Refinement of Peptide Conformational Ensembles by 2D IR Spectroscopy: Application to Ala‒Ala‒Ala

Characterizing ensembles of intrinsically disordered proteins is experimentally challenging because of the ill-conditioned nature of ensemble determination with limited data and the intrinsic fast dynamics of the conformational ensemble. Amide I two-dimensional infrared (2D IR) spectroscopy has picosecond time resolution to freeze structural ensembles as needed for probing disordered-protein ensembles and conformational dynamics. Also, developments in amide I computational spectroscopy now allow a quantitative and direct prediction of amide I spectra based on conformational distributions drawn from molecular dynamics simulations, providing a route to ensemble refinement against experimental spectra. We performed a Bayesian ensemble refinement method on Ala–Ala–Ala against isotope-edited Fourier-transform infrared spectroscopy and 2D IR spectroscopy and tested potential factors affecting the quality of ensemble refinements. We found that isotope-edited 2D IR spectroscopy provides a stringent constraint on Ala–Ala–Ala conformations and returns consistent conformational ensembles with the dominant ppII conformer across varying prior distributions from many molecular dynamics force fields and water models. The dominant factor influencing ensemble refinements is the systematic frequency uncertainty from spectroscopic maps. However, the uncertainty of conformer populations can be significantly reduced by incorporating 2D IR spectra in addition to traditional Fourier-transform infrared spectra. Bayesian ensemble refinement against isotope-edited 2D IR spectroscopy thus provides a route to probe equilibrium-complex protein ensembles and potentially nonequilibrium conformational dynamics.     

金属内肽酶底物Glutaryl－Ala－Ala－Phe－2NA的合成

文本以苯丙萘胺（Ｐｈｅ－２ＮＡ）为原料,通过Ｂｏｃ－Ｎ－羟基丁二酰亚胺活化酯法合成了金属内肽酶底物Ｇｌｕｔａｒｙｌ－Ａｌａ－Ａｌａ－Ｐｈｅ－２ＮＡ     

Molecular & biochemical analysis of Pro12Ala variant of PPAR-γ2 gene in type 2 diabetes mellitus

Diabetes has emerged as a major threat to human life globally. Genomic studies have found a significant link between the Pro12Ala polymorphism of the PPAR-γ2 gene with incidence as well as occurrence of the risk of metabolic syndrome. The present study was aimed at assessing the PPAR-γ2 variant in an Asian Indian cohort of type 2 diabetes patients and its correlation with metabolic parameters. The present case-control study involved 100 type 2 diabetic patients and 100 asymptomatic healthy volunteers enrolled in random. Assessment of demographic factors and biochemical parameters were done for all enrolled. In addition, genotyping for the Pro12Ala (CCA to GCA) polymorphism was done by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) technology. The genotyping study detected the frequency of the CC genotype (Pro12Pro) to be higher in frequency in comparison to the heterozygous CG genotype in both, cases and controls. The homozygous GG genotype (Ala12Ala) was not detected in any of the cases or controls assessed. Biochemical analysis of the levels of malondialdehyde (MDA) detected a significant increase (p < 0.0001). Additionally, increase in levels of fasting and postprandial glucose, total cholesterol, triglycerides, and parameters of the liver and renal function tests were detected. This study detected the PPAR-γ2 to be a significant biomarker for type 2 diabetes mellitus.     

The Association between the Pro12Ala Variant in the PPARγ2 Gene and Type 2 Diabetes Mellitus and Obesity in a Chinese Population

Background

Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity.

Methods and Findings

A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49–0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42–0.96; P = 0.030).

Conclusion

Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population.     

Association between PPARγ2 Pro12Ala polymorphism and myocardial infarction and obesity in Han Chinese in Hohhot, China

Activation of the peroxisome proliferator-activated receptor g (PPARg) improves insulin sensitivity and inhibits atherosclerosis. Whether PPARg2 Pro12Ala polymorphism affects myocardial infarction is not clearly understood. We investigated a possible association of PPARg2 Pro12Ala polymorphism with obesity and myocardial infarction in Han Chinese in Hohhot, Inner Mongolia, China. We included 121 subjects with myocardial infarction and 137 healthy controls in our study. Triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured. The following information was recorded for each subject: age, gender, body height, body weight, systolic blood pressure, and diastolic blood pressure; the body mass index was calculated. PCR-RFLP was used to examine Pro12Ala polymorphism. There were significant differences in clinical characteristics between myocardial infarction patients and healthy controls, except for diastolic blood pressure and triglycerides. The PP, PA/AA genotype frequencies were 88.4 and 11.6% in myocardial infarction patients and 95.6 and 4.4% in controls, respectively (P = 0.031). Individuals with the A allele had a significantly higher risk of myocardial infarction. The A allele was not an independent risk factor for obesity. We conclude that PPARg2 Pro12Ala polymorphisms are associated with increased risk for myocardial infarction in Han Chinese in Hohhot.     

高受体结合和低免疫原性的[Bl—Ala,B2—Ala]—胰岛素

通过化学半合成从天然猪胰岛素得到［Ｂｌ－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素,这一胰岛素类似物经聚丙烯酰胺凝胶电泳和ＨＰＬＣ鉴定证明是均一的,氨基酸组成与理论值相符,生物活性测定结果表明：［Ｂｌ－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素的体内活力与天然猪胰岛素相同,而与人胎盘细胞膜胰岛素受的结合能力为天然猪胰岛素的１３２％。这一结果进一步说明胰岛素Ｂ链Ｎ端肽段参予与受体相互作用,此外,［Ｂｌ－Ａｌａ,Ｂ２－Ａｌａ     

Roles of β-Tubulin Residues Ala428 and Thr429 in Microtubule Formation in Vivo

The C termini of β-tubulin isotypes are regions of high sequence variability that bind to microtubule-associated proteins and motors and undergo various post-translational modifications such as polyglutamylation and polyglycylation. Crystallographic analyses have been unsuccessful in resolving tubulin C termini. Here, we used a stepwise approach to study the role of this region in microtubule assembly. We generated a series of truncation mutants of human βI and βIII tubulin. Transient transfection of HeLa cells with the mutants shows that mutants with deletions of up to 22 residues from βIII and 16 from βI can assemble normally. Interestingly, removal of the next residue (Ala⁴²⁸) results in a complete loss of microtubule formation without affecting dimer formation. C-terminal tail switching of human βI and βIII tubulin suggests that C-terminal tails are functionally equivalent. In short, residues outside of 1–429 of human β-tubulins make no contribution to microtubule assembly. Ala⁴²⁸, in the C-terminal sequence motif N-QQYQDA⁴²⁸, lies at the end of helix H12 of β-tubulin. We hypothesize that this residue is important for maintaining helix H12 structure. Deletion of Ala⁴²⁸ may lead to unwinding of helix H12, resulting in tubulin dimers incapable of assembly. Thr⁴²⁹ plays a more complex role. In the βI isotype of tubulin, Thr⁴²⁹ is not at all necessary for assembly; however, in the βIII isotype, its presence strongly favors assembly. This result is consistent with a likely more complex function of βIII as well as with the observation that evolutionary conservation is total for Ala⁴²⁸ and frequent for Thr⁴²⁹.Microtubules are involved in a great variety of cellular functions. Their constituent protein tubulin is an αβ heterodimer, both α- and β-tubulin existing as multiple isotypes, encoded by different genes and differing in amino acid sequence (1). The differences among the isotypes are highly conserved in evolution. In mammals, the β isotypes are βIa, βIb, βII, βIII, βIVa, βIVb, βV, and βVI. There is evidence that the isotype differences have functional significance. For instance, the βIV isotype is found in all axonemes (2).Structurally, both α- and β-tubulin consist of a globular region of 427 amino acids followed by a C-terminal region of 17–24 amino acids (3–5). The C-terminal region is highly negatively charged, being especially rich in glutamate residues and lacking in basic residues, and is likely to project outward from the rest of the molecule, because of its high negative charge and the electrostatic repulsion among the glutamate residues (3). The three-dimensional structure of the globular domain has been determined by electron and x-ray crystallography (4, 5). However, the C-terminal region has never been localized in the three-dimensional reconstructions except by computer modeling. The probable reasons for this are 1) that, if the C-terminal region projects out from the rest of molecule, it is likely to be very flexible with respect to the rest of the molecule and 2) the C-terminal region undergoes post-translational modification. Both of these can lead to structural heterogeneity and cause the C terminus to be invisible to crystallographic techniques.In this work, we examine the role of the C termini of human β-tubulins to determine the minimal sequence requirement for microtubule incorporation through structure/function analyses. The human βI and βIII tubulin isotypes were utilized based on their high degree of sequence variability clustered at the C terminus (Fig. 1) and the fact that βI is broadly distributed among normal tissues, whereas βIII has a very narrow tissue distribution. These two isotypes share 92% sequence identity, with differences among these isotypes occurring in both the globular domain and the C-terminal region (1).Open in a separate windowFIGURE 1.Sequence alignment of human βIa and βIII tubulin isotypes. Human βIa and βIII tubulin isotypes were aligned with ClustalX 1.83 and processed with BioEdit. Hyphens denote identical residues between sequences.

TABLE 1

The C-terminal amino acid sequences of the human β-tubulin isotypes

高受体结合和低免疫原性的［B1—Ala，B2—Ala］－胰岛素

通过化学半合成从天然猪胰岛素得到［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］胰岛素。这一胰岛素类似物经聚丙烯酰胺凝胶电泳和ＨＰＬＣ鉴定证明是均一的,氨基酸组成与理论值相符生物活性测定结果表明：［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素的体内活力与天然猪胰岛素相同,而与人胎盘细胞膜胰岛素受体的结合能力为天然猪胰岛素的１３２％。这一结果进一步说明胰岛素Ｂ链Ｎ端肽段参子与受体相互作用。此外,［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素的免疫活性很低,远小于天然猪胰岛素的４％。     

［B1－Ala，B2－Ala］－胰岛素：受体结合特性及生物活力研究

本文报道了［Ｂ１～Ａｌａ,Ｂ２－Ａｌａ］－胰岛素与人胎盘细胞膜胰岛素受体结合的特性和体外生物活力,并与胰岛素进行比较。在３７℃和杆菌肽存在下,１２５Ｉ－［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素和１２５Ｉ－胰岛素与人胎盘细胞膜作用依赖于反应时间,反应６分钟到达平衡,此时,［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素和胰岛素与胰岛素受体的最大结合分别为每毫克膜蛋白结合６．４４ｆｍｏｌ和３．４７ｆｍｏｌ：达到平衡一半所需时间（Ｔ１／２）分别为１９秒和２５秒。用１２５Ｉ－［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素作为放射配体进行竞争性结合研究,从ＩＣ（５０）得［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］胰岛素的受体结合活力为胰岛素的１３９．６％。Ｓｃａｔｏｈａｒｄ分析求得;［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素与高亲和和低亲和结合位点的结合常数在４℃时分别为５．８８×１０８Ｌ／ｍｏｌ和７．６３×１０５Ｌ／ｍｏｌ,而胰岛素分别为４．８３×１０８Ｌ／ｍｏｌ和３．３９×１０５Ｌ／ｍｏｌ。促脂肪细胞生成脂的实验表明：［Ｂ１－Ａｌａ,Ｂ２－Ａｌａ］－胰岛素的活力为胰岛素的１３０％。     

[B_1Ala,B_2Ala,B_3Lys]-胰岛素的制备和生物活性(英文)

本文报道了胰岛素分子中Ｂ１～３序列（Ｐｈｅ－Ｖａｌ－Ａｓｎ）为Ａｌａ－Ａｌａ－Ｌｙｓ取代的胰岛素类似物制备及其生物性质。［Ｂ１Ａｌａ,Ｂ２Ａｌａ,Ｂ３Ｌｙｓ］－胰岛素仍保留天然胰岛素的全部体内活性和受体结合能力,但体外促脂肪生成活性和免疫活性分别只为胰岛素的７０％和０．８８％。本文还就胰岛素Ｂ链Ｎ端肽段对其结构和功能的影响进行了讨论。     

Effects of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ2 gene on metabolic syndrome risk: A meta-analysis

Background

Associations between peroxisome proliferator-activated receptor γ2 (PPARγ2) gene polymorphism and metabolic syndrome risk remained controversial and ambiguous. Thus, we performed a meta-analysis to assess the association between Pro12Ala polymorphism in PPARγ2 gene and metabolic syndrome susceptibility.

Methods

An electronic literature search was conducted on Medline, OVID, Cochrane Library database, and the China National Knowledge Internet up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the fixed or random effects model.

Results

Ten studies involving a total of 4456 cases and 10343 controls were included in this meta-analysis. No statistical evidence of association was found between Pro12Ala polymorphism and metabolic syndrome risk in all genetic models (homozygote model: OR = 0.83, 95% CI = 0.62–1.12; heterozygote model: OR = 1.04, 95% CI = 0.94–1.14; dominant model: OR = 1.02, 95% CI = 0.93–1.12; recessive model: OR = 0.83, 95% CI = 0.62–1.11). No statistical evidence of significant association was observed when stratified by ethnicity, definition of metabolic syndrome, source of control groups and quality score of the selected articles. All in all, the results did not support a major role of the Pro12Ala variant of the PPARγ2 gene in metabolic syndrome risk.

Conclusions

This meta-analysis suggested that the effect of Pro12Ala polymorphism in PPARγ2 gene may not be related to metabolic syndrome as an entity. However, Pro12Ala may affect the single component of metabolic syndrome. A large, well designed study is required to more adequately assess the role for Pro12Ala polymorphism on metabolic syndrome.     

Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala,Arg184Serand Ser7Ala) and therapeutic response to deferiprone in β-thalassemia major patients

Deferiprone is used as a chelation agent in chronic iron overload in β-thalassemia patients. Patients on deferiprone therapy show variable response to this drug in terms of reduction in iron overload as well as adverse drug reactions (ADRs). The pharmacogenetic studies on deferiprone have not carried out in patients with blood disorders in India. Therefore, the present study was carried out to evaluate the three most common nonsynonymous UGT1A6 polymorphisms Thr181Ala (541 A/G), Arg184Ser (552 A/C) and Ser7Ala (19 T/G) and therapeutic response to deferiprone in β-thalassemia major patients. Two hundred and eighty six (286) β-thalassemia major patients were involved in the study. Serum ferritin levels were estimated periodically to assess the status of the iron overload and the patients were grouped into responders and non-responders depending on the ferritin levels. The UGT1A6*2 polymorphisms were detected by PCR-RFLP methods. The association between the genotypes and outcome as well as ADRs was evaluated by Open EPI software. A significant difference was observed in the genotypic distribution of UGT1A6*2 Thr181Ala polymorphism in responders and non-responders. However, there was no difference in the genotypic distribution between patients with and without ADRs. As far as the UGT1A6*2 Arg184Ser polymorphism is concerned, no significant difference was observed between responders and non-responders. Further, evaluating the association of UGT1A6*2 Ser7Ala polymorphism with drug response, there was no significant difference in the genotypic distribution between responders and non-responders. However, there was a significant difference between responders with and without ADRs and non-responders with and without ADRs. In addition to this haplotype analysis was also carried out. However, we did not find any specific haplotype to be significantly associated with the deferiprone response in β-thalassemia major patients.     

Methyl-detected ‘out-and-back’ NMR experiments for simultaneous assignments of Alaβ and Ileγ2 methyl groups in large proteins

A set of sensitive methyl-detected ‘out-and-back’ NMR experiments for simultaneous assignments of Alaβ and Ileγ2 methyl positions in large proteins is described. The developed methodology is applied to an 82-kDa enzyme Malate Synthase G. Complete alanine β and isoleucine γ2 ¹H–¹³C methyl chemical shift assignments could be obtained from the set of new methyl-detected ‘out-and-back’ 3D experiments. The described methodology for methyl assignments should be applicable to protein molecules within approximately 100-kDa molecular weight range irrespective of the labeling strategy chosen to produce selectively protonated Alaβ and Ileγ2 ¹³CH₃ sites on a deuterated background.     

Influence of different CLA isomers on insulin resistance and adipocytokines in pre-diabetic, middle-aged men with PPARγ2 Pro12Ala polymorphism

Conjugated linoleic acids (CLAs) are natural PPARγ ligands, which showed conflicting effects on metabolism in humans. We examined metabolic effects of different isomers of CLA in subjects with PPARγ2 Pro12Ala polymorphisms. A total of 35 men underwent four intervention periods in a crossover study design: subjects with either genotypes received c9, t11 CLA or t10, c12 CLA, a commercially available 1:1 mix of both isomers or reference oil (linoleic acid (LA)). Adipocytokines, insulin, glucose and triglycerides were assessed in the fasting state and after a standardized mixed meal. Across all genotypes, there was a significant (p = 0.025) CLA treatment effect upon postprandial (pp) HOMA-IR values, with c9, t11 CLA and CLA isomer mix improving, but t10, c12 CLA isomer worsening. In Ala12Ala subjects, the t10, c12 isomer caused weight gain (p = 0.03) and tended to increase postprandial insulin levels (p = 0.05). In Pro12Pro subjects, t10, c12 resulted in reduction in waist circumference (p = 0.03). The comparison of the different genotype groups revealed statistically different changes in fasting and postprandial insulin, HOMA-IR and leptin after intervention. c9, t11 CLA and the commercial CLA mix showed beneficial effects on insulin sensitivity compared with LA, while t10, c12 CLA adversely affects body weight and insulin sensitivity in different PPAR genotypes. CLA isomers have different effects on metabolism in Ala and Pro carriers.     

Relationship between PPARγ Pro12Ala gene polymorphism and type 2 diabetic nephropathy risk in Asian population: results from a meta-analysis

Abstract

The relationship between peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala gene polymorphism and type 2 diabetic nephropathy (T2DN) risk in Asians is still unclear. This study was performed to evaluate if there was an association between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Asians using meta-analysis. The relevant reports were searched and identified from PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 October 2013, and eligible studies were included and synthesized. Ten reports were recruited into this meta-analysis for the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk. The Pro12Ala gene polymorphism in the Asian population was shown to be not associated with T2DN risk (Ala/Ala: OR?=?0.67, 95% CI: 0.22–2.00, p?=?0.47; Pro/Pro: OR?=?1.77, 95% CI: 0.82–1.65, p?=?0.39; Ala allele: OR?=?0.74, 95% CI: 0.47–1.16, p?=?0.19). In the sensitivity analysis according to Hardy-Weinberg equilibrium (HWE), the control source from hospital, the control source from population, the genotyping methods using PCR-RFLP, the genotyping methods using Taqman, sample size of case (≥100), the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk was also not found. Interestingly, in the sensitivity analysis according to sample size of case (<100), Ala allele was associated with T2DN risk, but not the Pro/Pro genotype. However, the sample size for sensitivity analysis according to sample size of case (<100) was relatively small and therefore, the results should be interpreted with care. In conclusion, the PPARγ Pro12Ala gene polymorphism was not associated with T2DN risk in Asians. However, Ala allele was associated with T2DN risk when the sample size of case was less than 100. Nonetheless, additional studies are required to firmly establish a correlation between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Asians.     

Novel variant Pro143Ala in <Emphasis Type="Italic">HTRA2</Emphasis> contributes to Parkinson’s disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria

Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson’s disease (PD). We assessed the presence of HTRA2 mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire HTRA2 coding region was sequenced in 113 early-onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C > G (Pro143Ala) and c.906 +3 G > A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late-onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5–2.8, P = 0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD.     

The Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor Gamma-2 Gene (PPARγ2) Is Associated with Increased Risk of Coronary Artery Disease: A Meta-Analysis

Background

Contradictory results have been reported regarding the association between Pro12Ala polymorphism of PPARγ2 and coronary artery disease (CAD). We sought to estimate the inconsistent results by performing a comprehensive meta-analysis.

Methods

Studies in English or Chinese publications were identified by screening MEDLINE, Embase, CNKI, Wanfang and CBM. 22 studies including 8948 cases and 14427 controls were selected. A random-effects model was applied to combine the divergent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias.

Results

The Pro12Ala polymorphism of control population followed Hardy-Weinberg equilibrium for all studies (P>0.05). Overall, a marginal increased risk of CAD under the recessive genetic model (AlaAla vs ProAla+ProPro: P = 0.04, OR = 1.31, 95%CI 1.01–1.69, P_{heterogeneity} = 0.67, I² = 0%) and the homozygote comparison (AlaAla vs ProPro: P = 0.04,OR = 1.30, 95%CI 1.01–1.68, P_{heterogeneity} = 0.68, I² = 0%) was observed. In the subgroup analysis by ethnicity, carriers of AlaAla homozygotes had a significant increased risk for CAD among Caucasians (AlaAla vs ProAla+ProPro: P = 0.01, OR = 1.45, 95%CI 1.08–1.96, P_{heterogeneity} = 0.48, I² = 0%; AlaAla vs ProPro: P = 0.02,OR = 1.44, 95%CI 1.07–1.93, P_{heterogeneity} = 0.46, I² = 0%). After dividing into population source, the CAD risk magnitude of hospital-based studies was distinctly strengthened under the recessive model (P = 0.03,OR = 1.85,95%CI 1.07–3.19, P_{heterogeneity} = 0.87,I² = 0%) and the homozygote comparison (P = 0.03,OR = 1.83, 95%CI 1.06–3.16, P_{heterogeneity} = 0.88, I² = 0%). There was no observable publication bias as reflected by funnel plot and Egger’s linear regression test (t = -0.12, P = 0.91).

Conclusion:

Our results demonstrated that the PPARγ2 Pro12Ala polymorphism might be risk-conferring locus for the progression of CAD among Caucasians, but not among Asians.     

[B1Ala,B2Al2,B3Lys]—胰岛素的制备和生物活性

本文报道了胰岛素分子中Ｂ１￣３序列（Ｐｈｅ－Ｖａｌ－Ａｓｎ）为Ａｌａ－Ａｌａ－Ｌｙｓ取代的胰岛素类似物制备及其生物性质。［Ｂ１Ａｌａ,Ｂ２Ａｌａ,Ｂ３Ｌｙｓ］－胰岛素仍保留天然胰岛素的全部体内活性和受体结合能力,但体外促脂肪生成活性和免疫活性分别只为胰岛素的７０％和０．８８％。本文还就胰岛素Ｂ链Ｎ端肽段对其结构和功能的影响进行了讨论。