （HDL and LDL） elevations, in order to obtain better quantitative understandings on structure-function relationship of lipoproteins. Finally, we also provide an approach for further research on the lipoprotein in cholesterol transport.

ANALYSIS OF SERUM LIPIDS IN PSORIASIS

Serum lipids were determined in 100 psoriatics and the results indicated (1) the incidences of hypercholesterolemia (9%) and hypertriglyceridemia (17%) in psoriatics were significantly higher than in controls; (2) the mean values of serum TC, LDL-C and TC/HDL-C in psoriatics were significantly higher as compared with normal healthy controls matched for sex and age; (3) serum TC, LDL-C and TG values were significantly higher in cases whose disease was progressive or whose lesions involved more than 20% of body surface area than in cases whose disease stationary or lesions less than 20%. As the incidences of hypertension and coronary heart disease were also significantly higher in psoriatics than in controls, the authors proposed that some integrated relationship would exist.

Oxidative alterations in sickle cell disease: Possible involvement in disease pathogenesis

Sickle cell disease(SCD) is the first molecular disease in the literature. Although the structural alteration and dysfunction of the sickle hemoglobin(HbS) are well understood, the many factors modifying the clinical signs and symptoms of the disease are under investigation. Besides having an abnormal electrophoretic mobility and solubility, HbS is unstable. The autooxidation rate of the abnormal HbS has been reported to be almost two times of the normal. There are two more components of the oxidative damage in SCD: Free radical induced oxidative damage during vaso-occlusion induced ischemia-reperfusion injury and decreased antioxidant capacity in the erythrocyte and in the circulation. We will discuss the effects of oxidative alterations in the erythrocyte and in the plasma of SCD patients in this review.

Co-modulated interface binding energy and electric field distribution of layer-structured PVDF–LDPE dielectric composites with BaTiO3: experiment and multiscale simulations

The layer-structured composites were built by the dielectric and insulating layers composed of polyvinylidene fluoride(PVDF)and low-density polyethylene(LDPE)composites containing barium titanate(BT)to modulate the dielectric and energy storage properties of the composites.The simulations on the interface models for molecular dynamics and the geometric models for finite element analysis were performed together with the experimental characterization of the morphology,dielectric,and energy storage properties of the composites.The results revealed that polyethylene as an insulating layer played a successful role in modulating dielectric permittivity and breakdown strength while BT particles exerted positive effects in improving the miscibility between the composed layers and redistributing the electric field.The strong interface binding energy and the similar dielectric permittivity between the PVDF layer and the BT20/LDPE layer made for the layer-structured composites with a characteristic breakdown strength(Eb)of 188.9 kV·mm^(−1),a discharge energy density(Ud)of 1.42 J·cm^(−3),and a dielectric loss factor(tanδ)of 0.017,which were increased by 94%,141%,and decreased by 54%in comparison with those of the BT20/PVDF composite,respectively.

Hypolipidemic and anti-atherosclerogenic effects of aqueous extract of Ipomoea batatas leaves in diet-induced hypercholesterolemic rats

Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the aqueous extract of I.batatas leaves in a rat model of diet-induced hypercholesterolemia.Methods:Hypercholesterolemia was induced in male Wistar rats by exclusive feeding with a cholesterolenriched(1%)standard diet for four weeks.Then,rats were treated once daily(per os)with I.batatas extract at doses of 400,500 and 600 mg/kg or with atorvastatin(2 mg/kg),for four weeks.Following treatment,animals were observed for another four weeks and then sacrificed.Aortas were excised and processed for histopathological studies,and blood glucose level and lipid profile were measured.Results:Hypercholesterolemic animals experienced a 21.5%faster increase in body weight,significant increases in blood glucose and blood lipids(148.94%triglycerides,196.97%high-density lipoprotein cholesterol,773.04%low-density lipoprotein cholesterol,148.93%very low-density lipoprotein cholesterol and 210.42%total cholesterol),and increases in aorta thickness and atherosclerotic plaque sizes compared to rats fed standard diet.Treatment of hypercholesterolemic rats with the extract mitigated these alterations and restored blood glucose and blood lipid levels to normocholesterolemic values.Conclusion:Our findings suggest that I.batatas leaves have hypolipidemic and anti-atherosclerogenic properties and justify their use in traditional medicine.

Early testing of insulin resistance: a tale of two lipid ratios in a group of 5th graders screened by the Coronary Artery Risk Detection in Appalachian Communities Project (CARDIAC Project)

Background In West Virginia (WV),47% of fifth-grade children are either overweight or obese.There is no clear consensus regarding the definition of insulin resistance in children,and directly measuring insulin on the population level is costly.Two proposed measures examined further in this study include triglyceride (TRIG)/high-density lipoprotein cholesterol (HDL-C) ratio and TRIG/low-density lipoprotein (LDL-C) ratio.The purpose of this study is to examine the relationship between TRIG/HDL-C ratio,TRIG/LDL-C ratio and insulin resistance in fifth-graders with acanthosis nigricans (AN).Methods Between 2007 and 2016,52,545 fifth-grade students in WV were assessed for AN.Fasting glucose and insulin levels were collected only for a sub-group of students who were AN-positive and was used to determine insulin resistance using the Homeostatic Model for Insulin Resistance (HOMA-IR) equation.Statistical analysis included t tests and logistic regression with receiver operating characteristic curves.Results Of the students assessed for AN,4.5% (n =2360) tested positive.The prevalence of insulin resistance was 79% (n =814) among 1030 with AN and complete HOMA-IR.TRIG/HDL-C ratio and TRIG/LDL-C ratio were significantly associated with insulin resistance (TRIG/HDL-C:Est.=0.36,P < 0.0001,AUC =0.68;TRIG/LDL-C:Est.=0.87,P < 0.0001,AUC =0.69).Multivariate analysis showed that increased body mass index (Est.=0.05,P < 0.0001),gender (Est.=0.49,p < 0.0001) and TRIG/HDL-C ratio (Est.=0.21,P < 0.0001) were significantly associated with insulin resistance.Conclusions TRIG/HDL-C is a better surrogate marker of insulin resistance in AN-positive children compared to TRIG/ LDL-C ratio;so,on a population-level,cholesterol rather than insulin may be obtained for preliminary testing of early insulin resistance in children.

Fatty acid desaturase 1 polymorphisms are associated with coronary heart disease in a Chinese population

Background A recent genome-wide association study in Caucasians revealed that three loci （rs174547 in fatty acid desaturase 1 （FADS1）, rs2338104 near mevalonate kinase/methylmalonic aciduria, cobalamin deficiency, cblB type （MVK/MMAB） and rs10468017 near hepatic lipase （LIPC）） influence the plasma concentrations of high-density lipoprotein-cholesterol （HDL-C） and triglycerides （TG）. However, there are few reports on the associations between these polymorphisms and plasma lipid concentrations in Chinese individuals. This study aimed to evaluate the associations between these three polymorphisms with HDL-C and TG concentrations, as well as coronary heart disease （CHD） susceptibility in Chinese individuals.

Prediction of medium-to-coal ratio effect in a dense medium cyclone by using both traditional and coarse-grained CFD-DEM models

Dense medium cyclone(DMC)is the working horse in coal industry.In practice,it is usually operated under constant pressure and the operational conditions(mainly medium-to-coal(M:C)ratio and oper-ational pressure)need to be adjusted according to coal washability data(mainly coal particle size and density distributions).Nonetheless,until now it is still not well understood how the M:C ratio would affect the performance of DMCs especially under the practical conditions.In this work,the effect of M:C ratio is for the first time numerically studied under conditions similar to plant operation by using both tra-ditional and coarse-grained(CG)combined approach of computational fluid dynamics(CFD)and discrete element method(DEM),called as traditional CFD-DEM and CG CFD-DEM,in which the flow of coal par-ticles is modelled by DEM or CG DEM which applies Newton's laws of motion to individual particles and that of medium flow by the conventional CFD which solves the local-averaged Navier-Stokes equations,allowing consideration of particle-fluid mutual interaction and particle-particle collisions.Moreover,impulse and momentum connection law is used to achieve energy conservation between traditional CFD-DEM and CG CFD-DEM.It is found that under constant pressure,the M:C ratio affects DMC perfor-mance significantly.The specific effect depends on coal washability or coal type.Under extremely low M:C ratio,the phenomenon that high-quality coal product is misplaced to reject is successfully repro-duced,which has been observed in plants in Australian coal industry and called as"low-density tail".Moreover,strategies are proposed to mitigate the"low-density tail"phenomenon based on the model.