Genetic variants of lipid transport genes, dyslipidaemia and coronary heart disease.

PhDCoronary heart disease (CHD) is one of the most common causes of death in Western Countries. Genetic factors playa major role in the aetiology of CHD, however, the primary defects responsible for the disease have not been identified in most cases. With the application of recombinant DNA technology, it is possible to analyse the putative aetiological role of candidate genes. The role of the Lipoprotein Lipase (LPL) gene and the Apolipoprotein AI-CIII-AIV gene cluster were examined in German and Chinese controls, dyslipidaemics and arteriopaths (coronary artery disease and/or peripheral artery disease). Analyses of four allelic distributions (HindIlI-RFLP, Ser447_Ter, Asp9-Asn and Asn291_Ser mutations) of the LPL gene in German and Chinese populations with or without arterial disease did not show any significant frequency differences. In the German group, plasma triglycerides and VLDL-triglycerides were lower in subjects possessing the Ser447_Ter mutation (p=0.06 and < 0.05 respectively), this mutation was also significantly less frequent in the highest tertiles for triglycerides (p<0.02) and VLDL(P<0.04). The Ser447_Ter variant was found at lower frequencies in the Chinese lipaemic subjects. In addition, two disease related genetic variants (Asp9-Asn and Asn291 _Ser) in Europeans were not found in the Chinese group (P<0.03). Analyses of four genotypic distributions (the ApoAI PstI, MspI, XmnI RFLPs and the ApoCIII G3175_C variant) of the ApoAI-CIII-AIV gene cluster in German and Chinese populations with or without arterial disease did not show any significant differences. However, significant associations between high triglyceride, VLDL, TGIHDL ratio and the PstI RFLP at the ApoAI gene were shown in the German group (p=O.OOl, p<0.02 and p<0.04). In the Chinese group, the rare alleles of the Apo CIII G3175 -C variant and the Apo AI MspI polymorphic variant were both found more frequently in the upper tertile distributions for apo CIII levels and plasma triglyceride/HDL ratios (p<0.05 and p<0.04 respectively). The frequencies of two disease related RFLPs of the ApoAI gene (detected Pane 2 b with Mspl and Xmnl) and the ApoC1I1 G3175 -C variant were significantly different (p<0.0006, p<0.004 and p<0.003 respectively) between Chinese and German control groups. Out of eighteen French patients with diabetes m., obesity and severe hypertriglyceridaemia, eight subjects were found to possess mutations at the LPL gene locus by direct DNA sequencing. Three of these: Argl92_Ter (C829_ T); Phe351 _Leu (C1308_ G) and Thr361 -Thr (C1338 _ A) had not previously been described. Thr361_ Thr appears to be a common population polymorphism whose allele frequency in normolipidaemic diabetics was found to be 0.120 (162 chromosomes studied). The others are all rare at frequencies of <0.01 and may contribute to the phenotype by impairi~g clearance of plasma triglycerides. In eleven of the most lipaemic Chinese subjects, Thr361_Thr (C1338_A) was observed, additionally, the previously published mutations, Ala261_ Thr and Ser447 -Ter, were also noticed. Finally, a Finnish kindred, with premature coronary heart disease and decreased HDL cholesterol levels, was identified having an ApoAI variant (Lys107 ~~) by Single-Strand Conformation Polymorphisms (SSCP) and direct DNA sequencing. This variant was caused by a 3 bp deletion of nucleotides 1396 through 1398 in exon 4 of the ApoAI gene. Ten family members were heterozygous for this mutation. Mean serum apoAI and apoAII levels in heterozygotes were reduced by 18% and 220/0, and cholesteryl ester transfer protein activity (CETP) was reduced by 25% compared with unaffected family members (both p<0.05) respectively, while the plasma lecithin:cholesterol acyltransferase (LCAT) activity did not show any difference between heterozygotes and unaffected family members. The ability of the isolated apoAI variant to serve as a co-factor for LCAT in vitro did not differ from that of normal apoAI

San Bruno, puerta a los cerros: arquitectura como vínculo entre el ciudadano y su entorno natural

Artículo de gradoSe realiza un proyecto urbano a escala de tres barrios: Egipto, El Parejo y La Peña. igualmente se realiza un proyecto urbano a menor escala en el sector San Bruno (Egipto) y un proyecto arquitectónico dentro de este, en la entrada a los Cerros Orientales de Bogotá, se propone una casa del árbol.1. INTRODUCCIÓN 1.1 DISPOSITIVOS DE APROPIACIÓN DEMOCRATICA 2. METODOLOGÍA 3. RESULTADOS 3.1 ETAPAS DE DESARROLLO 3.2 BARRIO EGIPTO, EL PAREJO Y LA PEÑA 3.3 SECTOR SAN BRUNO 3.4 MEMORIA Y ACCESIBILIDAD 3.5 BOSQUE DE COLUMNAS 3.5.1 ACTIVA 3.5.2 PASIVA 3.5.3 PRODUCTIVA 4. LA CASA DEL ARBOL 5. DISCUSIÓN 6. CONCLUSION 7. REFERENCIAS 8. ANEXOSPregradoArquitect

Expression of the mismatch repair gene hMLH1 is enhanced in non-small cell lung cancer with EGFR mutations

Mismatch repair (MMR) plays a pivotal role in keeping the genome stable. MMR dysfunction can lead to carcinogenesis by gene mutation accumulation. HMSH2 and hMLH1 are two key components of MMR. High or low expression of them often mark the status of MMR function. Mutations (EGFR, KRAS, etc) are common in non-small cell lung cancer (NSCLC). However, it is not clear what role MMR plays in NSCLC gene mutations. The expression of MMR proteins hMSH2 and hMLH1, and the proliferation markers PCNA and Ki67 were measured by immunohistochemistry in 181 NSCLCs. EGFR and KRAS mutations were identified by high resolution melting analysis. Stronger hMLH1 expression correlated to a higher frequency of EGFR mutations in exon 19 and 21 (p<0.0005). Overexpression of hMLH1 and the adenocarcinoma subtype were both independent factors that related to EGFR mutations in NSCLCs (p=0.013 and p<0.0005). The expression of hMLH1, hMSH2 and PCNA increased, while Ki67 expression significantly decreased (p=0.030) in NSCLCs with EGFR mutations. Overexpression of hMLH1 could be a new molecular marker to predict the response to EGFR-TKIs in NSCLCs. Furthermore, EGFR mutations might be an early event of NSCLC that occur before MMR dysfunction.This work was supported by the National Nature Science Funds in China (Fund No. 81071805; URL: http://isisn.nsfc.gov.cn/egrantweb/), and Dalian Merricon Gene Diagnosis Technology Co., Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

CBP/p300 bromodomain: new promising epigenetic target

CREB (cAMP responsive element binding protein) binding protein (CBP) and adenovirus E1A-associated 300 kDa protein (p300) are histone acetyltransferases, which are necessary for multiple cellular processes. Thus, CBP/p300 are promising potential antitumor targets. To date, despite various small molecule inhibitors of CBP/p300 bromodomain (BRD) having been reported, no specific inhibitor was approved by U.S. Food and Drug Administration (FDA). In this review, we described the discovery, optimization, binding mode evaluation, selectivity and potency evaluation, and therapeutic opportunities of our CBP/p300 bromodomain inhibitors, aiming to inspire new inhibitor design and advance drug discovery research in this field. One video presents the development of CBP/p300 bromodomain inhibitors

Experimental observation of wave localization at the Dirac frequency in a two-dimensional photonic crystal microcavity

Trapping light within cavities or waveguides in photonic crystals is an effective technology in modern integrated optics. Traditionally, cavities rely on total internal reflection or a photonic bandgap to achieve field confinement. Recent investigations have examined new localized modes that occur at a Dirac frequency that is beyond any complete photonic bandgap. We design Al2O3 dielectric cylinders placed on a triangular lattice in air, and change the central rod size to form a photonic crystal microcavity. It is predicted that waves can be localized at the Dirac frequency in this device without photonic bandgaps or total internal reflections. We perform a theoretical analysis of this new wave localization and verify it experimentally. This work paves the way for exploring localized defect modes at the Dirac point in the visible and infrared bands, with potential applicability to new optical devices