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Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled. Hepatic DNL increases in IR state. Blocking hepatic insulin/INSR/IRS/AKT signaling can reduce lipid deposition, implying that insulin can directly regulate DNL in IR. Besides, hepatic glucose disorders and extrahepatic factors such as metabolites and secreted proteins from adipose and muscle can also contribute to DNL. [ABSTRACT FROM AUTHOR]

It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30–78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test—grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. https://www.chictr.org.cn/showproj.html?proj=166181 [ABSTRACT FROM AUTHOR]

High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer's disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications. Here, Song et al. present a concept called "cholesterol toxicity," which stems from the emerging evidence of adverse effects of excess cholesterol in multiple organs. They suggest that excess cholesterol contributes to the pathogenesis of several diseases other than atherosclerosis. This concept potentially expands the therapeutic use of cholesterol-lowering medications. [ABSTRACT FROM AUTHOR]

The recent renaming of 'non-alcoholic fatty liver disease' (NAFLD) to 'metabolic dysfunction-associated steatotic liver disease' (MASLD) emphasizes metabolic dysfunction in steatotic liver disease and advocates for tailored, comprehensive treatment strategies, driving forward the development of personalized care and innovative therapeutic approaches. [ABSTRACT FROM AUTHOR]

Breakthrough SARS-CoV-2 infections of vaccinated individuals are being reported globally, resulting in an increased risk of hospitalization and death among such patients. Therefore, it is crucial to identify the modifiable risk factors that may affect the protective efficacy of vaccine use against the development of severe COVID-19 and thus to initiate early medical interventions. Here, in population-based studies using the UK Biobank database and the 2021 National Health Interview Survey (NHIS), we analyzed 20,362 participants aged 50 years or older and 2,588 aged 18 years or older from both databases who tested positive for SARS-COV-2, of whom 33.1% and 67.7% received one or more doses of vaccine, respectively. In the UK Biobank, participants are followed from the vaccination date until October 18, 2021. We found that obesity and metabolic abnormalities (namely, hyperglycemia, hyperlipidemia, and hypertension) were modifiable factors for severe COVID-19 in vaccinated patients (all p < 0.05). When metabolic abnormalities were present, regardless of obesity, the risk of severe COVID-19 was higher than that of metabolically normal individuals (all p < 0.05). Moreover, pharmacological interventions targeting such abnormalities (namely, antihypertensive [adjusted hazard ratio (aHR) 0.64, 95% CI 0.48–0.86; p = 0.003], glucose-lowering [aHR 0.55, 95% CI 0.36–0.83; p = 0.004], and lipid-lowering treatments [aHR 0.50, 95% CI 0.37–0.68; p < 0.001]) were significantly associated with a reduced risk for this outcome. These results show that more proactive health management of patients with obesity and metabolic abnormalities is critical to reduce the incidence of severe COVID-19 after vaccination. [Display omitted] • Obesity and metabolic abnormalities are highly prevalent in patients with severe COVID-19 • Obesity and metabolic abnormalities are associated with an increased risk of severe COVID-19 • In vaccinated patients, metabolic abnormalities are risk factors for severe COVID-19 • Interventions targeting metabolic abnormalities may reduce the risk of severe COVID-19 Fan et al. show that obesity and metabolic abnormalities were modifiable risk factors for severe COVID-19 events in vaccinated patients. When metabolic abnormalities (namely, hyperglycemia, hyperlipidemia, or hypertension) were present, regardless of obesity, the risk of severe COVID-19 was higher than that of metabolically normal people. Moreover, pharmacological interventions targeting such abnormalities were significantly associated with a reduced risk for this outcome. [ABSTRACT FROM AUTHOR]

Processing-structure (PS) linkages play a significant role in materials development. Nevertheless, currently there is a fascinating but of bottleneck task in terms of instantiating microstructure to understand and validate PS linkages. Its challenge lies on the lack of a robust method in computation efficiency and accuracy. Inspired from several advanced techniques such as hybrid input-output (HIO) algorithm, image processing operations and different-phase neighbors-based pixel swapping rule, we proposed a continually reactivating iterative-projection process (CRIP) method to address the challenge above. The output at each iteration in CRIP is continuously improved by eliminating and moving isolated or noise pixels towards an error-reduction direction to activate the iterative-projection process of the next iteration. The performance of the method was examined on two microstructure examples. It shows at least 99.86% improvement in convergence time compared with the classical simulated annealing algorithm and around 6.14 × 10−4 reduction in error compared with the traditional HIO algorithm. More importantly, CRIP is suitable for the task of instantiating microstructure from periodic two-point statistics predicted by PS linkage, which has been demonstrated by applying it to two experimental datasets of Ni-based superalloys and dual-phase steels. Our proposed method has the advantages of high efficiency, easy operation, reliable accuracy and remarkable generalization ability. [Display omitted] [ABSTRACT FROM AUTHOR]

• A Pearson-KPCA based multi-domain feature fusion method is proposed. • Analyze the correlation and differentiation between multi-domain features to compensate for the traditional feature extraction methods that do not consider the correlation between features. • Combining the LSTM with the Cox proportional-hazards model for multi-dimensional performance degradation trend decision fusion and reliability analysis of rolling bearings. In the feature selection process, a subset of features is selected from the original set of features based on the feature redundancy and importance. However, most of the existing methods for fusing multiple features ignore the connection between original features which leads to increased redundancy and affects the final classification results. To address this issue, in this study, an effective feature fusion method is proposed for predicting the remaining useful life (RUL) of rolling bearings based on Pearson correlation coefficient and kernel principal component analysis (KPCA). Firstly, the multi-domain features reflecting the bearing degradation state are extracted, and the correlation between the multi-domain features is obtained by Pearson correlation analysis before the feature fusion by KPCA. The features are grouped in such a way that that the correlation between the fused features is higher and the redundancy is lower. Secondly, a RUL prediction model of bearings is established based on the long short-term memory (LSTM) neural network and the Cox proportional-hazards model. In this model, the fused feature set is input into the LSTM neural network to predict the bearing performance degradation trend, which is then used as a multi-dimensional covariate in the Cox proportional-hazards model to assess the reliability of the bearing over time, thereby predicting the bearing RUL. Finally, based on experimental verification, the bearing failure prediction error for two different bearings is obtained to be 1.6 % and 3.4 %, which indicates the feasibility and efficacy of the proposed method for RUL prediction of mechanical equipment. [ABSTRACT FROM AUTHOR]

Obesity is associated with an increased risk of digestive polyps, whereas all obesity are not created equally. The role of metabolic states in occurrence risks of polyps among individuals with varying degrees of obesity remains unknown. Our study aimed to evaluate the association between metabolic obesity phenotypes and the occurrence of digestive polyps. Data from 9,278,949 patients between 2016 and 2018 from the National Inpatient Sample (NIS) database, a nationally representative database of all discharges from US health-care hospitals, were analyzed. According to obesity phenotype, the study population was classified into four groups: metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). We calculated the incidence rates of various digestive polyps (stomach/duodenum, colon and rectum polyps) among these participants by searching the hospital records for ICD-10 diagnosis codes indicating each gastric, duodenum, colon or rectal polyps. The multiple stepwise regression analysis and further in-depth subgroup analysis were used to determine the associations between metabolic obesity phenotypes and the occurrence of digestive polyps. In the total or female population, those with the MUNO and MUO phenotypes had significantly higher prevalence of digestive polyps compared with individuals with the MHNO or MHO phenotypes (all p < 0.05) and a significant difference was not found between MUNO and MUO phenotypes (p > 0.05). Obese subjects seem to be more likely to develop stomach and duodenum polyps or colon polyps than non-obese subjects in metabolically healthy people of males (MHO vs. MHNO, p < 0.05), whereas obesity status seems to have little effect on the occurrence of digestive polyps in metabolically healthy people of females (MHO vs. MHNO, p >0.05). After adjusting for the potential confounders, the MHO, MUNO and MUO phenotypes were all risk factors for stomach and duodenum polyps (OR = 1.46, 95% CI: 1.36–1.58, p < 0.01; OR = 1.19, 95% CI: 1.14–1.25, p < 0.01; OR = 1.44, 95% CI: 1.35–1.55, p < 0.01, respectively) or colon polyps (OR = 1.28, 95% CI: 1.21–1.35, p < 0.01; OR = 1.18, 95% CI: 1.14–1.22, p < 0.01; OR = 1.46, 95% CI: 1.38–1.54, p < 0.01, respectively) compared with the MHNO phenotype，especially in menopausal female. Interestingly, we also observed in further in-depth subgroup analysis that metabolic abnormalities may have a greater impact on the occurrence of digestive polyps than obesity (all p < 0.05). Both metabolic abnormities and obesity were associated with a higher risk of digestive polyps. The effect of metabolism on digestive polyp occurrence may be stronger than that of obesity, highlighting the importance of abnormal metabolic status modification regardless of obesity status. Clinical intervention should not only focus on obesity, but also on metabolic abnormalities to decrease digestive polyp risk. [Display omitted] • Both metabolic abnormities and obesity were associated with a higher risk of digestive polyps. • The effect of metabolism on the occurrence of digestive polyps may be stronger than that of obesity. • Clinical intervention should not only focus on obesity but also on metabolic abnormalities. • Sex differences in the occurrence of digestive polyps were highlighted. [ABSTRACT FROM AUTHOR]

Microstructure damage created by high-energy particle irradiation has an inevitable effect on the performance of material. Helium (He) as the transmutation element in irradiated solid prefers to occupy the vacancy (V) center to form He V complex, which in turn induces the formation of He bubble. Herein, the external applied stress driven irradiation-induced He bubble formation and evolution in single-crystalline tungsten (W) has been investigated using the phase-field method. Importantly, the trapping and resolution kinetic behavior between He atom and He bubble is described by the diffusion coefficient in terms of rate theory continuum model, and the effect of external stress on the movements of vacancy, self-interstitial and He atom has been implemented into their diffusivities as well. We first concentrate on the intrinsic lattice distortion (stress) patterns of void and bubble to validate the developed model by comparing the reported numerical results. Then, the accelerated growth velocity of bubble along the loading direction is predicted, which agrees well with the previously observed stress pattern around the void/bubble. The evolution behaviors of the stress-assisted single, bi-dispersed and multiple bubbles vary with the direction and magnitude of external loading, indicating a strong correlation between the size and density of bubble and the loading level. It is found that with the contribution of increasing external stress, more bubbles can be generated at the formation stage and visible bubbles tend to reduce at the coarsening stage due to bubble coalescence. • Trapping and resolution kinetic behavior between gas atom and bubble is considered in the gas diffusion coefficient. • Effect of external stress on the movement of point defects and gas atom is incorporated in the developed phase-field model. • High applied loading dramatically reduces the number of bubbles in the coarsening stage. [ABSTRACT FROM AUTHOR]

This work proposed a novel strategy for manufacturing biodegradable pH-response packaging. Briefly, to minimize the amount and thermal processing times of blueberry extract (BE), ethanol-dissolved BE (≤ 3‰ w/w) was sprayed onto the starch/poly(butylene adipate- co -terephthalate) (PBAT) pellets before extrusion blowing. BE was well-integrated into the matrix, forming uniformly colored films. The films with BE exhibited superior mechanical (7.85 MPa of strength, 606.53% of elongation) and enhanced barrier capabilities against ultraviolet light, moisture, and gas. Additionally, they exhibited good antioxidant capacity (68.69%), antibacterial activity (72.40%), and maintained color stability. The film with 3‰ w/w BE presented excellent color responsiveness (ΔE ⁎ ≥ 15) in the alkaline range, and successfully monitored the spoilage of shrimp. The pigments in the film had the maximum migration degree (≥ 70%) and rate in 50% ethanol simulation, following a first-order kinetic behavior dominated by Fickian diffusion. Findings supported the application of this strategy in the fabrication of starch/PBAT/BE films for pH-response intelligent packaging. [Display omitted] • A novel strategy was developed for biodegradable smart films via blown extrusion. • Color response was achieved by adding a tiny amount of blueberry extract (≤ 3‰). • Films showed good mechanical and barrier properties with multifunctional activity. • The freshness of shrimp was successfully monitored by the films. • Pigment release was a first-order kinetic behavior dominated by Fickian diffusion. [ABSTRACT FROM AUTHOR]

Diet-driven obesity is increasingly widespread. Its consequences pose major challenges to human health and health care systems. There are MAP kinase-interacting kinases (MNKs) in mice, MNK1 and MNK2. Studies have demonstrated that mice lacking either MNK1 or MNK2 were partially protected against high-fat diet (HFD)-induced weight gain and insulin resistance. The aims of this study were to evaluate the phenotype of mice lacking both MNKs when given an HFD, to assess whether pharmacological inhibition of MNK function also protects against diet-induced obesity (DIO) and its consequences and to probe the mechanisms underlying such protection. Male wild-type (WT) C57Bl6 mice or mice lacking both MNK1 and MNK2 (double knockout, DKO) were fed an HFD or control diet (CD) for up to 16 weeks. In a separate study, WT mice were also given an HFD for 6 weeks, after which half were treated with the recently-developed MNK inhibitor ETC-206 daily for 10 more weeks while continuing an HFD. Metabolites and other parameters were measured, and the expression of selected mRNAs and proteins was assessed. MNK-DKO mice were almost completely protected from HFD-induced obesity. Higher energy expenditure (EE) in MNK-DKO mice was observed, which probably reflects the changes in a number of genes or proteins linked to lipolysis, mitochondrial function/biogenesis, oxidative metabolism, and/or ATP consumption. The MNK inhibitor ETC-206 also prevented HFD-induced weight gain, confirming that the activity of the MNKs facilitates weight gain due to excessive caloric consumption. Disabling MNKs in mice, either genetically or pharmacologically, strongly prevents weight gain on a calorie-rich diet. This finding likely results from increased energy utilisation, involving greater ATP consumption, mitochondrial oxidative metabolism, and other processes. • Knockout of MNK1/MNK2 protects mice against diet-induced obesity. • MNK1/2 DKO mice have higher energy expenditure. • MNK1/2 DKO increases the expression of genes of lipid and mitochondrial metabolism. • Pharmacological inhibition of MNKs has similar effects. [ABSTRACT FROM AUTHOR]

The utilization of non-fullerene acceptors has greatly promoted the development of organic photovoltaics in past few years. Herein, two new non-fullerene small-molecule electron acceptors, CRIC and CRIC-4F, with a four-fused-rings containing chrysene core, are designed and synthesized. Benefiting from the rigid and planar chrysene segment, these two acceptors exhibit strong intramolecular π electron transition with intense optical absorption from 550 to 750 nm. Both molecules present deep lowest unoccupied molecular orbital (LUMO) energy levels at around −4.0 eV, thereby making them suitable to employ as electron acceptors. In combination with electron donor J52-2F, organic solar cells based on CRIC achieved a decent power conversion efficiency (PCE) of 6.12% with a low energy loss of 0.59 eV owning to their complementary absorption, higher energy levels, and reduced charge recombination, thus surpassing the J52-2F:CRIC-4F based counterpart (PCE = 5.61%). This work demonstrates that chrysene derivatives are potential acceptors for applications in organic photovoltaics with low energy losses. • Both of our newly synthesized acceptors, CRIC and CRIC-4F, demonstrate deep LUMO energy levels and broad absorption. • OSCs based on CRIC-4F presented a PCE of 5.61%, while CRIC-based devices achieved an improved PCE of 6.12%. • Devices based on J52-2F:CRIC exhibited a quite low total energy loss of 0.59 eV. [ABSTRACT FROM AUTHOR]

• Normal motion with hybrid mesh construction is proposed for three-dimensional coking simulation. • Competing effect between flow speed and temperature governs the pyrolysis of fuel. • Higher thermal risk and pressure drop are the penalties of coking. • Buoyancy effect is reflected and analyzed by Gr-based criterion. • The method is applicable in other deposition-involved fields. Coking is an inevitable phenomenon in regenerative cooling system of hypersonic vehicles using endothermic hydrocarbon fuels (EHF) as coolant, which affects cooling performance and even clogs cooling channels. This work proposes an upgraded dynamic mesh method, normal motion with O-type-based hybrid mesh construction, which successfully breaks 2D dimension barrier of normal elementary numerical method and realizes 3D simulation. The framework is tested in two circular tubes with different diameters (Tube A and Tube B) and one elliptical tube (Tube C) under supercritical pressure of 4 MPa. Under heavy deposition (the cross-sectional area reduces to 70 % of its initial), the circumferential and axial distribution of the deposit are simulated and its effect on flow, heat transfer, pyrolysis, and cooling capacity is discussed. Results indicate that the deposition elevates the maximum temperature and pressure drop, leading increased thermal risk and flow resistance. The acceleration effect from reduced cross-sectional area outweighs the thermal effect from deteriorated heat transfer, manifested as increased outlet temperature but decreased n -decane conversion and cooling capacity. The buoyancy effect is significant in Tube B, resulting in non-uniform circumferential distribution of coke deposit. It is proved that the dimensionless Gr q / Gr th with criterion of 1.0 can well explain the buoyancy effect quantitatively. The upgraded dynamic mesh method well achieves the coking effect evaluation in real 3D regenerative cooling, which also shows great potential to be applied to other field involving deposition phenomenon such as petroleum industry. [ABSTRACT FROM AUTHOR]

• Mechanical properties of partially recrystallized HEAs stay the same. • A new hetero-deformation between heterogeneous precipitate regions is identified. • Origins of the similar ductility and strength are discussed in details. • Discontinuous coarsening contributes to the formation of heterogeneous precipitates. Heterogeneous microstructure alloys provide a possibility for the combination of strength and ductility. As a typical heterogeneous microstructure, partially recrystallized microstructure is attractive because of the convenient processing route and great potential for industrial applications. However, the mechanical properties of this microstructure vary dramatically with different morphology factors, especially the recrystallization fraction, which restricts the processing window and the property consistency. In this study, we found that the yield strength (∼1.3 GPa) and ductility (∼20 %) of the partially recrystallized Ni 2 CoCrFeTi 0.24 Al 0.2 do not change when the recrystallization fraction increases from 21 % to 72 %. This novel phenomenon is attributed to an additional hetero-deformation induced (HDI) strain hardening effect produced by heterogeneous precipitates. With the increased recrystallization fraction, this additional HDI stress keeps the ductility unchanged by offsetting the decreased HDI stress arising from the hetero-deformation between recrystallized (RX) and non-recrystallized (NRX) areas. The unchanged yield strength comes from the increased strengthening effects of the lamellar precipitates and grain boundaries. We also confirmed that the discontinuous coarsening contributes to the formation of heterogeneous precipitates. These findings would open a new pathway for enhancing the consistency and processability of hetero-structured alloys and thus promote their broader industrial applications. [Display omitted] [ABSTRACT FROM AUTHOR]

• Hydrodynamics of pile-supported OWC breakwaters have been analytically modeled. • A local increase in back draft is adopted to improve performance. • Effects of chamber breadth and wall draft on hydrodynamic performance are studied. • Air compressibility on energy extraction and wave transmission are investigated. • A practical optimization strategy by setting PTO damping at two constants is tested. A pile-supported OWC breakwater is a novel marine structure in which an oscillating water column (OWC) is integrated into a pile-supported breakwater, with a dual function: generating carbon-free energy and providing shelter for port activities by limiting wave transmission. In this work we investigate the hydrodynamics of this novel structure by means of an analytical model based on linear wave theory and matched eigenfunction expansion method. A local increase in the back-wall draft is adopted as an effective strategy to enhance wave power extraction and reduce wave transmission. The effects of chamber breadth, wall draft and air chamber volume on the hydrodynamic performance are examined in detail. We find that optimizing power take-off (PTO) damping for maximum power leads to both satisfactory power extraction and wave transmission, whereas optimizing for minimum wave transmission penalizes power extraction excessively; the former is, therefore, preferable. An appropriate large enough air chamber volume can enhance the bandwidth of high extraction efficiency through the air compressibility effect, with minimum repercussions for wave transmission. Meanwhile, the air chamber volume is found to be not large enough for the air compressibility effect to be relevant at engineering scales. Finally, a two-level practical optimization strategy on PTO damping is adopted. We prove that this strategy yields similar wave power extraction and wave transmission as the ideal optimization approach. [ABSTRACT FROM AUTHOR]

Nucleolin (NCL) is a multifunctional protein that mainly localized in the nucleolus, it is also found in the nucleoplasm, cytoplasm and cell membrane. The three main structural domains allow the interaction of NCL with different proteins and RNA sequences. Moreover, specific post-translational modifications and its shuttling property also contribute to its multifunctionality. NCL has been demonstrated to be involved in a variety of aspects such as ribosome biogenesis, chromatin organization and stability, DNA and RNA metabolism, cytokinesis, cell proliferation, angiogenesis, apoptosis regulation, stress response and microRNA processing. NCL has been increasingly implicated in several pathological processes, especially in tumorigenesis and viral infection, which makes NCL a potential target for the development of anti-tumor and anti-viral strategies. In this review, we present an overview on the structure, localizations and various functions of NCL, and further describe how the multiple functions of NCL are correlated to its multiple cellular distributions. [ABSTRACT FROM AUTHOR]

• The coking process considering secondary cracking of n -decane is simulated. • The coking layer formation is directly simulated via dynamic mesh techniques. • Coking renders increased thermal risk, reduced cooling capacity and increased pressure drop. • The maximum conversion rate of n -decane is unaffected by the coking process. Carbon deposition is an inevitable phenomenon in regenerative cooling systems using endothermic hydrocarbon fuels (EHFs), which seriously affects heat transfer performance and even clogs cooling channels. In this study, a framework of 2D dynamic coking study is established by coupling simultaneously a detailed pyrolysis model with the MC-II coking model. Two types of coke, i.e. , catalytic coke and pyrolytic coke, are considered, and the coking process is simulated via dynamic mesh techniques. The flow and heat transfer characteristics, and heat sink before and after the carbon deposition under typical working conditions are compared and discussed in detail. The results reveal that the secondary cracking reactions promote the concentration of the coking precursors, and the coking simulation results agree well with the experiment. The maximum fluid flow velocity and maximum solid temperature are increased after the coking formation due to the reduction of the cross section area and the poor thermal conductivity of the deposited coke. As the coke deposits, the total heat sink per temperature rise and pressure drop both deteriorate. However, the maximum conversion of n -decane is almost unchanged, which can be well explained by the local DamkÖhler (Da) number. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to analyze the incidence of proximal avulsion of the five main ligaments and to revise the diagonal tension/compression concept in tibial plateau fractures.Methods: Computed tomographic images of 1263 cases of tibial plateau fractures were retrospectively analyzed by the OTA/AO classification and four-column nine-segment classification. The correlation between proximal avulsion of five ligaments and the injury mechanism was analyzed.Results: In total, 1263 tibial plateau fractures in 1253 patients were included. A total of 92 cases (7.3%) associated with proximal avulsions were identified among the 1263 tibial plateau fracture cases obtained from our institution's database. The 92 avulsions occurred in 82 patients, among whom 10 patients had two different avulsions in a single knee. The incidence of proximal avulsion fracture of the medial and lateral collateral ligament was 3.6% (45/1263) and 2.1% (26/1263), respectively. The incidence of avulsion of the anterior cruciate ligament and avulsion of the posterior cruciate ligament was much lower at 0.2% (2/1263) and 0.1% (1/1263), respectively. Proximal avulsion of the patellar ligament occurred in 18 cases (incidence rate = 1.4%). Several combinations of injuries, composed of distal tibial plateau fractures and proximal avulsion of ligaments, were identified.Conclusions: Among the patients with tibial plateau fracture, the incidence of proximal avulsion of the five ligaments was 7.3% (92/1263). The four-column and nine-segment classification is an exhaustive method for recording injuries in these ligaments. The revised diagonal injury concept is useful for understanding the injury mechanism and choosing the appropriate surgical strategy. [ABSTRACT FROM AUTHOR]

Central hypothyroidism (CH) is characterized by low T 4 levels and reduced levels or bioactivity of circulating TSH. However, there is a lack of studies on CH-related intestinal maldevelopment. In particular, the roles of TH and TSH/TSHR signaling in CH-related intestinal maldevelopment are poorly understood. Herein, we utilized Tshr −/− mice as a congenital hypothyroidism model with TH deprival and absence of TSHR signaling. The morphological characteristics of intestines were determined by HE staining, periodic acid–shiff staining, and immunohistochemical staining. T 4 was administrated into the offspring of homozygous mice from the fourth postnatal day through weaning or administrated after weaning. RT-PCR was used to evaluate the expression of markers of goblet cells and intestinal digestive enzymes. Single-cell RNA-sequencing analysis was used to explore the cell types and gene profiles of metabolic alternations in early-T 4 -injected Tshr −/− mice. Tshr deletion caused significant growth retardation and intestinal maldevelopment, manifested as smaller and more slender small intestines due to reduced numbers of stem cells and differentiated epithelial cells. Thyroxin supplementation from the fourth postnatal day, but not from weaning, significantly rescued the abnormal intestinal structure and restored the decreased number of proliferating intestinal cells in crypts of Tshr −/− mice. Tshr −/− mice with early-life T 4 injections had more early goblet cells and impaired metabolism compared to Tshr +/+ mice. TH deprival leads to major defects of CH-associated intestinal dysplasia while TSH/TSHR signaling deficiency promotes the differentiation of goblet cells and impairs nutrition metabolism. • TH deprival and TSH/TSHR signaling deficiency lead to CH-associated intestinal maldevelopment. • TSH/TSHR signaling deficiency leads to impaired nutrient metabolism. • Early-life thyroxin supplementation has better improvement on CH-associated intestinal dysplasia. [ABSTRACT FROM AUTHOR]

Abstract The mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate eukaryotic initiation factor 4E (eIF4E) and play important roles in promoting tumorigenesis and metabolic disease. Thus, inhibiting these enzymes might be valuable in the treatment of such conditions. We designed and synthesized a series of 4-((4-fluoro-2-isopropoxyphenyl)amino)-5-methylthieno[2,3- d ]pyrimidine derivatives, and evaluated their inhibitory activity against the MNKs. We found 15 compounds that were active as MNK inhibitors and that one in particular, designated MNK-7g , which was potent against MNK1 and substantially more potent against MNK2. The compound MNK-7g did not affect other signaling pathways tested and had no adverse effects on cell viability. As expected from earlier studies, MNK-7g also inhibited cell migration. Therefore, the compound MNK-7g , which forms an ionic bond with Asp226 in MNK2 and possesses a substituted aniline in a thieno[2,3-d] pyrimidine structure, is a promising starting point for the future development of novel drugs for treating or managing cancer and metabolic disease. Graphical abstract Image 1 Highlights • The MNK protein kinases (MNK1/2) play roles in cancer and metabolic disease. • From a set of 28 thienopyrimidines, 15 MNK inhibitors were identified. • One compound in particular, termed 7g, shows selectivity for MNK2 compared to MNK1. • Molecular docking revealed two H-bonds that are important for binding to MNKs. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The expression of miR-217 was clearly decreased in steroid-associated osteonecrosis. • DKK1 is negatively regulated by miR-217 in BMSCs. • MiR-217 promotes cell proliferation and osteogenic differentiation by targeting DKK1. • Negative modulation of DKK1 by miR-217 results in nuclear translocation of β-catenin. Abstract MicroRNAs (miRNAs) have recently been recognized to play an important role in bone-associated diseases. This study aims to explore the expression profile and biological function of miR-217, which is known to be related to tumor cell proliferation and migration, to the proliferation and osteogenic differentiation of MSCs from the patients with steroid-associated osteonecrosis (ONFH). Bone marrow was obtained from the proximal femur of 10 patients with ONFH and 10 patients with femoral neck fractures. Bone marrow-derived mesenchymal stem cells (MSCs) were isolated and cultured. The expression profile, biological function of miR-217 and the interaction between miR-217 and DKK1 were assayed using cell viability measurement, western blot, Real-time PCR, luciferase reporter assay, Alizarin Red S (ARS) staining. We noted that the expression level of miR-217 was significantly decreased in the ONFH samples compared to the control samples (P < 0.0001). By targeting DKK1, miR-217 promoted nuclear translocation of β-catenin, increased expression of RUNX2, COL1A1 and obviously promoted the proliferation and differentiation of MSCs. Restoring the expression of DKK1 in the MSCs partially reversed the role of miR-217. These findings suggest that miR-217 promotes cell proliferation and osteogenic differentiation by inhibiting DKK1 during the development of steroid-associated osteonecrosis. [ABSTRACT FROM AUTHOR]

Abstract Man-made mineral fibres (MMMFs) such as glass wool (GW), rock wool (RW) and refractory ceramic fibres (RCFs) are widely used as substitutes of asbestos. The present study aimed to investigate the cytotoxic effects on human bronchial epithelial cells (BEAS-2B) exposed to GW1, RW1 and RCF2, considering their properties similar to that of asbestos. We assessed cell viability; cell morphological changes; apoptotic rate; DNA damage; reactive oxygen species (ROS) generation; activities of caspase-3, caspase-8 and caspase-9; and expression levels of FasL, phosphorylated p38, and total p38 MAPK proteins. N -acetyl- l -cysteine (NAC) was used as an ROS scavenger. We observed that MMMFs, especially RCF2, evidently changed cellular morphology, promoted DNA damage, and induced apoptosis. In addition, the cytotoxicities of MMMFs were dependent on ROS generation, and NAC could decrease their toxicity. Furthermore, our results showed that apoptosis induced by MMMFs was mediated by the mitochondrial apoptotic pathway and Fas death receptor pathway. Moreover, the p38 MAPK signalling pathway was also involved in the cytotoxicities of MMMFs. NAC exerts a protective effect against apoptosis and DNA damage induced by GW1, RW1 and RCF2. This study provides important implications for understanding the potential toxic effects of GW1, RW1 and RCF2 exposure; it also indicates that NAC may prevent respiratory diseases induced by exposure to MMMFs. Highlights • MMMFs evidently changed cell morphology, promoted DNA damage, and induced apoptosis, especially for RCF2. • MMMFs induced cytotoxicity of BEAS-2B and NAC has the protective effect. • The mitochondrial apoptotic pathway and Fas death receptor pathway involved in apoptosis induced by MMMFs. • p38 MAPK signal pathway was also involved in the cytotoxicities of MMMFs. [ABSTRACT FROM AUTHOR]

Obesity is a potentially modifiable factor for reducing readmissions, with heterogeneity that varies according to the metabolic status. Our objective was to examine the independent or mutual relationship between obesity and metabolic abnormalities and diabetic kidney disease (DKD)-related hospitalizations. 493,570 subjects with DKD were enrolled in the 2018 Nationwide Readmission Database (NRD, United States). The at-risk population was reclassified into refined obesity subtypes based on the body mass index (BMI) classification of metabolic abnormalities (hypertension and/or dyslipidemia) to investigate the 180 d readmission risk and hospitalization costs related to DKD. The overall readmission rate was 34.1%. Patients with metabolic abnormalities, regardless of obesity, had a significantly higher risk of readmission compared to non-obese counterparts (adjusted HR, 1.11 [95% CI, 1.07–1.14]; 1.12 [95% CI, 1.08–1.15]). Hypertension appeared to be the only metabolic factor associated with readmission among individuals with DKD. Obesity without metabolic abnormalities was independently associated with readmission (adjusted HR,1.08 [1.01,1.14]), especially among males and those >65 years (adjusted HR,1.10 [1.01–1.21]; 1.20 [1.10–1.31]). Women or those ≤65 years with metabolic abnormalities (all p <0.050) had elevated readmission rates, regardless of obesity; however, no such trend was observed in obese subjects without metabolic abnormalities (adjusted HR, 1.06 [0.98,1.16]). Additionally, obesity and metabolic abnormalities were associated with elevated hospitalization costs (all p <0.0001). Increased BMI and hypertension are positively associated with readmissions and related costs among patients with DKD, which should be considered in future studies. [ABSTRACT FROM AUTHOR]

Aims: To determine the epidemiological characteristics of lower extremity arterial disease (LEAD) in high-risk patients and identify practical gaps in LEAD management.Methods: This cross-sectional study consecutively enrolled 10681 patients with type 2 diabetes from 30 hospitals across China from June 2016 to January 2017. All patients were assessed for LEAD by the Ankle-Brachial Index in conjunction with lower limb ultrasonography according to local guidelines.Results: The mean age of patients was 64.2 years, and the median duration of diabetes was 9.0 years. The overall prevalence of LEAD was 21.2%, with 10.6% of patients diagnosed with LEAD before enrollment and 11.8% newly diagnosed at the present visit. Patients with older age, hypertension and dyslipidemia as well as those who smoked were at higher risk of developing LEAD. Only 55.0%, 28.2%, and 42.5% of participating patients reached the guideline-recommended goals for glycemic, blood pressure, and lipid control, respectively. Anti-hypertensive agents, lipid lowering therapies, anti-platelet agents, and vasodilators were underused, especially in newly diagnosed LEAD patients (44.1%, 46.2%, 35.3%, and 31.7%, respectively).Conclusions: Despite the high prevalence of LEAD, it was still found to be underdiagnosed and undertreated in Chinese diabetes patients. More efforts should be directed at encouraging awareness of early LEAD and achieving guideline-recommended goals in type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis. [ABSTRACT FROM AUTHOR]

Aim To gain more precise understanding of the epidemiology of comorbidities with diabetes and to clarify the correlation with coronary heart disease (CHD) in Chinese population. Methods Based on REACTION study, 18,696 participants aged over 40 years were included in the cross-sectional analysis. Prevalence and patterns of comorbid diseases were demonstrated, and their impact on CHD was also analyzed by logistic regression. Results Diabetes was more prevalent in patients with older age and lower education level, with relatively low awareness (36.3%), treatment (27.9%) and control (34.7%) rate. The proportion of diabetics with additional condition was 88.8%; 53.2% had more than two comorbidities. Compared with patients with comorbidities, diabetics only had the highest controlled HbA1c rate (37.9%). Dyslipidemia (71.97%) was the most common comorbidity, followed by hypertension (58.19%), and hypothyroidism (21.24%). A strong gradient existed between the number of comorbidities and CHD versus “diabetes only” group; the odds ratio was 1.38, 2.48 and 3.01 for diabetics with one, two and three additional diseases, respectively. Conclusions Low glycemic control and high prevalence of diabetes comorbidities are common in China, which increases the risk of CHD. Full-scale and individualized guidelines for diabetics should be planned. [ABSTRACT FROM AUTHOR]

Background & Aims Hallmarks of non-alcoholic fatty liver disease (NAFLD) are increased triglyceride accumulation within hepatocytes. The prevalence of NAFLD increases steadily with increasing thyrotropin (TSH) levels. However, the underlying mechanisms are largely unknown. Here, we focused on exploring the effect and mechanism of TSH on the hepatic triglyceride content. Methods As the function of TSH is mediated through the TSH receptor (TSHR), Tshr −/− mice (supplemented with thyroxine) were used. Liver steatosis and triglyceride content were analysed in Tshr −/− and Tshr +/+ mice fed a high-fat or normal chow diet, as well as in Srebp-1c −/− and Tshr −/− Srebp-1c −/− mice. The expression levels of proteins and genes involved in liver triglyceride metabolism was measured. Results Compared with control littermates, the high-fat diet induced a relatively low degree of liver steatosis in Tshr −/− mice. Even under chow diet, hepatic triglyceride content was decreased in Tshr −/− mice. TSH caused concentration- and time-dependent effects on intracellular triglyceride contents in hepatocytes in vitro . The activity of SREBP-1c, a key regulator involved in triglyceride metabolism and in the pathogenesis of NAFLD, was significantly lower in Tshr −/− mice. In Tshr −/− Srebp-1c −/− mice, the liver triglyceride content showed no significant difference compared with Tshr +/+ Srebp-1c −/− mice. When mice were injected with forskolin (cAMP activator), H89 (inhibitor of PKA) or AICAR (AMPK activator), or HeG2 cells received MK886 (PPARα inhibitor), triglyceride contents presented in a manner dependent on SREBP-1c activity. The mechanism, underlying TSH-induced liver triglyceride accumulation, involved that TSH, through its receptor TSHR, triggered hepatic SREBP-1c activity via the cAMP/PKA/PPARα pathway associated with decreased AMPK, which further increased the expression of genes associated with lipogenesis. Conclusions TSH increased the hepatic triglyceride content, indicating an essential role for TSH in the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]

Understanding the mechanism by which alpha-lipoic acid supplementation has a protective effect upon nonalcoholic fatty liver disease in vivo and in vitro may lead to targets for preventing hepatic steatosis. Male C57BL/6J mice were fed a normal diet, high-fat diet or high-fat diet supplemented with alpha-lipoic acid for 24 weeks. HepG2 cells were incubated with normal medium, palmitate or alpha-lipoic acid. The lipid-lowering effects were measured. The protein expression and distribution were analyzed by Western blot, immunoprecipitation and immunofluorescence, respectively. We found that alpha-lipoic acid enhanced sirtuin 1 deacetylase activity through liver kinase B1 and stimulated AMP-activated protein kinase. By activating the sirtuin 1/liver kinase B1/AMP-activated protein kinase pathway, the translocation of sterol regulatory element-binding protein-1 into the nucleus and forkhead box O1 into the cytoplasm was prevented. Alpha-lipoic acid increased adipose triacylglycerol lipase expression and decreased fatty acid synthase abundance. In in vivo and in vitro studies, alpha-lipoic acid also increased nuclear NF-E2-related factor 2 levels and downstream target amounts via the sirtuin 1 pathway. Alpha-lipoic acid eventually reduced intrahepatic and serum triglyceride content. The protective effects of alpha-lipoic acid on hepatic steatosis appear to be associated with the transcription factors sterol regulatory element-binding protein-1, forkhead box O1 and NF-E2-related factor 2. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Obesity and insulin resistance are risk factors for cardiovascular diseases. Whether insulin-sensitive obese individuals are at higher risk for cardiovascular diseases is still debated. We aim to investigate whether insulin-sensitive obesity associates with prevalent cardiovascular diseases and 10-year coronary heart disease (CHD) risk. Research design and methods: At the baseline of the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study, 211,641 participants aged 40years or older were recruited from 25 communities across the China mainland, in 2011 to 2012. Participants were categorized by insulin-sensitive/resistant and general/abdominal obese status. Cardiovascular diseases included CHD, stroke, and myocardial infarction. Framingham risk score (FRS) was calculated according to National Cholesterol Education Program-Adult Treatment Panel III and FRS greater than 20% or cardiovascular diseases were identified as high risk for 10-year CHD. Results: Controlling for potential confounders, compared with insulin-sensitive normal weight individuals, insulin-sensitive general obese individuals had increased risks for prevalent cardiovascular diseases (men: OR, 2.55, 95% CI, 2.04–3.18; women: 1.73, 1.45–2.06) and 10-year Framingham risk for CHD (men: 2.26, 1.86–2.76; women: 1.73, 1.46–2.06). Compared with insulin-sensitive normal waist subgroup, insulin-sensitive abdominal obesity was associated with higher risks for prevalent cardiovascular diseases (men: 1.32, 1.20–1.46; women: 1.36, 1.27–1.47) and 10-year Framingham risk for CHD (men, 1.34, 1.23–1.45; women, 1.37, 1.27–1.47). Conclusion: Both general and abdominal obesity were associated with elevated prevalent cardiovascular diseases and 10-year CHD risk, regardless of the presence or absence of insulin resistance. [Copyright &y& Elsevier]

Abstract: High-fat feeding is associated with a compromised myocardial energy metabolism, and the underlying mechanism has not been elucidated. In the present study, we tested different diets (high-fat and low-carbohydrate diet or normal control diet) on animal models. The high-fat and low-carbohydrate diet (experimental diet) consisted of 59% fat from lard, 24% carbohydrate, and 17% protein (5.95kcal/g total), whereas the normal control diet contained 10% fat, 70% carbohydrate, and 20% protein (4.24kcal/g total). After 22 weeks of feeding, in vivo cardiac function was monitored by echocardiography. Then, we examined the expression of AMPKα, the AMPK upstream kinase LKB1, and the potential AMPK targets, transcriptional coactivator PPARγ coactivator-1α (PGC-1α) and phosphofructokinase 2 (PFK-2), in cardiac muscle. We found that feeding rats an experimental diet induced cardiac contractile dysfunction, which was accompanied by reductions in the gene transcription, the protein level, and the activity of AMPKα. Similarly, the LKB1 phosphorylation, PGC-1α protein expression, and phosphorylation of PFK-2 were reduced in experimental diet-fed rats. However, there was no difference in the total LKB1 protein content between the hearts of rats fed the experimental and control diets. In conclusion, consumption of the experimental diet might result in cardiac dysfunction that is accompanied by abnormalities in the expression and activation of the AMPK pathway in cardiac muscle. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Kang-Jia-Wan (KJW), a traditional Chinese herbal medicine, is widely used to treat goiter in the clinics in China. Aim: The mechanisms by which KJW treats goiter are unclear. It is known that insufficient apoptosis of thyrocytes is involved in the formation of goiter. Here, we investigated whether KJW could induce apoptosis in goiter of rats given methimazole (MMI). Materials and methods: Fifty-six Wistar rats were randomly separated into four groups: normal, MMI, MMI+low-dose KJW and MMI+high-dose KJW. Except for the normal group (20 rats), all groups (each with 12 rats) were given 0.04% (w/v) MMI in their drinking water. One week later, the rats in MMI+low- and high-dose KJW groups were orally supplemented with KJW at 250mg/kgd−1 and 1000mg/kgd−1, respectively. Results: After KJW treatment for 12 weeks, the relative thyroid weight (mg/100g body weight) of the MMI+high-dose KJW group decreased significantly. Features of apoptosis were also apparent in thyroid tissues of rats given KJW treatment. Importantly, KJW markedly increased the caspase-3 and Fas protein expression, in a dose-dependent manner, in the thyroid specimens. Conclusions: These results showed that KJW played a therapeutic role via apoptosis induction in the goitrous glands. [Copyright &y& Elsevier]

Abstract: The objective of this study was to investigate the effect of chronic ethanol intake on the expression of insulin receptor β subunit (IR-β), insulin receptor substrate-1 (IRS-1), and glucose transporter 4 (Glut4) in rat cardiac muscle. Forty-eight male Wistar rats were randomly classified into four groups and to each group, ethanol was administered daily at the respective doses of 0 (control, C), 0.5gkg−1 (low ethanol, L), 2.5gkg−1 (middle ethanol, M), and 5gkg−1 (high ethanol, H). Twenty-two weeks later, the rats were anesthetized, and the left ventricle muscles were excised. The IR-β, IRS-1, and Glut4 mRNA levels in the cardiac muscle tissues were detected by reverse-transcription polymerase chain reaction (RT-PCR); The IR-β, tyrosine phosphorylation of IR-β (PY-IR-β), IRS-1, tyrosine phosphorylation of IRS-1 (PY-IRS-1), and Glut4 protein levels were measured by Western blotting. Compared to the control group, the IR-β, IRS-1, and Glut4 mRNA levels in groups H and M decreased remarkably. In addition, the protein levels of IR-β, IRS-1, and Glut4 showed a corresponding decline in ethanol-treated groups, especially in group H. Moreover, the PY-IR-β and PY-IRS-1 protein levels decreased in the hearts of ethanol-treated rats with corresponding changes in the IR-β and IRS-1 protein levels. The present study showed that chronic ethanol intake could downregulate the expression levels of IR-β, IRS-1, and Glut4 in rat cardiac muscles. [Copyright &y& Elsevier]

• Novel variants of SLC25A26 caused COXPD28. • Genotype-phenotype correlation of COXPD28. Summary of SLC25A26 variants. Combined oxidative phosphorylation deficiency 28 (COXPD28) is associated with mitochondrial dysfunction caused by mutations in SLC25A26 , the gene which encodes the mitochondrial S-adenosylmethionine carrier (SAMC) that responsible for the transport of S-adenosylmethionine (SAM) into the mitochondria. To identify and characterize pathogenic variants of SLC25A26 in a Chinese pedigree, provide a basis for clinical diagnosis and genetic counseling. We conducted a systematic analysis of the clinical characteristics of a female with COXPD28. Whole-exome and mitochondrial genome sequencing was applied for the genetic analysis, together with bioinformatic analysis of predicted consequences of the identified variant. A homotrimer model was built to visualize the affected region and predict possible outcomes of this mutation. Then a literature review was performed by online searching all cases reported with COXPD28. The novel compound heterozygous SLC25A26 variants (c.34G > C, p.A12P; c.197C > A; p.A66E) were identified in a Chinese patient with COXPD28. These two variants are located in the transmembrane region 1 and transmembrane region 2, respectively. As a member of the mitochondrial carrier family, the transmembrane region of SAMC is highly conserved. The variants were predicted to be pathogenic by in silico analysis and lead to a change in the protein structure of SAMC. And the change of the SAMC structure may lead to insufficient methylation and cause disease by affecting the SAM transport. The variants in this region probably resulted in a variable loss of mitochondrial SAMC transport function and cause the COXPD28. This study that further refine genotype-phenotype associations can provide disease prognosis with a basis and families with reproductive planning options. [ABSTRACT FROM AUTHOR]

Abstract: Aims: An inflammatory reaction is commonly found in the pathogenesis of diabetic nephropathy (DN). Cilostazol, a type 3 phosphodiesterase (PDE) inhibitor, has been previously reported to be anti-inflammatory, independent of an anti-platelet property. In the present study, we evaluated the hypothesis that cilostazol has protective effects on diabetic nephropathy by modulating the inflammatory process. Main methods: Cilostazol was administered (27 or 9 mg kg−1 d−1) to streptozotocin (STZ)-induced diabetic rats for eight weeks. We studied the kidney expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 by immunofluorescence, western blotting and real-time PCR. The renal monocyte chemoattractant protein (MCP)-1 and vascular endothelial growth factor (VEGF) levels were examined by ELISA. The nuclear factor (NF)-κB-DNA binding activity was assessed by electrophoresis mobility shift assay (EMSA). Key findings: Our results showed cilostazol inhibited diabetes-induced hypertrophy of the glomeruli and infiltration of inflammatory cells, as well as the increase in the VCAM-1 and ICAM-1 mRNA and protein expression, and MCP-1 and VEGF contents in the kidneys. Consistent with these findings, cilostazol attenuated the enhanced activation of NF-κB in diabetic rats. Significance: These results demonstrate that the renoprotective effects of cilostazol may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation and the subsequent decrease in proinflammatory factors, such as VCAM-1, ICAM-1, MCP-1 and VEGF expression in kidneys of diabetic rats. [Copyright &y& Elsevier]

• The scale behaviors of three indicators were examined in delineating expansion dynamics. • These indicators are the quantitative OUER metric and their variates GUER and BUER. • OUER and GUER yield polynomial scaling relations in delineating expansion dynamics. • BUER does not comply with any known functions in terms of the scaling relations. • 1800–2700 m was identified as the optimal scale range of urban expansion analysis. The delineation of spatiotemporal urban expansion highly depends on the selection of moving window size. Few studies examine the effects of moving window size and the scaling mechanism when analyzing urban expansion patterns. This study selected nine moving windows from 450 m to 4050 m with a scale (size) interval of 450 m to examine the urban expansion dynamics of Shanghai from 1995 to 2005, and from 2005 to 2015. Three urban expansion rate indicators were selected to explore the scale dependence of urban expansion, and these indicators include the overall urban expansion rate (OUER), the gridded urban expansion rate (GUER), and the boxed urban expansion rate (BUER). In addition, Global Moran's I was used to measure the spatial autocorrelation of urban expansion on different scales. The results show that the changing moving window size has varying impacts on delineating urban dynamics when using these three indicators. Specifically, OUER and GUER yield polynomial relationships with the moving window size, while BUER does not comply with any known functions in terms of the scaling relations. All three indicators reach their extreme points and/or inflection points at sizes of 1800 m, 2250 m and 2700 m, and the optimal size is speculated in the range of 1800–2700 m. This study should help to choose appropriate moving window sizes and suitable urban expansion indicators to more accurately capture the spatial differences in urban expansion dynamics and assist land-use planning. [ABSTRACT FROM AUTHOR]