Self-Assembly of Cluster-Mediated 3D Catenanes with Size-Specific Recognition Behavior.

Although interlocked three-dimensional molecules display unique properties associated with their spatial structures, their synthesis and study of their host-guest properties remain challenging. We report the formation of a novel [2]catenane, [Et4N]@[(Tp*WS3Cu3Cl)2(cis-bpype)3]2(OTf)5 ([Et4N][1](OTf)5), by self-assembly of the cluster node [Tp*WS3Cu3Cl]+ and the organic linker (Z)-1,2-diphenyl-1,2-bis(4-(pyridin-4-yl)phenyl)ethene (cis-bpype). Single-crystal X-ray and NMR analyses established that [1]4+ is formed by the interpenetration of two cluster-organic cages. Unique cation-in-cation host-guest complexes were observed with this catenane. The crystalline, empty catenane was formed by taking advantage of the electrostatic repulsion-induced weak binding of the host. Encapsulation experiments also reveal that the empty catenane can adaptively encapsulate cations such as [Et4N]+ and [Pr4N]+ in the cross cavity but is unable to encapsulate [Bu4N]+ and [Me4N]+, although the size of the latter is compatible with that of the cavity. Theoretical calculations and volume analysis allow to unravel the ingenious role of catenane structures and the interplay between electrostatic repulsion and attractive noncovalent interactions for size-specific recognition behavior in host-guest systems involving species with similar electric charges.

No evidence of supracrustal recycling in Si-O isotopes of Earth's oldest rocks 4 Ga ago.

Identifying the oldest evidence for the recycling of hydrated crust into magma on Earth is important because it is most effectively achieved by subduction. However, given the sparse geological record of early Earth, the timing of first supracrustal recycling is controversial. Silicon and oxygen isotopes have been used as indicators of crustal evolution on Archean igneous rocks and minerals to trace supracrustal recycling but with variable results. We present Si-O isotopes of Earth's oldest rocks [4.0 billion years ago (Ga)] from the Acasta Gneiss Complex, northwest Canada, obtained using multiple techniques applied to zircon, quartz, and whole rock samples. Undisturbed zircon is considered the most reliable recorder of primary Si signatures. By combining reliable Si isotope data from the Acasta samples with filtered data from Archean rocks globally, we observe that widespread evidence for a heavy Si signature is recorded since 3.8 Ga, marking the earliest record of surface silicon recycling.

Post-Marketing Safety Concerns with Upadacitinib: A Disproportionality Analysis of the FDA Adverse Event Reporting system.

BACKGROUND: Upadacitinib was approved to treat rheumatoid arthritis, psoriasis, ulcerative colitis, ankylosing spondylitis, and atopic dermatitis. This study assessed the adverse events (AEs) associated with upadacitinib by mining data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of upadacitinib-associated AEs. RESULTS: A total of 3,837,420 reports of AEs were collected from the FAERS database, of which 4494 reports were identified with upadacitinib as the "primary suspect (PS)". Upadacitinib-induced AEs occurrence targeted 27 system organ clases (SOCs). A total of 200 significant disproportionality PTs conforming to the four algorithms were simultaneously retained. Unexpected significant AEs, such as arthralgia, musculoskeletal stiffness, diverticulitis, and cataract might also occur. The median onset time of upadacitinib-associated AEs was 65 days (interquartile range [IQR] 21-182 days), and most of the onsets occurred within the first 1, 2, 3, and 4 months after initiation of upadacitinib. CONCLUSION: This study found potential new AEs signals and might provide important support for clinical monitoring and risk identification of upadacitinib.

Construction of cluster-based supramolecular wire and rectangle.

Reactions of [Et4N][Tp*WS3(CuCl)3] (1) (Tp* = hydridotris(3,5-dimethylpyrazol-1-yl)borate) with 2 equiv. of AgOTf (OTf- = trifluoromethanesulfonate) and 1 equiv. of several bidentate pyridine ligands including 2,5-bis(pyridine-4-yl)thiazolo[5,4-d]thiazole (L1), 2,7-di(pyridin-4-yl)-9H-fluorene (L2), 2,7-di(pyridin-4-yl)-9H-carbazole (L3), and 2,7-di(pyridin-4-yl)-9H-fluoren-9-one (L4) afforded four W/Cu/S cluster-based supramolecular compounds [(Tp*WS3Cu2Cl)2(L1)] (2), {[(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]2(L2)2}(OTf)2 (3), {[(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]2(L3)2}(OTf)2 (4) and {[(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]2(L4)2}(OTf)2 (5). Compounds 2-5 were characterized by elemental analysis, IR, UV-vis, 1H NMR, and single-crystal X-ray diffraction analysis. The neutral cluster 2 behaves as a supramolecular wire constructed by L1 bridging two butterfly-shaped [Tp*WS3Cu2Cl] cores. The cluster cations of 3-5 contain two [(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]+ cores linked by two L2, L3, or L4 ligands, which finally formed a cationic supramolecular rectangle. The third-order nonlinear-optical (NLO) properties of 3-5 in DMF were also investigated by Z-scan techniques and their NLO responses were enhanced compared to those of their precursor 1.

Copper migration and isotope fractionation in a typical paddy soil profile of the Yangtze Delta.

To decipher Cu migration in paddy soils, which is important for understanding Cu supply in rice cultivation, Cu concentrations and isotope compositions were measured in a paddy soil profile in Suzhou, Eastern China, in the central Yangtze Delta. The results show that the variations in δ65Cu values and Cu concentrations are not coupled along the profile. From top to bottom, the δ65Cu values show small variations (0.07 ± 0.03‰ to 0.25 ± 0.01‰) in the upper layers (Ap-Br1), with a decrease in the subsurface Br2 layer (from 0.16 ± 0.04‰ to -0.19 ± 0.02‰), are almost homogeneous in the transitional Br3-BCrg layers (-0.01 ± 0.01‰ to -0.10 ± 0.02‰), and further decrease to -0.33 ± 0.01‰ in the permanently submerged G1 and G2 layers. Copper concentrations in the Ap layer show some fluctuations (25.8 to 29.0 µg/g), increase in the Br2 and Br3 layers (23.9 µg/g to 31.9 µg/g), and then decrease to 15.1 µg/g in the lower layers. The lack of coupling between δ65Cu values and Cu concentrations may be ascribed to various physicochemical conditions in different layers. In the upper layers, Cu(I) enriched in light isotopes migrates downward with soil solutions under flooded conditions, leaving the soils of the Ap and Br1 layers enriched in heavy Cu isotopes. In the Br2 layer, the readsorption of light Cu isotopes on clay minerals results in decreased δ65Cu values and increased Cu concentrations. In the Br3-BCrg layers, Cu(I) can be oxidized to Cu(II). The homogeneous Cu isotopes in these layers may mainly result from equilibrium adsorption of Cu on clay minerals. The decreased δ65Cu values and Cu concentrations in the G layer are mainly attributed to groundwater transport in this layer. This study represents the Cu isotope variations in a paddy soil profile and the possible mechanism of Cu isotope fractionation.

The expression of mimecan in adrenal tissue plays a role in an organism's responses to stress.

Mimecan encodes a secretory protein that is secreted into the human serum as two mature proteins with molecular masses of 25 and 12 kDa. We found 12-kDa mimecan to be a novel satiety hormone mediated by the upregulation of the expression of interleukin (IL)-1ß and IL-6 in the hypothalamus. Mimecan was found to be expressed in human pituitary corticotroph cells and was up-regulated by glucocorticoids, while the secretion of adrenocorticotropic hormone (ACTH) in pituitary corticotroph AtT-20 cells was induced by mimecan. However, the effects of mimecan in adrenal tissue on the hypothalamic-pituitary-adrenal (HPA) axis functions remain unknown. We demonstrated that the expression of mimecan in adrenal tissues is significantly downregulated by hypoglycemia and scalded stress. It was down-regulated by ACTH, but upregulated by glucocorticoids through in vivo and in vitro studies. We further found that 12-kDa mimecan fused protein increased the corticosterone secretion of adrenal cells in vivo and in vitro. Interestingly, compared to litter-mate mice, the diurnal rhythm of corticosterone secretion was disrupted under basal conditions, and the response to restraint stress was stronger in mimecan knockout mice. These findings suggest that mimecan stimulates corticosterone secretion in the adrenal tissues under basal conditions; however, the down-regulated expression of mimecan by increased ACTH secretion after stress in adrenal tissues might play a role in maintaining the homeostasis of an organism's responses to stress.

Cadmium Isotopic Fractionation in the Soil-Plant System during Repeated Phytoextraction with a Cadmium Hyperaccumulating Plant Species.

Analysis of stable metal isotopes can provide important information on biogeochemical processes in the soil-plant system. Here, we conducted a repeated phytoextraction experiment using the cadmium (Cd) hyperaccumulator Sedum plumbizincicola X. H. Guo et S. B. Zhou ex L. H. Wu (Crassulaceae) in four different Cd-contaminated agricultural soils over five consecutive crops. Isotope composition of Cd was determined in the four soils before and after the fifth crop, in the plant shoots harvested in all soils in the first crop, and in the NH4OAc extracts of two contrasting soils with large differences in soil pH (5.73 and 7.32) and clay content (20.4 and 31.3%) before and after repeated phytoextraction. Before phytoextraction NH4OAc-extractable Cd showed a slight but significant negative isotope fractionation or no fractionation compared with total Cd (Δ114/110Cdextract-soil = -0.15 ± 0.05 (mean ± standard error) and 0.01 ± 0.01‰), and the extent of fractionation varied with soil pH and clay content. S. plumbizincicola preferentially took up heavy Cd from soils (Δ114/110Cdshoot-soil = 0.02-0.14‰), and heavy isotopes were significantly depleted in two soils after repeated phytoextraction (Δ114/110Cdsoil:P5-soil:P0 = -0.15 ± 0.02 and -0.12 ± 0.01‰). This provides evidence for the existence of specific Cd transporters in S. plumbizincicola, leading to positive isotope fractionation during uptake. After phytoextraction by five sequential crops, the NH4OAc-extractable Cd pool was significantly enriched in heavy isotopes (Δ114/110Cdextract:P5-extract:P0 = 0.07 ± 0.02 and 0.18 ± 0.05‰) despite the preferential uptake of heavy isotopes, indicating the occurrence of root-induced Cd mobilization in soils, which is supposed to favor heavy Cd in the organo-complexes with root exudates. Our results demonstrate that Cd is taken up by S. plumbizincicola via specific transporters, partly after active mobilization from the more strongly bound soil pool such as iron/manganese (hydr)oxide-bound Cd during repeated phytoextraction. This renders S. plumbizincicola a suitable plant for large-scale field phytoremediation.

Iron Stable Isotopes in Bulk Soil and Sequential Extracted Fractions Trace Fe Redox Cycling in Paddy Soils.

In paddy soils, iron (Fe) forms are highly influenced by the seasonal redox changes and leave detectable isotope signals because of fractionation between different Fe forms. Here, we present Fe concentrations and Fe isotope compositions (expressed as δ56Fe values) in a paddy soil profile from Suzhou, China. Light Fe isotopes were enriched in two iron-accumulation layers (Br3 and G1) with high Fe concentrations. In particular, large shifts in both Fe concentrations and δ56Fe values were found at the Br2 and Br3 boundaries, showing fast and efficient transformation between these horizons. With sequential extraction, we show that Fe isotopes in the short-range-ordered Fe minerals and crystalline Fe oxides were lighter than those in the residual silicate minerals. Iron enriched in light isotopes was leached from the Ap horizon and subsequently moved to Br horizon, quickly precipitating there as Fe oxides.

Isolating Rare Cells and Circulating Tumor Cells with High Purity by Sequential eDAR.

Isolation and analysis of circulating tumor cells (CTCs) from the blood of patients at risk of metastatic cancers is a promising approach to improving cancer treatment. However, CTC isolation is difficult due to low CTC abundance and heterogeneity. Previously, we reported an ensemble-decision aliquot ranking (eDAR) platform for the rare cell and CTC isolation with high throughput, greater than 90% recovery, and high sensitivity, allowing detection of low surface antigen-expressing cells linked to metastasis. Here we demonstrate a sequential eDAR platform capable of isolating rare cells from whole blood with high purity. This improvement in purity is achieved by using a sequential sorting and flow stretching design in which whole blood is sorted and fluid elements are stretched using herringbone features and the parabolic flow profile being sorted a second time. This platform can be used to collect single CTCs in a multiwell plate for downstream analysis.

Effect of dietary zinc pectin oligosaccharides chelate on growth performance, enzyme activities, Zn accumulation, metallothionein concentration, and gene expression of Zn transporters in broiler chickens1.

This study was to investigate the effect of zinc pectin oligosaccharides chelate (Zn-POS) on growth performance, serum enzyme activities, tissue zinc accumulation, metallothionein (MT) concentrations, and gene expression of zinc transporters (ZnT) in broilers. Five hundred forty 1-d-old Arbor Acres broiler chicks were randomly assigned to 5 dietary groups with 6 replicates of 18 birds per replicate. The diets were formulated with the same supplemental Zn level (80 mg/kg diet) but different amount of the Zn-POS: 0, 200, 400, 600, and 800 mg Zn-POS/kg diet. ZnSO4 was used to adjust to the desired amount of the Zn (80 mg/kg) in the Zn-POS diets. Broilers were fed with the experimental diets for 42 d including the starter (days 1 to 21) and grower (days 22 to 42) phases. Our results showed that dietary supplementation of Zn-POS linearly and quadratically increased (P < 0.05) the average daily gain and gain-to-feed ratio during 22 to 42 d and 1 to 42 d as well as body weight on day 42, whereas reduced (P < 0.05) the sum of mortality and lag abnormalities in broilers on day 42. Besides, serum alkaline phosphatase and copper-zinc superoxide dismutase activities increased (P < 0.05) linearly and quadratically in response to dietary Zn-POS supplemental level on day 42. Dietary Zn-POS supplementation increased Zn accumulation in serum (linear, P < 0.05), liver (linear, P < 0.05), and pancreas (linear and quadratic, P < 0.05). In addition, Zn-POS supplementation linearly and quadratically increased (P < 0.01, P < 0.05, respectively) MT concentrations in liver and pancreas of broilers. Pancreatic mRNA levels of MT, ZnT-1, and ZnT-2 increased (P < 0.05) linearly and quadratically, and the mRNA expression of metal response element-binding transcription factor-1 increased linearly (P < 0.05), in response to dietary Zn-POS supplementation. In conclusion, supplementation of Zn-POS in the diet increases Zn enrichment in the metabolic organs such as liver and pancreas and promotes productive performance in broilers.

Influence of room temperature on magnesium isotope measurements by multi-collector inductively coupled plasma mass spectrometry.

RATIONALE: We observed that the accuracy and precision of magnesium (Mg) isotope analyses could be affected if the room temperature oscillated during measurements. To achieve high-quality Mg isotopic data, it is critical to evaluate how the unstable room temperature affects Mg isotope measurements by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). METHODS: We measured the Mg isotopes for the reference material DSM-3 using MC-ICP-MS under oscillating room temperatures in spring. For a comparison, we also measured the Mg isotopes under stable room temperatures, which were achieved by the installation of an improved temperature control system in the laboratory. RESULTS: The δ26 Mg values measured under oscillating room temperatures have a larger deviation (δ26 Mg from -0.09 to 0.08‰, with average δ26 Mg = 0.00 ± 0.08‰) than those measured under a stable room temperature (δ26 Mg from -0.03 to 0.03‰, with average δ26 Mg = 0.00 ± 0.02‰) using the same MC-ICP-MS system. CONCLUSIONS: The room temperature variation can influence the stability of MC-ICP-MS. Therefore, it is critical to keep the room temperature stable to acquire high-precision and accurate isotopic data when using MC-ICP-MS, especially when using the sample-standard bracketing (SSB) correction method.

Ectopic expression of glycosyltransferase UGT76E11 increases flavonoid accumulation and enhances abiotic stress tolerance in Arabidopsis.

Although plant glycosyltransferases are thought to play important roles in growth and interaction with the environment, little is known about their physiological roles for most members of the plant glycosyltransferase family. We cloned and characterised an Arabidopsis glycosyltransferase gene, UGT76E11. Its in vivo physiological effects on flavonoid accumulation and plant tolerance to abiotic stresses were investigated. The UGT76E11 gene was up-regulated in transcription expression under stress conditions of salinity, drought and H2 O2 treatment. Transgenic plants ectopically overexpressing UGT76E11 showed substantially enhanced tolerance to salinity and drought at germination and during post-germination growth. Enzyme activity of UGT76E11 to glucosylate quercetin and other flavonoids was confirmed. Ectopic expression of UGT76E11 resulted in significantly increased flavonoid content in transgenic plants compared to wild type, suggesting a contribution of UGT76E11 to modulation of flavonoid metabolism. Consistent with this result, several biosynthesis genes in the flavonoid pathway were clearly up-regulated in transgenic plants. Furthermore, overexpression of UGT76E11 also enhanced the scavenging capacity for ROS and increased expression levels of a number of stress-related genes. Based on these results, we suggest that the glycosyltransferase UGT76E11 plays an important role in modulating flavonoid metabolism and enhancing plant adaptation to environmental stresses. Our findings might allow use of glycosyltransferase UGT76E11 in crop improvement, towards both enhanced stress tolerance and increased flavonoid accumulation.

Congenital Hyperinsulinism in China: A Review of Chinese Literature Over the Past 15 Years.

OBJECTIVE: Congenital hyperinsulinism (CHI) is a rare but severe cause of hypoglycemia. The present study investigates the clinical presentation, therapeutic outcomes and genetic mutations of CHI in Chinese individuals over the past 15 years. METHODS: The authors retrospectively reviewed one case in their department and 206 cases reported from January 2002 to October 2016 in China. PubMed, Ovid Medline, Springer and Wanfang Database, CBMD database, and CKNI database were the sources used to collect the data. RESULTS: In total, 207 cases were recruited. Of these, the ages of 100 (48.3%) were within the 4th week after birth. Seventy-seven cases (37.2%) were born large for gestational age (LGA). Seizures occurred in 140 cases (67.6%). Among 140 cases (67.6%) who were administered diazoxide treatment, 90 (64.3%) were responsive. Seven cases (3.4%) received octreotide treatment and 19 cases (9.2%) underwent surgery. 63/129 cases (48.8%) were detected to have gene mutations, including ABCC8 (69.8%), KCNJ11 (12.7%), GLUD1, GCK, HADH, and HNF4A. Among the diazoxide-unresponsive cases, gene mutations were detected in 20/36 (55.6%) cases with ABCC8 and in 2 (5.6%) cases with KCNJ11. Among the diazoxide-responsive cases, gene mutations were detected in 8 patients with ABCC8, 4 with KCNJ11, 5 with GLUD1, and 1 with GCK. CONCLUSION: The present study indicates that most CHI cases occurred in neonates and that 1/3 of the cases were born LGA. ABCC8 and KCNJ11 are the most common gene mutations. More than half of the diazoxide-unresponsive CHI detected mutations are in ABCC8 and KCNJ11 genes. The GLUD1 gene mutations cause diazoxide-responsive CHI. Identifying the gene mutations can assist in the diagnosis and treatment of CHI.

Mitochondrial genome of the sweet potato hornworm, Agrius convolvuli (Lepidoptera: Sphingidae), and comparison with other Lepidoptera species.

In the present study, we sequenced the complete mitochondrial genome (mitogenome) of Agrius convolvuli (Lepidoptera: Sphingidae) and compared it with previously sequenced mitogenomes of lepidopteran species. The mitogenome was a circular molecule, 15 349 base pairs (bp) long, containing 37 genes. The order and orientation of genes in the A. convolvuli mitogenome were similar to those in sequenced mitogenomes of other lepidopterans. All 13 protein-coding genes (PCGs) were initiated by ATN codons, except for the cytochrome c oxidase subunit 1 (cox1) gene, which seemed to be initiated by the codon CGA, as observed in other lepidopterans. Three of the 13 PCGs had the incomplete termination codon T, while the remainder terminated with TAA. Additionally, the codon distributions of the 13 PCGs revealed that Asn, Ile, Leu2, Lys, Phe, and Tyr were the most frequently used codon families. All transfer RNAs were folded into the expected cloverleaf structure except for tRNASer(AGN), which lacked a stable dihydrouridine arm. The length of the adenine (A) + thymine (T)-rich region was 331 bp. This region included the motif ATAGA followed by a 19-bp poly-T stretch and a microsatellite-like (TA)8 element next to the motif ATTTA. Phylogenetic analyses (maximum likelihood and Bayesian methods) showed that A. convolvuli belongs to the family Sphingidae.

The Arabidopsis UDP-glycosyltransferases UGT79B2 and UGT79B3, contribute to cold, salt and drought stress tolerance via modulating anthocyanin accumulation.

The plant family 1 UDP-glycosyltransferases (UGTs) are the biggest GT family in plants, which are responsible for transferring sugar moieties onto a variety of small molecules, and control many metabolic processes; however, their physiological significance in planta is largely unknown. Here, we revealed that two Arabidopsis glycosyltransferase genes, UGT79B2 and UGT79B3, could be strongly induced by various abiotic stresses, including cold, salt and drought stresses. Overexpression of UGT79B2/B3 significantly enhanced plant tolerance to low temperatures as well as drought and salt stresses, whereas the ugt79b2/b3 double mutants generated by RNAi (RNA interference) and CRISPR-Cas9 strategies were more susceptible to adverse conditions. Interestingly, the expression of UGT79B2 and UGT79B3 is directly controlled by CBF1 (CRT/DRE-binding factor 1, also named DREB1B) in response to low temperatures. Furthermore, we identified the enzyme activities of UGT79B2/B3 in adding UDP-rhamnose to cyanidin and cyanidin 3-O-glucoside. Ectopic expression of UGT79B2/B3 significantly increased the anthocyanin accumulation, and enhanced the antioxidant activity in coping with abiotic stresses, whereas the ugt79b2/b3 double mutants showed reduced anthocyanin levels. When overexpressing UGT79B2/B3 in tt18 (transparent testa 18), a mutant that cannot synthesize anthocyanins, both genes fail to improve plant adaptation to stress. Taken together, we demonstrate that UGT79B2 and UGT79B3, identified as anthocyanin rhamnosyltransferases, are regulated by CBF1 and confer abiotic stress tolerance via modulating anthocyanin accumulation.

The Arabidopsis UGT87A2, a stress-inducible family 1 glycosyltransferase, is involved in the plant adaptation to abiotic stresses.

Glycosyltransferase (GT) family-1, the biggest GT family in plants, typically participates in modification of small molecules and affects many aspects during plant development. In Arabidopsis thaliana, although some UDP glycosyltransferases (UGTs) of family-1 have been functionally characterized, functions of most the UGTs remain unknown or fragmentary. Here, we report data for the Arabidopsis UGT87A2, a stress-regulated GT. We found that UGT87A2 could be dramatically induced by salinity, osmotic stress, drought and ABA. Overexpression of UGT87A2 (87A2OE) leads to accelerated germination and greening, higher survival rate as well as increased root length against abiotic stresses compared with those of wild-type (WT) plants. In addition, we observed lower water loss rate in the 87A2OE plants due to smaller stomatal apertures. The transgenic plants also showed reduced levels of H2 O2 and superoxide under low water status compared with those of WT plants. Consistently, function loss of UGT87A2 in ugt87a2 knockout lines resulted in opposite performances under these conditions. A transcriptome profiling revealed that 121 genes were differentially regulated upon UGT87A2 overexpression, and a large number of stress-induced genes were upregulated in UGT87A2 overexpression plants. Expression of seven genes among them were assessed by quantitative real-time polymerase chain reaction (qRT-PCR), including CPK32, CYP81F2, MYB96, DREB2A, FBS1, PUB23 and RAV2 under both control and stress treatments, and the results greatly validated our transcriptome data. Taken together, our findings support an explicit role of UGT87A2 in adaptation to abiotic stresses.

Ascending aortic adventitial remodeling and fibrosis are ameliorated with Apelin-13 in rats after TAC via suppression of the miRNA-122 and LGR4-ß-catenin signaling.

Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50µg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFß1, CTGF, NFAT5, LGR4, and ß-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-ß-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100nmolL-1) led to significant increases in cellular migration and levels of TGFß1, CTGF, NFAT5, LGR4 and ß-catenin, which were effectively reversed by pre-treatment with Apelin (100nmolL-1) and miRNA-122 inhibitor (50nmolL-1). In conclusion, Apelin counterregulated against TAC-mediated ascending aortic remodeling and angiotensin II-induced promotion of cellular migration by blocking AT1 receptor and miRNA-122 levels and preventing activation of the TGFß1-CTGF-NFAT5 and LGR4-ß-catenin signaling, ultimately contributing to attenuation of aortic adventitial fibrosis. Our data point to Apelin as an important regulator of aortic remodeling and adventitial fibrosis and a promising target for vasoprotective therapies.

Angiotensin-converting enzyme 2 ameliorates renal fibrosis by blocking the activation of mTOR/ERK signaling in apolipoprotein E-deficient mice.

Angiotensin-converting enzyme 2 (ACE2) has been shown to prevent atherosclerotic lesions and renal inflammation. However, little was elucidated upon the effects and mechanisms of ACE2 in atherosclerotic kidney fibrosis progression. Here, we examined regulatory roles of ACE2 in renal fibrosis in the apolipoprotein E (ApoE) knockout (KO) mice. The ApoEKO mice were randomized to daily deliver either angiotensin (Ang) II (1.5mg/kg) and/or human recombinant ACE2 (rhACE2; 2mg/kg) for 2 weeks. Downregulation of ACE2 and upregulation of phosphorylated Akt, mTOR and ERK1/2 levels were observed in ApoEKO kidneys. Ang II infusion led to increased tubulointerstitial fibrosis in the ApoEKO mice with greater activation of the mTOR/ERK1/2 signaling. The Ang II-mediated renal fibrosis and structural injury were strikingly rescued by rhACE2 supplementation, associated with reduced mRNA expression of TGF-ß1 and collagen I and elevated renal Ang-(1-7) levels. In cultured mouse kidney fibroblasts, exposure with Ang II (100nmolL(-1)) resulted in obvious elevations in superoxide generation, phosphorylated levels of mTOR and ERK1/2 as well as mRNA levels of TGF-ß1, collagen I and fibronectin 1, which were dramatically prevented by rhACE2 (1mgmL(-1)) or mTOR inhibitor rapamycin (10µmolL(-1)). These protective effects of rhACE2 were eradicated by the Ang-(1-7)/Mas receptor antagonist A779 (1µmolL(-1)). Our results demonstrate the importance of ACE2 in amelioration of kidney fibrosis and renal injury in the ApoE-mutant mice via modulation of the mTOR/ERK signaling and renal Ang-(1-7)/Ang II balance, thus indicating potential therapeutic strategies by enhancing ACE2 action for preventing atherosclerosis and fibrosis-associated kidney disorders.

[Acute coronary syndrome in women below 50 years of age: risk factors and clinical and angiographic features].

OBJECTIVE: To investigate the risk factors and angiographic features of acute coronary syndrome (ACS) in women below 50 years of age. METHODS: A total of 131 women with ACS aged 50 years or younger were enrolled in this study as the case group, with another 425 women aged below 50 years with normal coronary angiographic findings as the control group. The risk factors and clinical and coronary angiographic features of ACS were analyzed. RESULTS: Compared with the control group, significantly higher frequencies of dyslipidemia, hypertension (especially diastolic hypertension), diabetes, or a positive family history for coronary artery disease (CAD) were found in ACS group (P<0.05) . The proportion of post-menopausal women and the menopausal ages were similar between the two groups (P>0.05), but the mean diastolic pressure was significantly higher in ACS group than in the control group (P<0.05). Among the menopausal women, the conventional risk factors for ACS were similar between the two groups with the exception of family history CAD, which was more frequent in ACS group. Serum total cholesterol and triglyceride levels were significantly higher in ACS group than in the control group (P<0.05), but the levels of high- and low-density lipoprotein cholesterol levels were comparable between them. Positive findings of urine protein were more frequent in ACS group. In ACS group, 54.2% of the patients had a single diseased artery, 29.6% had more than one diseased artery, and 16.0% had slightly diseased or even normal coronary arteries; the lesion was found most commonly in the left anterior descending artery. CONCLUSION: In women with ACS below 50 years of age, the risk factors of ACS included the conventional risk factors of CAD and a positive finding of urine protein. Menopause is not associated with an increased incidence of ACS. A substantial portion of these ACS patients can have slightly diseased and even normal coronary arteries.

[Interforaminal regions of 287 Han adults evaluated by cone-beam computed tomography].

PURPOSE: The mandibular anatomical structures including mental foramen, accessory mental foramina, anterior loop were measured and analyzed by cone-beam CT (cone-beam computed tomography, CBCT) , in order to provide some information during surgical procedures in interforaminal regions. METHODS: Two hundred and eighty-seven Chinese Han patients who visited Stomatological Department of Xiangya Hospital were included in this study. Patients were scanned by cone-beam computed tomography, and the information of interforaminal region was collected from the images. SPSS17.0 software package was used for statistical analysis. RESULTS: The mental foramen was usually apical to the second premolar or between the premolars（60.80% and 30.14%, respectively). The accessory mental foramina was observed in 4.88% of the mandibles, most of which were located under the second premolar, superiorly and distally to the mental foramen. The anterior loop was identified in 89.20% of cases with the mean length being (1.99±1.39) mm. The distance from the apex of the second mandibular premolar to the anterior loop or the inferior alveolar nerve was (5.21±2.50) mm. CONCLUSIONS: Accessory mental foramina is present in some mandibles. The anterior loop is highly prevalent in Chinese Han people, and its length is highly variable.