Tenecteplase for Acute Ischemic Stroke Treatment.

The introduction of thrombolytic therapy in the 1990s has transformed acute ischemic stroke treatment. Thus far, intravenous recombinant tissue plasminogen activator (rt-PA) also known as alteplase is the only thrombolytic proven to be efficacious and approved by the United States Food and Drug Administration. But the thrombolytic agent tenecteplase (TNK) is emerging as a potential replacement for rt-PA. TNK has greater fibrin specificity, slower clearance, and higher resistance to plasminogen activator inhibitor-1 than rt-PA. Hence, TNK has the potential to provide superior lysis with fewer hemorrhagic complications. Also, easier bolus-only administration makes TNK a very practical rt-PA alternative. In several clinical trials, TNK has shown similar efficacy and safety to rt-PA, and the potential to be at least noninferior to rt-PA in some settings. TNK may be superior to rt-PA for reperfusing large vessel occlusions in patients with salvageable penumbra, although this has not yet translated to improved clinical outcomes. Further phase 3 studies are in progress comparing rt-PA with TNK for acute ischemic stroke during the first 4.5 hours. Studies are also in progress to evaluate the use of TNK for extended applications, such as wake-up stroke.

Joint geophysical prospecting for groundwater exploration in weathered terrains of South Guangdong, China.

Groundwater occurrence in a hard rock terrain is strongly controlled by the weathered/fractured zones. However, delineation of such zones is a challenging task given their structural heterogeneity. Traditionally, large numbers of well tests are conducted to assess the subsurface formation. But, such tests suffer from efficiency in terms of cost, time, and data coverage. Non-invasive geophysical methods can be the best alternative of expensive drilling methods. However, a geophysical method alone is ambiguous to interpret the highly heterogeneous subsurface formation. In this study, joint application of electrical resistivity tomography (ERT), magnetic method, and joint profile method (JPM) was conducted for groundwater exploitation in a weathered terrain of South Guangdong, China. ERT, magnetic, and JPM data were acquired along different geophysical profiles via a variety of survey parameters. The interpreted 2D models of electrical resistivity and magnetic data coupled with the local accessible boreholes and hydrogeological information constrain the subsurface geologic formation into four discrete layers with specific electrical resistivity range, i.e., topsoil cover, highly weathered saturated layer, semi-weathered saturated layer, and un-weathered substratum. Incorporation of JPM (ER, SP, and IP methods) with ERT and magnetic models reveal three faults (F1, F2, and F3) and several saturated intense fractures/discontinuities. The groundwater reserves associated with the weathered/fractured rock were estimated via hydraulic parameters, namely hydraulic conductivity and transmissivity. The results suggest that high-yield groundwater resources are found within the weathered/fractured zones. Geophysical results of this joint application fit pretty well to the local hydrogeological data of the study area. Our novel approach reduces any ambiguity caused in the geophysical interpretation and provides clearer insight of the subsurface formation with more confident solutions to the most challenging problems of the hard rock sites. This hydrogeophysical study provides important contributions to groundwater exploration in areas where weathering has significant effects on the hard rock aquifer system. Compared with traditional methods, this approach is more advantageous for assessment of groundwater resources in hard rock terrains.

Delineation of contaminated aquifers using integrated geophysical methods in Northeast Punjab, Pakistan.

A decline in surface water sources in Pakistan is continuously causing the over-extraction of groundwater resources which is in turn costing the saltwater intrusion in many areas of the country. The saltwater intrusion is a major problem in sustainable groundwater development. The application of electrical resistivity methods is one of the best known geophysical approaches in groundwater study. Considering the accuracy in extraction of freshwater resources, the use of resistivity methods is highly successful to delineate the fresh-saline aquifer boundary. An integrated geophysical study of VES and ERI methods was carried out through the analysis and interpretation of resistivity data using Schlumberger array. The main purpose of this investigation was to delineate the fresh/saline aquifer zones for exploitation and management of fresh water resources in the Upper Bari Doab, northeast Punjab, Pakistan. The results suggest that sudden drop in resistivity values caused by the solute salts indicates the saline aquifer, whereas high resistivity values above a specific range reveal the fresh water. However, the overlapping of fresh/saline aquifers caused by the formation resistivity was delineated through confident solutions of the D-Z parameters computed from the VES data. A four-layered unified model of the subsurface geologic formation was constrained by the calibration between formation resistivity and borehole lithologs. i.e., sand and gravel-sand containing fresh water, clay-sand with brackish water, and clay having saline water. The aquifer yield contained within the fresh/saline aquifers was measured by the hydraulic parameters. The fresh-saline interface demarcated by the resistivity methods was confirmed by the geochemical method and the local hydrogeological data. The proposed geophysical approach can delineate the fresh-saline boundary with 90% confidence in any homogeneous or heterogeneous aquifer system.

Adipocyte phospholipid transfer protein and lipoprotein metabolism.

OBJECTIVE: Phospholipid transfer protein (PLTP) is highly expressed in adipose tissues. Thus, the effect of adipose tissue PLTP on plasma lipoprotein metabolism was examined. APPROACH AND RESULTS: We crossed PLTP-Flox-ΔNeo and adipocyte protein 2 (aP2)-Cre recombinase (Cre) transgenic mice to create PLTP-Flox-ΔNeo/aP2-Cre mice that have a 90 and a 60% reduction in PLTP mRNA in adipose tissue and macrophages, respectively. PLTP ablation resulted in a significant reduction in plasma PLTP activity (22%), high-density lipoprotein-cholesterol (21%), high-density lipoprotein-phospholipid (20%), and apolipoprotein A-I (33%) levels, but had no effect on nonhigh-density lipoprotein levels in comparison with those of PLTP-Flox-ΔNeo controls. To eliminate possible effects of PLTP ablation by macrophages, we lethally irradiated PLTP-Flox-ΔNeo/aP2-Cre mice and PLTP-Flox-ΔNeo mice, and then transplanted wild-type mouse bone marrow into them to create wild-type→PLTP-Flox-ΔNeo/aP2-Cre and wild-type→PLTP-Flox-ΔNeo mice. Thus, we constructed a mouse model (wild-type→PLTP-Flox-ΔNeo/aP2-Cre) with PLTP deficiency in adipocytes but not in macrophages. These knockout mice also showed significant decreases in plasma PLTP activity (19%) and cholesterol (18%), phospholipid (17%), and apolipoprotein A-I (26%) levels. To further investigate the mechanisms behind the reduction in plasma apolipoprotein A-I and high-density lipoprotein lipids, we measured apolipoprotein A-I-mediated cholesterol efflux in adipose tissue explants and found that endogenous and exogenous PLTP significantly increased cholesterol efflux from the explants. CONCLUSIONS: Adipocyte PLTP plays a small but significant role in plasma PLTP activity and promotes cholesterol efflux from adipose tissues.

Liver-specific phospholipid transfer protein deficiency reduces high-density lipoprotein and non-high-density lipoprotein production in mice.

OBJECTIVE: The liver is one of the critical organs for lipoprotein metabolism and a major source for phospholipid transfer protein (PLTP) expression. The effect of liver-specific PLTP deficiency on plasma lipoprotein production and metabolism in mice was investigated. APPROACH AND RESULTS: We created a liver-specific PLTP-deficient mouse model. We measured plasma high-density lipoprotein (HDL) and apolipoprotein B (apoB)-containing lipoprotein (or non-HDL) levels and their production rates. We found that hepatic ablation of PLTP leads to a significant decrease in plasma PLTP activity, HDL lipids, non-HDL lipids, apoAI, and apoB levels. In addition, nuclear magnetic resonance examination of lipoproteins showed that the deficiency decreases HDL and apoB-containing lipoprotein particle numbers, as well as very low-density lipoprotein particle size, which was confirmed by electron microscopy. Moreover, HDL particles from the deficient mice are lipid-poor ones. To unravel the mechanism, we evaluated the apoB and triglyceride production rates. We found that hepatic PLTP deficiency significantly decreases apoB and triglyceride secretion rates. To investigate the role of liver PLTP on HDL production, we set up primary hepatocyte culture studies and found that the PLTP-deficient hepatocytes produce less nascent HDL. Furthermore, we found that exogenous PLTP promotes nascent HDL production through an ATP-binding cassette A 1-mediated pathway. CONCLUSIONS: Liver-specific PLTP deficiency significantly reduces plasma HDL and apoB-containing lipoprotein levels. Reduction of production rates of both particles is one of the mechanisms.

Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol.

Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci.

Measurement of the phospholipase activity of endothelial lipase in mouse plasma.

Endothelial lipase (EL) is a major negative regulator of plasma HDL levels in mice, rabbits, and most probably, humans. Although this regulatory function is critically dependent on EL's hydrolysis of HDL phospholipids, as yet there is no phospholipase assay specific for EL in plasma. We developed such an assay for the mouse enzyme using a commercially available phospholipid-like fluorescent substrate in combination with an EL neutralizing antibody. The specificity of the assay was established using EL knockout mice and its utility demonstrated by detection of an increase in plasma EL phospholipase activity following exposure of wild-type mice to lipopolysaccharide. The assay revealed that murine pre-heparin plasma does not contain measurable EL activity, indicating that the hydrolysis of HDL phospholipids by EL in vivo likely occurs on the cell surface.

Hepatic proprotein convertases modulate HDL metabolism.

The risk of atherosclerosis is inversely associated with plasma levels of high-density lipoprotein cholesterol (HDL-C). However, HDL metabolism is incompletely understood, and there are few effective approaches to modulate HDL-C levels. Here we show that inhibition in the liver of the classical proprotein convertases (PCs), but not the atypical PCs S1P and PCSK9, decreases plasma HDL-C levels. This metabolic effect of hepatic PCs is critically dependent on expression of endothelial lipase (EL), an enzyme that directly hydrolyzes HDL phospholipids and promotes its catabolism. Hepatic PCs reduce EL function through direct inactivating cleavage of EL as well as through activating cleavage of angiopoietin-like protein 3 (ANGPTL3), an endogenous inhibitor of EL. Thus, inhibition of hepatic PCs results in increased EL activity, leading to reduced HDL-C as well as impaired reverse cholesterol transport. The hepatic PC-ANGPTL3-EL-HDL pathway is therefore a novel mechanism controlling HDL metabolism and cholesterol homeostasis.

Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity.

Angiopoietin-like protein 4 (ANGPTL4) has been associated with a variety of diseases. It is known as an endogenous inhibitor of lipoprotein lipase (LPL), and it modulates lipid deposition and energy homeostasis. ANGPTL4 is cleaved by unidentified protease(s), and the biological importance of this cleavage event is not fully understood with respect to its inhibitory effect on LPL activity. Here, we show that ANGPTL4 appears on the cell surface as the full-length form, where it can be released by heparin treatment in culture and in vivo. ANGPTL4 protein is then proteolytically cleaved into several forms by proprotein convertases (PCs). Several PCs, including furin, PC5/6, paired basic amino acid-cleaving enzyme 4, and PC7, are able to cleave human ANGPTL4 at a consensus site. PC-specific inhibitors block the processing of ANGPTL4. Blockage of ANGPTL4 cleavage reduces its inhibitory effects on LPL activity and decreases its ability to raise plasma triglyceride levels. In summary, the cleavage of ANGPTL4 by these PCs modulates its inhibitory effect on LPL activity.

Determination of lipoprotein lipase activity using a novel fluorescent lipase assay.

A novel, real-time, homogeneous fluorogenic lipoprotein lipase (LPL) assay was developed using a commercially available substrate, the EnzChek lipase substrate, which is solubilized in Zwittergent. The triglyceride analog substrate does not fluoresce, owing to apposition of fluorescent and fluorescent quenching groups at the sn-1 and sn-2 positions, respectively, fluorescence becoming unquenched upon release of the sn-1 BODIPY FA derivative following hydrolysis. Increase in fluorescence intensity at 37°C was proportional to LPL concentration. The assay was more sensitive than a similar assay using 1,2-O-dilauryl-rac-glycero-3-glutaric acid-(6-methylresorufin ester) and was validated in biological samples, including determination of LPL-specific activity in postheparin mouse plasma. The simplicity and reproducibility of the assay make it ideal for in vitro, high-throughput screening for inhibitors and activators of LPL, thus expediting discovery of drugs of potential clinical value.

Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases.

Lipoprotein lipase (LPL)-mediated lipolysis of triglycerides is the first and rate-limiting step in chylomicron/very low density lipoprotein clearance at the luminal surface of the capillaries. Angiopoietin-like protein 3 (ANGPTL3) is shown to inhibit LPL activity and plays important roles in modulating lipoprotein metabolism in vivo. However, the mechanism by which it inhibits LPL activity remains poorly understood. Using cell-based analysis of the interaction between ANGPTL3, furin, proprotein convertase subtilisin/kexin type 5 (PCSK5), paired amino acid converting enzyme-4 (PACE4), and LPL, we demonstrated that the cleavage of LPL by proprotein convertases is an inactivation process, similar to that seen for endothelial lipase cleavage. At physiological concentrations and in the presence of cells, ANGPTL3 is a potent inhibitor of LPL. This action is due to the fact that ANGPTL3 can enhance LPL cleavage by endogenous furin and PACE4 but not by PCSK5. This effect is specific to LPL but not endothelial lipase. Both N- and C-terminal domains of LPL are required for ANGPTL3-enhanced cleavage, and the N-terminal domain of ANGPTL3 is sufficient to exert its effect on LPL cleavage. Moreover, ANGPTL3 enhances LPL cleavage in the presence of either heparan sulfate proteoglycans or glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1). By enhancing LPL cleavage, ANGPTL3 dissociates LPL from the cell surface, inhibiting both the catalytic and noncatalytic functions of LPL. Taken together, our data provide a molecular connection between ANGPTL3, LPL, and proprotein convertases, which may represent a rapid signal communication among different metabolically active tissues to maintain energy homeostasis. These novel findings provide a new paradigm of specific protease-substrate interaction and further improve our knowledge of LPL biology.

[Genetic analysis of ß -thalassemia mutations in the minority populations of Guizhou province].

OBJECTIVE: To investigate the gene mutation frequencies and patterns of ß-thalassemia (ß-thal) in the minority populations of Guizhou province. METHODS: Three thousand and five hundred couples in the reproductive age were screened by using automatic hemocyte analyzer and hemoglobin autoanalyzer-variant. The diagnostic criteria for ß-thal were: the mean corpuscular volume (MCV) was ≤ 82 fl, and the HbA(2) level was ≥ 3.5%. A total of 194 positive samples were detected and further identified by PCR-reverse dot blot (PCR-RDB) assay for 18 common ß -thal mutations in Chinese population. Those subjects with positive phenotypes but without the 18 common ß-thal mutations were subjected to DNA sequence analysis of the ß-globin gene. RESULTS: One hundred and eighty-nine samples with gene mutations were observed from the 3500 samples, with the incidence of ß-thal being 5.4%. A total of 10 different ß-thal mutations were identified from the 189 diagnosed samples. The five most common mutations were as the following: CD17 (43.9%), CD41-42 (38.6%), IVS-II-654(10.1%), -28 (2.6%) and CD71-72 (1.6%). In addition, a novel ß-globin gene mutation (-CD53) allele was detected. One rare mutation of IntM was observed. CONCLUSION: The minority population in Guizhou province is of high risk of ß-thal. It is recommended that more attention should be paid to detect the carriers of ß-thal in the population in reproductive age by hematologic screening and common gene diagnosis in the area with high risk of ß-thal.

Structural and luminescent properties of co-crystals of tetra-iodo-ethyl-ene with two aza-phenanthrenes.

Two new co-crystals, tetra-iodo-ethyl-ene-phenanthridine (1/2), 0.5C2I4·C13H9N (1) and tetra-iodo-ethyl-ene-benzo[f]quinoline (1/2), 0.5C2I4·C13H9N (2), were obtained from tetra-iodo-ethyl-ene and aza-phenanthrenes, and characterized by IR and fluorescence spectroscopy, elemental analysis and X-ray crystallography. In the crystal structures, C-I⋯π and C-I⋯N halogen bonds link the independent mol-ecules into one-dimensional chains and two-dimensional networks with subloops. In addition, the planar aza-phenanthrenes lend themselves to π-π stacking and C-H⋯π inter-actions, leading to a diversity of supra-molecular three-dimensional structural motifs being formed by these inter-actions. Luminescence studies show that co-crystals 1 and 2 exhibit distinctly different luminescence properties in the solid state at room temperature.

Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.

UNLABELLED: The gene encoding the proprotein convertase subtilisin/kexin type 9 (PCSK9) is linked to familial hypercholesterolemia, as are those of the low-density lipoprotein receptor (LDLR) and apolipoprotein B. PCSK9 enhances LDLR degradation, resulting in low-density lipoprotein accumulation in plasma. To analyze the role of hepatic PCSK9, total and hepatocyte-specific knockout mice were generated. They exhibit 42% and 27% less circulating cholesterol, respectively, showing that liver PCSK9 was responsible for two thirds of the phenotype. We also demonstrated that, in liver, PCSK9 is exclusively expressed in hepatocytes, representing the main source of circulating PCSK9. The data suggest that local but not circulating PCSK9 regulates cholesterol levels. Although transgenic mice overexpressing high levels of liver and circulating PCSK9 led to the almost complete disappearance of the hepatic LDLR, they did not recapitulate the plasma cholesterol levels observed in LDLR-deficient mice. Single LDLR or double LDLR/PCSK9 knockout mice exhibited similar cholesterol profiles, indicating that PCSK9 regulates cholesterol homeostasis exclusively through the LDLR. Finally, the regenerating liver of PCSK9-deficient mice exhibited necrotic lesions, which were prevented by a high-cholesterol diet. However, lipid accumulation in hepatocytes of these mice was markedly reduced under both chow and high-cholesterol diets, revealing that PCSK9 deficiency confers resistance to liver steatosis. CONCLUSION: Although PCSK9 is a target for controlling hypercholesterolemia, our data indicate that upon hepatic damage, patients lacking PCSK9 could be at risk.

Upregulation of macrophage endothelial lipase by toll-like receptors 4 and 3 modulates macrophage interleukin-10 and -12 production.

Limited data suggest that endothelial lipase (EL) is synthesized not only by endothelial cells but also by macrophages. Previous studies showed that proinflammatory cytokines upregulate EL in endothelial cells, but there are very few data regarding EL expression, regulation, and functional consequences in macrophages. In the present study, RAW cells and mouse peritoneal macrophages were treated with Toll-like receptor (TLR) ligands and EL expression and its consequences were assessed. We demonstrate that lipopolysaccharide, a TLR4 ligand; and polyinosinic:polycytidylic acid (poly I:C), a TLR3 ligand; but not lipoteichoic acid, a TLR2 ligand, upregulate macrophage EL expression both ex vivo and in vivo. In contrast, macrophage lipoprotein lipase expression is significantly repressed by lipopolysaccharide or poly I:C. Using C3HJ and TLR3 knockout mice, we further show that upregulation of macrophage EL expression by lipopolysaccharide or poly I:C is TLR4 or TLR3 dependent, respectively. Furthermore, we demonstrate that lipopolysaccharide induced interleukin (IL)-10 production was significantly reduced, whereas IL-12 production is significantly increased in J744 macrophages and mouse peritoneal macrophages overexpressing human EL. Conversely, significantly increased IL-10 and significantly decreased IL-12 expression were observed in mouse peritoneal macrophages isolated from EL knockout mice. Finally we show that the catalytic activity is required for EL to modulate the balance of macrophage IL-10 and IL-12 production. These results suggest that macrophage EL may play important roles in modulating the macrophage inflammatory response through local hydrolysis of HDL.

Endothelial lipase provides an alternative pathway for FFA uptake in lipoprotein lipase-deficient mouse adipose tissue.

Lipoprotein lipase (LPL) is thought to be the only enzyme responsible for the catabolism of triglycerides (TGs) associated with TG-rich lipoproteins in adipose tissue (AT). However, LPL deficiency in humans and induced mutant mice is not associated with decreased fat mass. We investigated whether endothelial lipase (EL), a recently discovered phospholipase, might represent an alternative mechanism for the uptake of phospholipid-derived fatty acids in murine lipoprotein-deficient AT. When LPL was expressed in AT and isolated murine adipocytes, EL mRNA was not detectable. In contrast, mouse AT and isolated adipocytes that lacked LPL expressed large amounts of EL mRNA. The cellular phospholipase activity in LPL-deficient fat pads was increased 4-fold compared with control fat pads and could be inhibited to control levels by a specific EL antibody. Fatty acids produced by EL activity were absorbed by adipocytes and incorporated into the TG moiety of AT. Our results suggest that EL activity in AT and other peripheral tissues might contribute to the tissue uptake of free fatty acids, which could have important implications for the metabolism of plasma lipoproteins.

Studies on the effects of metal ions and counter anions on the aggregate behaviors of meso-tetrakis(p-sulfonatophenyl)porphyrin by absorption and fluorescence spectroscopy.

The aggregation behaviors of meso-tetrakis(p-sulfonatophenyl)porphyrin (TPPS) in the function of metal ions and their counter anions (Cl(-), SO4(2-), and NO3(-)) were investigated by absorption, fluorescence spectroscopy and resonance scattering spectrum. It was shown that the TPPS J-aggregates could be effectively promoted by metal ions under lower ionic strength. Moreover, the prominent effects of counter ions (Cl(-), SO4(2-), and NO3(-)) on TPPS J- and/or H-aggregate formation at higher ionic strength were observed. These results suggested that the counter anions play a significant role in the formation of TPPS J- and/or H-aggregates and their conversion each other. Very interestingly, the absorption spectrum of metal ions investigated except for Co2+ leaves a WINDOW from ca. 450 to 550 nm centered at 490 nm in which the absorption of Cu2+ or Ni2+ ions per se was very weak. The spectrum window might be really significant in avoiding possible spectrum interferences when porphyrins are chosen as spectrometric reagents for the determination of metal ions based on J-aggregation.

Geophysical Assessment of Groundwater Potential: A Case Study from Mian Channu Area, Pakistan.

An integrated study using geophysical method in combination with pumping tests and geochemical method was carried out to delineate groundwater potential zones in Mian Channu area of Pakistan. Vertical electrical soundings (VES) using Schlumberger configuration with maximum current electrode spacing (AB/2 = 200 m) were conducted at 50 stations and 10 pumping tests at borehole sites were performed in close proximity to 10 of the VES stations. The aim of this study is to establish a correlation between the hydraulic parameters obtained from geophysical method and pumping tests so that the aquifer potential can be estimated from the geoelectrical surface measurements where no pumping tests exist. The aquifer parameters, namely, transmissivity and hydraulic conductivity were estimated from Dar Zarrouyk parameters by interpreting the layer parameters such as true resistivities and thicknesses. Geoelectrical succession of five-layer strata (i.e., topsoil, clay, clay sand, sand, and sand gravel) with sand as a dominant lithology was found in the study area. Physicochemical parameters interpreted by World Health Organization and Food and Agriculture Organization were well correlated with the aquifer parameters obtained by geoelectrical method and pumping tests. The aquifer potential zones identified by modeled resistivity, Dar Zarrouk parameters, pumped aquifer parameters, and physicochemical parameters reveal that sand and gravel sand with high values of transmissivity and hydraulic conductivity are highly promising water bearing layers in northwest of the study area. Strong correlation between estimated and pumped aquifer parameters suggest that, in case of sparse well data, geophysical technique is useful to estimate the hydraulic potential of the aquifer with varying lithology.

Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes.

BACKGROUND: Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development; however, little is known about the regulation of PLTP. The effect of hepatic prodomain of furin (profurin) expression on PLTP processing and function is investigated. METHODS AND RESULTS: We used adenovirus expressing profurin in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We coexpressed PLTP and profurin in human hepatoma cell line cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity, and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explored the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP; instead, it forms a complex with PLTP, likely through its prodomain. CONCLUSIONS: Our study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin expression, which could be a novel posttranslational mechanism underlying PLTP regulation.