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Nghiên cứu nhằm xác định mật độ ương thích hợp lên sự tăng trưởng và tỷ lệ sống của ấu trùng và hậu ấu trùng tôm sú bằng công nghệ biofloc. Thí nghiệm gồm 4 nghiệm thức được bố trí hoàn toàn ngẫu nhiên, 3 lần lặp lại, với các mật độ ương khác nhau: 150; 200; 250 và 300 con/L, cách. Bể ương tôm có thể tích 500L, độ mặn 30‰, bổ sung rỉ đường để tạo biofloc với tỷ lệ C/N=25. Kết quả nghiên cứu cho thấy các yếu tố môi trường, mật độ vi khuẩn và các chỉ tiêu biofloc ở nghiệm thức mật độ 150 và 200 con/L nằm trong khoảng thích hợp cho ấu trùng và hậu ấu trùng tôm phát triển. Chiều dài Postlarvae-15 (12,37±0,21 mm), và tỷ lệ sống (61,2±4,3%) ở nghiệm thức mật độ 150 con/L lớn nhất khác biệt không có ý nghĩa thống kê (p>0,05) so với mật độ 200 con/L, nhưng khác biệt có ý nghĩa thống kê (p

ABSTRACT Antioxidants from natural sources hold high values regarding their indispensible roles in the development of nutraceuticals, pharmaceuticals and cosmetic products. Oroxylum indicum L. is a common medicinal plant with a wide range of therapeutic properties, including a notable antioxidant potency that was reported, yet has not been subjected to more detailed studies. The present study evaluated the potency of Oroxylum indicum methanol stem bark extract, along with its hexane, ethyl acetate, methanol fractions, three flavones including baicalein, oroxylin A and chrysin using DPPH assay. In terms of IC50 values, the crude extract (65,48 μg/mL) exhibited moderate inhibitory activity which was as half potent as that of its ethyl acetate fraction (32,94 μg/mL). This fraction was also superior to the methanol and hexane fractions, as their IC50 were 57,19 and 137,95 μg/mL respectively. Remarkably, a yellow powdery sub-fraction consisted of isolated compounds showed powerful activity (32,89 μg/mL) compared to those of its components, revealing the intriguing effect of synergism while giving evidence for the theory of structure-activity relationship between some flavones and their antioxidant capability. Perpetual search for new radical scavenging agents in Oroxylum indicum is emboldened considering its partially exploited potential in this study.

Benzimidazole và các dẫn xuất của chúng đóng vai trò quan trọng trong lĩnh vực y học với nhiều hoạt tính dược lý như kháng viêm, kháng khuẩn, kháng virus, chống đái tháo đường và kháng ung thư. Trong nghiên cứu này, bốn dẫn xuất naphthalene-benzimidazole đã được tổng hợp thành công với hiệu suất tốt qua năm bước bắt đầu từ 2,5-dimethoxybenzaldehyde. Phương pháp tổng hợp sử dụng phản ứng ngưng tụ Stobbe, sau đó đóng vòng tạo khung sườn ethyl-4-acetoxy-5,8-dimethoxy-2-napthoate. Chuyển hóa nhóm chức ethyl ester thành nhóm aldehyde, sau đó ngưng tụ với các dẫn xuất o-phenyldiamine và o-nitroaniline trong những điều kiện khác nhau để tạo thành các dẫn xuất 2-naphthalyl-1H-benzimidazole tương ứng. Cấu trúc của các hợp chất này được xác nhận đầy đủ bằng một số phương pháp quang phổ như phổ MS, IR, 1H-NMR và 13C-NMR. Kết quả đánh giá độc tính đối với tế bào ung thư cho thấy hai dẫn xuất 5,8-dimethoxy-3-(5-methyl-1H-benzo[d]imidazol-2-yl)naphthalene-1-ol (6a) và 3-(1H-benzo[d]imidazol-2-yl)-5,8-dimethoxynaphthalen-1-ol (7a) thể hiện độc tính yếu đối với dòng tế bào ung thư da ác tính Mouse skin B16 melanoma.

Phương pháp một bước đơn giản gồm sự khử/đóng vòng in situ các N-alkyl-o-nitroaniline và các aldehyde tương ứng tạo ra dẫn xuất N-alkylbenzimidazole sử dụng tác nhân oxy hóa là Na2S2O4. Dựa trên phương pháp này, mười dẫn xuất mới N-(3-morpholinopropyl) benzimidazole đã tổng hợp thành công với hiệu suất từ 42-91%. Cấu trúc của các dẫn xuất được xác nhận bằng các phương pháp phổ nghiệm hiện đại như MS, IR, 1H-NMR và 13C-NMR.

Recently, a cell-based smoothed discrete shear gap method (CS-FEM-DSG3) based on the firstorder shear deformation theory (FSDT) was proposed for static and free vibration analyses of Mindlin plates. The CS-FEM-DSG3 uses three-node triangular elements that can be easily generated automatically for arbitrary complicated geometric domains. This paper further extends the CS-FEMDSG3 for static, free vibration, and dynamic response of the stiffened plate resting on viscoelastic foundation subjected to a moving vehicle. The viscoelastic foundation is modeled by discrete springs and dampers whereas the stiffened plate can be considered as the combination between the Mindlin plate and the Timoshenko beam elements. The moving vehicle is transformed into one concentrated load at its central point. Some numerical examples are investigated and numerical results show that the CS-FEMDSG3 overcomes shear-locking phenomena and has a fast convergence. The results also illustrate the good agreement of the CS-FEM-DSG3 for static and free vibration analyses of un-stiffened plate compared with the previous published methods. In addition, the numerical results for dynamic analysis of stiffened plates by the CS-FEM-DSG3 also show the expected property in which the deflection of the stiffened plate is much smaller than those of the un-stiffened plate.

This paper presents a finite element formulation to study the mechanical buckling of stiffened functionally graded material (FGM) plates. The approach is based on a third-order shear deformation theory (TSDT) introduced by Guangyu Shi. The material properties of the plate were assumed to be varied in the thickness direction by a power law distribution, but the material of the stiffener was the same as that of the one of the bottom surface where the stiffener was placed. A parametric study was carried out to highlight the effect of material distribution, the thickness-to-width ratio, and stiffener parameters on the buckling characteristics of the stiffened FGM plates. Numerical results showed that the addition of stiffener to the FGM plate could significantly reduce the weight of the FGM plate but that both the FGM plates with and without stiffener had equally high strength in the same boundary condition and compression loading.

A cell-based smoothed three-node Mindlin plate element (CS-MIN3) was recently proposed to improve the performance of the existing three-node Mindlin plate element (MIN3) for static and free vibration analyses of Mindlin plates. In this paper, the CSMIN3 is incorporated with spring systems for treating more complicated static and free vibration analyses of Mindlin plates on the elastic foundation. The plate-foundation system is modeled as a discretization of triangular plate elements supported by discrete springs at the nodal points representing the elastic foundation. The accuracy and reliability of the proposed method are verified by comparing with those of others available numerical results.

A linearly conforming point interpolation method (LC-PIM) was recently proposed for the solid mechanics problems. In this paper, the LC-PIM is further extended to perfect visco-elastoplastic analyses of 2D solids. A dual formulation for the LC-PIM with displacements and stresses as the main variables is performed. The von-Mises yield function and the Prandtl-Reuss flow rule are used. In the numerical procedure, however, the stress variables are eliminated and the problem becomes only displacementdependent. The numerical results show that the LC-PIM is much more accurate than the FEM and possesses the upper bound property which is very meaningful for the viscoelastoplastic analyses which almost have not got the analytical solutions. This suggests that we can use two models, LC-PIM and FEM, to bound the solution, and can even estimate the global relative error of numerical solutions.

Appeared since 2007, the Smoothed Finite Element Methods (S-FEM) have developed fast in both of number of methods and their applications. Hundreds of international papers on the leading computational Journals present new research results of S-FEM and their applications. In Vietnam, S-FEM have been developed strongly by some research groups and deployed very well in some basic research projects as well as in postgraduate at some universities. We can assert that the formulation of strong research groups connected closely to postgraduate will contribute to upgrade the quality of research as well as the quality of master and PhD theses in Vietnam. The paper hence presents specifically the prospective research directions of S-FEM in Vietnam and deployment in postgraduate of civil engineering major at Hochiminh city.

Landsat time series data were used to characterize forest degradation in Lam Dong Province, Vietnam. We conducted three types of image change analyses using Landsat time series data to characterize the land cover changes. Our analyses concentrated on the timeframe of 1973–2014, with much emphasis on the latter part of that range. We conducted a field trip through Lam Dong Province to develop a better understanding of the ground conditions of the region, during which we obtained many photographs of representative forest sites with Global Positioning System locations to assist us in our image interpretations. High-resolution Google Earth imagery and Landsat data of the region were used to validate results. In general, our analyses indicated that many land-use changes have occurred throughout Lam Dong Province, including gradual forest to non-forest transitions. Recent changes are most marked along the relatively narrow interfaces between agricultural and forest areas that occur towards the boundaries of the province. One important observation is that the most highly protected national reserves in the region have not changed much over the entire Landsat timeframe (1972–present). Spectral changes within these regions have not occurred at the same levels as those areas adjacent to the reserves.

There are few allometric equations available for dipterocarp forests, despite the fact that this forest type covers extensive areas in tropical Southeast Asia. This study aims to develop a set of equations to estimate tree aboveground biomass (AGB) in dipterocarp forests in Vietnam and to validate and compare their predictive performance with allometric equations used for dipterocarps in Indonesia and pantropical areas. Diameter at breast height (DBH), total tree height (H), and wood density (WD) were used as input variables of the nonlinear weighted least square models. Akaike information criterion (AIC) and residual plots were used to select the best models; while percent bias, root mean square percentage error, and mean absolute percent error were used to compare their performance to published models. For mixed-species, the best equation was AGB = 0.06203 × DBH 2.26430 × H 0.51415 × WD 0.79456 . When applied to a random independent validation dataset, the predicted values from the generic equations and the dipterocarp equations in Indonesia overestimated the AGB for different sites, indicating the need for region-specific equations. At the genus level, the selected equations were AGB = 0.03713 × DBH 2.73813 and AGB = 0.07483 × DBH 2.54496 for two genera, Dipterocarpus and Shorea, respectively, in Vietnam. Compared to the mixed-species equations, the genus-specific equations improved the accuracy of the AGB estimates. Additionally, the genus-specific equations showed no significant differences in predictive performance in different regions (e.g., Indonesia, Vietnam) of Southeast Asia.

Từ trái Khổ qua, hai chất: uracil (chất I, Hình 1) và momordicoside K (chất II, Hình 2) đã được cô lập từ cao ethyl acetate. Hai chất này được xác định bằng các phương pháp phổ hiện đại và so sánh với tài liệu đã công bố.

Từ dịch chiết cồn của vỏ trái Măng cụt, hai hợp chất ?-mangostin (VMC1) và ?-mangostin (VMC2) đã được cô lập. Cấu trúc của các chất được nhận danh bằng các phương pháp phổ hiện đại như 1H, 13C- NMR, DEPT, HSQC, HMBC và so sánh với tài liệu đã công bố. Ngoài ra, hoạt tính kháng oxi hóa và kháng khuẩn của VMC1 và VMC2 cũng được khảo sát.

Từ cao petroleum ether, cao ethyl acetate của cây rau Sam (Portulaca oleracea L.) thu hái tại tỉnh Sóc Trăng, chúng tôi đã phân lập được các chất: ?-Sitosterol, ?-sitosterol-3-O-?-D-glucopyranoside và (2?S,2R,3S,4R,8E)-2-(2'-hydroxypentacosanoylamino)-3,4-dihydroxy octadec-8-en-1-O-?-D-glucopyranoside. Cấu trúc hoá học của ba chất này được nhận danh bằng các phương pháp phổ hiện đại như hồng ngoại, cộng hưởng từ hạt nhân, phổ khối lượng? Từ cao petroleum ether, cao ethyl acetate của cây rau Sam (Portulaca oleracea L.) thu hái tại tỉnh Sóc Trăng, chúng tôi đã phân lập được các chất: ?-Sitosterol, ?-sitosterol-3-O-?-D-glucopyranoside và (2?S,2R,3S,4R,8E)-2-(2'-hydroxypentacosanoylamino)-3,4-dihydroxy octadec-8-en-1-O-?-D-glucopyranoside. Cấu trúc hoá học của ba chất này được nhận danh bằng các phương pháp phổ hiện đại như hồng ngoại, cộng hưởng từ hạt nhân, phổ khối lượng?

Từ cao ethyl acetate và cao n-butanol của cây Kim tiền thảo, chúng tôi đã cô lập và nhận danh được ba hợp chất: genistein, b-sitosterol-3-o-b-glucopyranoside và allantoin. Cấu trúc của các hợp chất này đã được xác định bằng các dữ liệu phổ và tính chất hóa lý.

Từ dịch chiết chloroform và ethyl acetate của cây Cỏ Mực đã cô lập được hai Oleanan-triterpene là Echinocystic acid (CMC2) và Eclalbasaponin II (CMA3) bằng các phương pháp sắc ký. Cấu trúc được xác định bằng các phương pháp phổ hiện đại như 1H-NMR, 13C-NMR, COSY, DEPT, HSQC,HMBC,MS.

Từ cao n-butanol của cây Bạch tật lê đã phân lập được một spirostanol saponin là tribulosin (TLB5) bằng các phương pháp sắc ký. Cấu trúc của nó được xác định bằng các phương pháp quang phổ hiện đại: 1H-NMR, 13C-NMR, COSY, DEPT, HSQC,HMBC,MSvà so sánh với các tài liệu tham khảo.

Từ dịch chiết etanol của cây Xuyên tâm liên trồng tại Phú Yên đã cô lập được hai diterpen lacton là andrographolid (XTL1) và neoandrographolid (XTL2) bằng các phương pháp sắc ký. Cấu trúc được xác định bằng các phương pháp phổ hiện đại như 1H-NMR, 13C-NMR, COSY, DEPT, HSQC,HMBC,MS.

Từ cao ethyl acetate của cây Bồ Công Anh (Taraxacum officinale WIGG) thu hái tại Đà Lạt chúng tôi đã phân lập được một flavonoid là luteolin-7-O-b-D-glucopyranoside. Chất này được nhận danh bằng các phương pháp phổ hiện đại.

Các chất có tác dụng ức chế men -glucosidase đã được dùng làm thuốc hạ đường huyết bằng đường uống nhằm kiểm soát sự tăng đường huyết ở các bệnh nhân tiểu đường type 2 ? không phụ thuộc vào insulin. Cao chiết bởi các dung môi khác nhau từ hạt mướp đắng đã được khảo sát tác dụng ức chế theo cơ chế này. Kết quả khảo sát bước đầu cho thấy, cao cồn có tác dụng ức chế mạnh nhất (IC50 =31,25àg/ml), cao clorofom có tác dụng yếu hơn, trong khi cao ete petrol không thể hiện hoạt tính.

Tinh dầu hạt tiêu trồng tại huyện Chư Sê, tỉnh Gia Lai, lần đầu tiên được chiết xuất bằng phương pháp CO2lỏng siêu tới hạn. Thành phần hoá học của tinh dầu được phân tích bằng GC và GC/MS. Kết quả cho thấy hàm lượng sesquiterpene cao hơn monoterpene. Khi áp suất đến 110 bar, thu được alkaloid piperine, một chất cay của thành phần nhựa tiêu.

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The presence of persistent organic compounds in water has become a worldwide issue due to its resistance to natural degradation, inducing its environmental resilience. Therefore, the accumulation in water bodies, soils, and humans produces toxic effects. Also, low levels of organic pollutants can lead to serious human health issues, such as cancer, chronic diseases, thyroid complications, immune system suppression, etc. Therefore, developing efficient and economically viable remediation strategies motivates researchers to delve into novel domains within material science. Moreover, finding approaches to detect pollutants in drinking water systems is vital for safeguarding water safety and security. Covalent organic frameworks (COFs) are valuable materials constructed through strong covalent interactions between blocked monomers. These materials have tremendous potential in removing and detecting persistent organic pollutants due to their high adsorption capacity, large surface area, tunable porosity, porous structure, and recyclability. This review discusses various synthesis routes for constructing non-functionalized and functionalized COFs and their application in the remediation and electrochemical sensing of persistent organic compounds from contaminated water sources. The development of COF-based materials has some major challenges that need to be addressed for their suitability in the industrial configuration. This review also aims to highlight the importance of COFs in the environmental remediation application with detailed scrutiny of their challenges and outcomes in the current research scenario., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

College students are likely to hold negative ageist views and attitudes toward older people. The compassionate presence (CP) intervention could be a promising approach to reduce ageist attitudes that younger adults have of older adults. College students were trained virtually in deep, active, and compassionate listening and were matched with older adults living in assisted-living facilities. The partners met virtually for an hour once per week. Students completed weekly reflections throughout the ten-week intervention. The weekly reflections revealed that students had preconceived notions about older adults before the CP training. After the CP training and throughout the intervention, we noted a positive shift in perception, knowledge, and attitudes toward older adults and aging. Students built meaningful social bonds with older adults, developed strong communication and interpersonal skills, and acquired research and core leadership skills needed for future careers and professional practice.

Background: Liveborn infants with non-mosaic trisomy 22 are rarely described in the medical literature. Reported lifespan of these patients ranges from minutes to 3 years, with the absence of cardiac anomalies associated with longer-term survival. The landscape for offering cardiac surgery to patients with rare autosomal trisomies is currently evolving, as has been demonstrated recently in trisomies 13 and 18. However, limited available data on patients with rare autosomal trisomies provides a significant challenge in perinatal counseling, especially when there are options for surgical intervention., Case Presentation: In this case report, we describe an infant born at term with prenatally diagnosed apparently non-mosaic trisomy 22 and multiple cardiac anomalies, including a double outlet right ventricle, hypoplastic aortic valve and severe aortic arch hypoplasia, who underwent cardiac surgery. The decisions made by her family lending to her progress and survival to this day were made with a focus on the shared decision making model and support in the prenatal and perinatal period. We also review the published data on survival and quality of life after cardiac surgery in infants with rare trisomies., Conclusions: This patient is the only known case of apparently non-mosaic trisomy 22 in the literature who has undergone cardiac surgery with significant survival benefit. This case highlights the impact of using a shared decision making model when there is prognostic uncertainty., (© 2023. The Author(s).)

Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival 1 . Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia 2-4 . However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer 5-8 , and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described 9-12 . Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.

Krebs cycle substrates (KCS) can stabilise the colour of packaged meat by oxygen reduction. This study tested whether this reduction releases reactive oxygen species that may lead to lipid oxidation in minced meat under two different storage conditions. KCS combinations of succinate and glutamate increased peroxide forming potential (PFP, 1.18-1.32 mmol peroxides/kg mince) and thiobarbituric acid reactive substances (TBARS, 0.30-0.38 mg malondialdehyde (MDA) equivalents/kg mince) under low oxygen storage conditions. Both succinate and glutamate were metabolised. Moreover, under high oxygen (75%) storage conditions, KCS combinations of glutamate, citrate and malate increased PFP (from 1.22 to 1.29 mmol peroxides/kg) and TBARS (from 0.37 to 0.40 mg MDA equivalents/kg mince). Only glutamate was metabolised. The KCS combinations that were added to stabilise colour were metabolised during storage, and acted as pro-oxidants that promoted lipid oxidation in both high and low oxygen conditions., (Copyright © 2015. Published by Elsevier Ltd.)

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation., (Copyright © 2014, American Association for the Advancement of Science.)

Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer., (©2014 American Association for Cancer Research.)

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.

Animal and muscle characteristics were recorded for 41 cattle. The oxygen consumption rate (OCR) of M. semimembranosus was measured between 3.0-6.4h post mortem (PM3-6) and after 3 weeks in a vacuum pack at 4°C. Colour change measurements were performed following the 3 weeks using reflectance spectra (400-1,100 nm) and the colour coordinates L, a and b, with the samples being packaged in oxygen permeable film and stored at 4°C for 167 h. Significant individual animal differences in OCR at PM3-6 were found for mitochondrial complexes I and II. OCR of complex I declined with increased temperature and time PM, while residual oxygen-consuming side-reactions (ROX) did not. OCR of stored muscles was dominated by complex II respiration. A three-way regression between samples, colour variables collected upon air exposure and OCR of 3 weeks old fibres revealed a positive relationship between OCR and complex II activity and also between OCR and OCR(ROX). The presence of complex I and β-oxidation activities increased metmyoglobin formation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are neurodegenerative disorders of the aging population characterized by the abnormal accumulation of alpha-synuclein (alpha-syn). Previous studies have suggested that excitotoxicity may contribute to neurodegeneration in these disorders, however the underlying mechanisms and their relationship to alpha-syn remain unclear. For this study we proposed that accumulation of alpha-syn might result in alterations in metabotropic glutamate receptors (mGluR), particularly mGluR5 which has been linked to deficits in murine models of PD. In this context, levels of mGluR5 were analyzed in the brains of PD and DLB human cases and alpha-syn transgenic (tg) mice and compared to age-matched, unimpaired controls, we report a 40% increase in the levels of mGluR5 and beta-arrestin immunoreactivity in the frontal cortex, hippocampus and putamen in DLB cases and in the putamen in PD cases. In the hippocampus, mGluR5 was more abundant in the CA3 region and co-localized with alpha-syn aggregates. Similarly, in the hippocampus and basal ganglia of alpha-syn tg mice, levels of mGluR5 were increased and mGluR5 and alpha-syn were co-localized and co-immunoprecipitated, suggesting that alpha-syn interferes with mGluR5 trafficking. The increased levels of mGluR5 were accompanied by a concomitant increase in the activation of downstream signaling components including ERK, Elk-1 and CREB. Consistent with the increased accumulation of alpha-syn and alterations in mGluR5 in cognitive- and motor-associated brain regions, these mice displayed impaired performance in the water maze and pole test, these behavioral alterations were reversed with the mGluR5 antagonist, MPEP. Taken together the results from study suggest that mGluR5 may directly interact with alpha-syn resulting in its over activation and that this over activation may contribute to excitotoxic cell death in select neuronal regions. These results highlight the therapeutic importance of mGluR5 antagonists in alpha-synucleinopathies.

Ciliary guanine nucleotide exchange factors (GEFs) potentially activate G proteins in intraflagellar transport (IFT) cargo release. Several classes of GEFs have been localized to cilia or basal bodies and shown to be functionally important in the prevention of ciliopathies, but ciliary Arl-type Sec 7 related GEFs have not been well characterized. Nair et al. [ 1999] identified a Paramecium ciliary Sec7 GEF, PSec7. In Tetrahymena, Gef1p (GEF1), tentatively identified by PSec7 antibody, possesses ciliary and nuclear targeting sequences and like PSec7 localizes to cilia and macronuclei. Upregulation of GEF1 RNA followed deciliation and subsequent ciliary regrowth. Corresponding to similar Psec7 domains, GEF1domains contain IQ-like motifs and putative PH domains, in addition to GBF/BIG canonical motifs. Genomic analysis identified two additional Tetrahymena GBF/BIG Sec7 family GEFs (GEF2, GEF3), which do not possess ciliary targeting sequences. GEF1 and GEF2 were HA modified to determine cellular localization. Cells transformed to produce appropriately truncated GEF1-HA showed localization to somatic and oral cilia, but not to macronuclei. Subtle defects in ciliary stability and function were detected. GEF2-HA localized near basal bodies but not to cilia. These results indicate that GEF1 is the resident Tetrahymena ciliary protein orthologous to PSec7. Cell Motil. Cytoskeleton 2009. (c) 2009 Wiley-Liss, Inc.

Reactive astrocytes in neurotrauma, stroke, or neurodegeneration are thought to undergo cellular hypertrophy, based on their morphological appearance revealed by immunohistochemical detection of glial fibrillary acidic protein, vimentin, or nestin, all of them forming intermediate filaments, a part of the cytoskeleton. Here, we used a recently established dye-filling method to reveal the full three-dimensional shape of astrocytes assessing the morphology of reactive astrocytes in two neurotrauma models. Both in the denervated hippocampal region and the lesioned cerebral cortex, reactive astrocytes increased the thickness of their main cellular processes but did not extend to occupy a greater volume of tissue than nonreactive astrocytes. Despite this hypertrophy of glial fibrillary acidic protein-containing cellular processes, interdigitation between adjacent hippocampal astrocytes remained minimal. This work helps to redefine the century-old concept of hypertrophy of reactive astrocytes.