Endothelin-converting Enzyme-1b Genetic Variants Increase the Risk of Coronary Artery Ectasia.

Coronary artery ectasia (CAE), defined as a 1.5-fold or greater enlargement of a coronary artery segment compared to the adjacent normal coronary artery, is frequently associated with atherosclerotic coronary artery disease (CAD). Membrane-bound endothelin converting enzyme-1 (ECE-1) is involved in the maturation process of the most potent vasoconstrictor ET-1. Polymorphisms in the endothelin (ET) gene family have been shown associated with the development of atherosclerosis. This study aims to investigate the effects of rs213045 and rs2038089 polymorphisms in the ECE-1 gene which have been previously shown to be associated with atherosclerosis and hypertension (HT), in CAE patients. Ninety-six CAE and 175 patients with normal coronary arteries were included in the study. ECE-1b gene variations rs213045 and rs2038089 were determined by real-time PCR. The frequencies of rs213045 C > A (C338A) CC genotype (60.4% vs. 35.4%, p < 0.001) and rs2038089 T > C T allele (64.58% vs. 35.42%, p = 0.017) were higher in the CAE group compared to the control group. The multivariate regression analysis showed that the ECE-1b rs213045 CC genotype (p = 0.001), rs2038089 T allele (p = 0.017), and hypercholesterolemia (HC) (p = 0.001) are risk factors for CAE. Moreover, in nondiabetic individuals of the CAE and control groups, it was observed that the rs213045 CC genotype (p < 0.001), and rs2038089 T allele (p = 0.003) were a risk factor for CAE, but this relationship was not found in the diabetic subgroups of the study groups (p > 0.05). These results show that ECE-1b polymorphisms may be associated with the risk of CAE and this relationship may change according to the presence of type II diabetes.

Receptor for advanced glycation end products polymorphisms in coronary artery ectasia.

BACKGROUND: Although the implication of receptor of advanced glycation endproducts (RAGE) has been reported in coronary artery disease, its roles in coronary artery ectasia (CAE) have remained undetermined. Furthermore, the effect of RAGE polymorfisms were not well-defined in scope of soluble RAGE (sRAGE) levels. Thus, we aimed to investigate the influence of the functional polymorphisms of RAGE -374T > A (rs1800624) and G82S (rs2070600) in CAE development. METHODS: This prospective observational study was conducted in 2 groups selected of 2452 patients who underwent elective coronary angiography (CAG) for evaluation after positive noninvasive heart tests. Group-I included 98 patients with non-obstructive coronary artery disease and CAE, and Group-II (control) included 100 patients with normal coronary arteries. SNPs were genotyped by real-time PCR using Taqman® genotyping assay. Serum sRAGE and soluble lectin-like oxidized receptor-1 (sOLR1) were assayed by ELISA and serum lipids were measured enzymatically. RESULTS: The frequencies of the RAGE -374A allele and -374AA genotype were significantly higher in CAE patients compared to controls (p < 0.001). sRAGE levels were not different between study groups, while sOLR1 levels were elevated in CAE (p = 0.004). In controls without systemic disease, -374A allele was associated with low sRAGE levels (p < 0.05), but this association was not significant in controls with HT. Similarly, sRAGE levels of CAE patients with both HT and T2DM were higher than those no systemic disease (p = 0.02). The -374A allele was also associated with younger patient age and higher platelet count in the CAE group in both total and subgroup analyses. In the correlation analyses, the -374A allele was also negatively correlated with age and positively correlated with Plt in all of these CAE groups. In the total CAE group, sRAGE levels also showed a positive correlation with age and a negative correlation with HDL-cholesterol levels. On the other hand, a negative correlation was observed between sRAGE and Plt in the total, hypertensive and no systemic disease control subgroups. Multivariate logistic regression analysis confirmed that the -374A allele (p < 0.001), hyperlipidemia (p < 0.05), and high sOLR1 level (p < 0.05) are risk factors for CAE. ROC curve analysis shows that RAGE -374A allele has AUC of 0.713 (sensitivity: 83.7 %, specificity: 59.0 %), which is higher than HLD (sensitivity: 59.2 %, specificity: 69.0 %), HT (sensitivity: 62.4 %, specificity: 61.1 %) and high sOLR1 level (≥0.67 ng/ml)) (sensitivity: 59.8 %, specificity: 58.5 %). CONCLUSION: Beside the demonstration of the relationship between -374A allele and increased risk of CAE for the first time, our results indicate that antihypertensive and antidiabetic treatment in CAE patients causes an increase in sRAGE levels. The lack of an association between the expected -374A allele and low sRAGE levels in total CAE group was attributed to the high proportion of hypertensive patients and hence to antihypertensive treatment. Moreover, the RAGE -374A allele is associated with younger age at CAE and higher Plt, suggesting that -374A may also be associated with platelet activation, which plays a role in the pathogenesis of CAE. However, our data need to be confirmed in a large study for definitive conclusions.

Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions.

Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.

This study evaluated the association of the Protein Convertase Subtilisin/Kexin-9 (PCSK9) E670G mutation with the serum lipids, PCSK9 levels and concomitant diseases on the in-stent restenosis (ISR) risk. The E670G-G allele, hyperlipidemia, and type 2 diabetes (T2DM) were found risk factors for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR, while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. Our results indicated that the unusual effects of both genotypes of the E670G that may be involved in the ISR risk in association with concomitant diseases.

(1 → 3),(1 → 6) and (1 → 3)-ß-D-glucan physico-chemical features drive their fermentation profile by the human gut microbiota.

Mushroom polysaccharides consist of a unique set of polymers that arrive intact in the human large intestine becoming available for fermentation by resident gut bacteria with potential benefits to the host. Here we have obtained four glucans from two mushrooms (Pholiota nameko and Pleurotus pulmonarius) under different extraction conditions and their fermentation profile by human gut bacteria in vitro was evaluated. These glucans were isolated and characterized as (1 â†’ 3),(1 â†’ 6)-ß-D-glucans varying in branching pattern and water-solubility. An aliquot of each (1 â†’ 3),(1 â†’ 6)-ß-D-glucan was subjected to controlled smith degradation process in order to obtain a linear (1 â†’ 3)-ß-D-glucan from each fraction. The four ß-D-glucans demonstrated different water solubilities and molar mass ranging from 2.2 × 105 g.mol-1 to 1.9 × 106 g.mol-1. In vitro fermentation of the glucans by human gut microbiota showed they induced different short chain fatty acid production (52.0-97.0 mM/50 mg carbohydrates), but an overall consistent high propionate amount (28.5-30.3 % of total short chain fatty acids produced). All glucans promoted Bacteroides uniformis, whereas Anaerostipes sp. and Bacteroides ovatus promotion was strongly driven by the ß-D-glucans solubility and/or branching pattern, highlighting the importance of ß-D-glucan discrete structures to their fermentation by the human gut microbiota.

Modification of the microstructure of tef [Eragrostis tef (Zucc.) Trotter] flour ultrasonicated at different temperatures. Impact on its techno-functional and rheological properties.

Tef flour comes from a nutritionally-rich ancient grain gaining increasing interest in gluten-free market. Gluten-free sources are modified by different means to improve their functionality. Ultrasound treatment (US) alters flours' structure and leads to physically modified flours with a wider application range. The aim of the present work was to evaluate the impact of US treatments of moderate treatment time, 10 min, and high concentration of the aqueous flour dispersion, 25%, on the microstructural, starch damage, apparent amylose content, techno-functional, pasting and rheological properties of two tef flour varieties, white and brown. Temperature was varied (20, 40, 45, 50, and 55 °C) to modulate the impact of sonication. US treatments led to general particle fragmentation which markedly increased starch damage and lightness (L*) values. Apparent amylose content was higher after ultrasonication, as consequence of molecular fragmentation due to cavitation. Increased starch granules' exposed area led to enhanced interaction with water, promoting the water absorption index (WAI) and swelling power (SP) of treated flours. Pasting properties showed increased pasting temperatures as well as decreased viscometric profiles with lower breakdown viscosities, indicative of starch rearrangement improved by increasing temperature. Rheological properties indicated higher consistency in gels after US treatments, with improved ability to withstand stress and lower values of tan(δ)1 reflecting a higher solid-like behavior and higher strength of the gel. Temperature was found to be a crucial variable during US treatments, showing an improved degree of modification at higher temperatures in ultrasonicated tef flours, following the same trend in both varieties.

Next-generation sequencing of prolidase gene identifies novel and common variants associated with low prolidase in coronary artery ectasia.

BACKGROUND: Decreased collagen biosynthesis and increased collagenolysis can cause ectasia progression in the arterial walls. Prolidase is a key enzyme in collagen synthesis; a decrease in prolidase activity or level may decrease collagen biosynthesis, which may contribute to ectasia formation. Considering that, the variations in PEPD gene encoding prolidase enzyme were evaluated by analyzing next-generation sequencing (NGS) for the first time together with known risk factors in coronary artery ectasia (CAE) patients. METHODS: Molecular analysis of the PEPD gene was performed on genomic DNA by NGS in 76 CAE patients and 76 controls. The serum levels of prolidase were measured by the sandwich-ELISA technique. RESULTS: Serum prolidase levels were significantly lower in CAE group compared to control group, and it was significantly lower in males than females in both groups (p < 0.001). On the other hand, elevated prolidase levels were observed in CAE patients in the presence of diabetes (p < 0.001), hypertension (p < 0.05) and hyperlipidemia (p < 0.05). Logistic regression analysis demonstrated that the low prolidase level (p < 0.001), hypertension (p < 0.02) and hyperlipidemia (p < 0.012) were significantly associated with increased CAE risk. We identified four missense mutations in the PEPD gene, namely G296S, T266A, P365L and S134C (novel) that could be associated with CAE. The pathogenicity of these mutations was predicted to be "damaging" for G296S, S134C and P365L, but "benign" for T266A. We also identified a novel 5'UTR variation (Chr19:34012748 G>A) in one patient who had a low prolidase level. In addition, rs17570 and rs1061338 common variations of the PEPD gene were associated with low prolidase levels in CAE patients, while rs17569 variation was associated with high prolidase levels in both CAE and controls (p < 0.05). CONCLUSIONS: Our findings indicate that the low serum prolidase levels observed in CAE patients is significantly associated with PEPD gene variations. It was concluded that low serum prolidase level and associated PEPD mutations may be potential biomarkers for the diagnosis of CAE.

Formation of cereal protein disulfide-linked stable matrices by apigeninidin, a 3-deoxyanthocyanidin.

The food matrix is a factor affecting digestion rate of macronutrients, like starch. Sorghum protein networks surrounding starch have been associated with its comparatively low starch digestibility, though their formation mechanism is unclear. Since sorghums contain 3-deoxyanthocyanidins with redox property that could promote sulfhydryl-disulfide interchanges, we hypothesized that added apigeninidin (a 3-deoxyanthocyanidin) will form matrices in a non-matrix-forming cereal (corn). A model system using ovalbumin determined apigeninidin as a polymerizing agent. Starch digestion and microstructure of cereal porridges from yellow corn with and without added apigeninidin, commercial blue corn, and white sorghum were examined. Apigeninidin addition promoted protein matrices in yellow corn and attenuated initial starch digestion rate that was related to matrix formation rather than α-amylase inhibition. Blue corn with 3-deoxyanthocyanidins formed protein matrices with similar lower overall starch digestibility as sorghum. Promoting matrix formation in cereal-based foods with 3-deoxyanthocyanidins may be a strategy to modulate starch digestion rate.

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY).

BACKGROUND/AIM: High-sensitivity C-reactive protein (hs-CRP) is used in the differential diagnosis of maturity-onset diabetes of the young (MODY)-3, but other inflammatory markers have not been investigated in MODY patients. We aimed to compare the serum levels of anti-inflammatory and proinflammatory cytokines between MODY patients and healthy subjects and show the inflammatory features in MODY subtypes. PATIENTS AND METHODS: Thirty patients with clinically suspected MODY and 34 healthy controls were included in this study. Next-generation sequencing (NGS) was used for the molecular diagnosis of MODY subtypes. Serum levels of cytokines were measured using a multiplexed cytokine assay and hs-CRP concentration was determined by the immunoturbidimetric assay. RESULTS: The hs-CRP levels were higher in both NGS-confirmed (MODY, n=17) (p=0.009) and NGS-unconfirmed (non-MODY, n=13) patients (p<0.001) than those in controls. However, IL-1ß (p=0.001), IL-6 (p=0.018), IL-31 (p=0.003), TNF-α (p<0.001), and sCD40L (p=0.007) levels of MODY patients and IL-1ß (p=0.002), IL-31 (p<0.001), IL-22 (p=0.018), and sCD40L (p=0.039) levels of non-MODY patients were lower than those of controls. While hs-CRP levels were lower in MODY3 patients than non-MODY3 patients (p=0.009), IL-17A (p=0.006) and IL-23 (p=0.016) levels for the first time in this study were found to be higher in patients with MODY3 than in patients with other MODY subtypes (p<0.05). CONCLUSION: MODY patients had lower serum levels of the proinflammatory cytokines IL-1ß, IL-6, TNF-α, IL-31, and sCD40L compared to healthy controls. High IL-17A and IL-23 levels along with low hs-CRP levels may be potential markers to distinguish MODY3 from other MODY subtypes.

Influence of Hofmeister anions on structural and thermal properties of a starch-protein-lipid nanoparticle.

A self-assembled soluble nanoparticle, composed of common food biopolymers (carbohydrate, protein) and lipid, was previously reported by our laboratory. Although carrying capacity of valuable small molecules was demonstrated, physical functional properties are also important. Given the stabilization or destabilization characteristics of Hofmeister anion on macromolecular structures, mainly on proteins, here, we investigated the effects of different sodium salts composed of different Hofmeister anions on the structural and thermal properties of these self-assembled nanoparticles for improved functionalities. The salts were added into the mixture that was prepared in a diluted system during nanoparticle formation. Increased concentration of kosmotropic anions, in contrast to the chaotropic anion tested, resulted in nanoparticles with higher molar mass, hydrodynamic radius, and molecular density with more compact arrangement. The nanoparticles produced in presence of kosmotropic anions dissociated at higher temperatures and required higher enthalpies compared to the control sample. Spherical nanoparticles were formed for the kosmotropes with shear thinning behavior, contrary to rod-like nanoparticles for the chaotrope with near-Newtonian behavior. These findings help to gain an understanding of the effect of altering environmental conditions on the nanoparticles with an aim of producing desired structures for applications.

Precision Diagnosis of Maturity-Onset Diabetes of the Young with Next-Generation Sequencing: Findings from the MODY-IST Study in Adult Patients.

Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as "deleterious" as well as those predicted as "benign." Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.

Latest developments in the applications of microfluidization to modify the structure of macromolecules leading to improved physicochemical and functional properties.

Microfluidization is a unique high-pressure homogenization technique combining various forces such as high-velocity impact, high-frequency vibration, instantaneous pressure drop, intense shear rate, and hydrodynamic cavitation. Even though it is mainly used on emulsion-based systems and known for its effects on particle size and surface area, it also significantly alters physicochemical and functional properties of macromolecules including hydration properties, solubility, viscosity, cation-exchange capacity, rheological properties, and bioavailability. Besides, the transformation of structure and conformation due to the combined effects of microfluidization modifies the material characteristics that can be a base for new innovative food formulations. Therefore, microfluidization is being commonly used in the food industry for various purposes including the formation of micro- and nano-sized emulsions, encapsulation of easily degradable bioactive compounds, and improvement in functional properties of proteins, polysaccharides, and dietary fibers. Although the extent of modification through microfluidization depends on processing conditions (e.g., pressure, number of passes, solvent), the nature of the material to be processed also changes the outcomes significantly. Therefore, it is important to understand the effects of microfluidization on each food component. Overall, this review paper provides an overview of microfluidization treatment, summarizes the applications on macromolecules with specific examples, and presents the existing problems.

Investigation of Scavenger Receptor Class B Type I gene variants in patients with coronary heart disease with a history of early myocardial infarction.

OBJECTIVE: The scavenger receptor class B type 1 (SR-BI, SCARB1), which is a high-density lipoprotein (HDL) receptor that mediates selective cholesteryl ester uptake, plays an important role in reverse cholesterol transport. This study investigated the distribution of polymorphic variants of the SR-BI gene in patients with coronary heart disease (CHD) with a history of early myocardial infarction (MI) at an early age and their effects on their serum lipid levels. METHODS: SR-BI rs5888(T>C), rs4238001(C>T), and rs10846744(G>C) were analyzed in 100 male patients with CHD with a history of MI (MI+) who were younger than 50 years and 89 male control subjects without MI history (MI-) using real-time polymerase chain reaction (PCR) and mutant-allele-specific PCR techniques. RESULTS: SR-BI rs4238001 common-CC genotype was found to be more frequent in patients with MI+ than in control subjects (MI-; odds ratio 4.046, p<0.001). The rs10846744 rare-C allele showed a significant association with increased total cholesterol (p=0.014) and triglyceride (p=0.009) levels in the MI+ CHD group. Logistic regression analysis confirmed that there may be an association between the rs4238001-CC genotype (p=0.002), smoking (p=0.026), and MI+ CHD in the presence of other risk factors associated with CHD, whereas haplotype analysis confirmed that patients with MI+ CHD (rs5888-C, rs10846744-G, and rs4238001-C alleles) and CCC (rs5888-C, rs10846744-C, and rs4238001-C alleles) haplotypes were highly frequent (p<0.01 and p=0.027, respectively). CONCLUSION: These results indicated that SR-BI gene variants show different distribution in patients with MI+ CHD compared with that in MI- control subjects, and these variants may have effects in favor of dyslipidemia.

Kallikrein 11 Down-regulation in Breast Carcinoma: Correlation With Prognostic Parameters.

BACKGROUND: Expression of kallikrein-11 (KLK11) has been found to be related to the prognosis of various human cancer types but its physiological functions in the steps of breast cancer (BC) progression are still unknown. MATERIALS AND METHODS: BC and adjacent normal breast tissue samples were collected from 28 patients. KLK11 expression levels were determined by real-time polymerase chain reaction for each sample and associations with known prognostic features were statistically analyzed. RESULTS: Although there was slight up-regulation in tumor tissues overall, significant down-regulation of KLK11 expression in tumor tissue was observed in the elderly and in patients with perineural invasion. Furthermore, tumor size, grade, mitotic score, necrosis, calcification, lymphatic invasion, hormone receptor status and Ki67 expression were associated with altered KLK11 level. CONCLUSION: Changes in expression levels of KLK11, associated with patient characteristics, might be used as complementary data in order to predict clinical outcome and prognosis in BC.

Antiproliferative effects of Turkish pomegranate (Punica granatum L.) extracts on MCF-7 human breast cancer cell lines with focus on antioxidant potential and bioactive compounds analyzed by LC-MS/MS.

In this study, eight different pomegranate (Punica granatum L.) cultivars from Turkey were evaluated for their antioxidant and cytotoxic effects on the MCF-7 breast cancer cell lines and MCF-10A breast fibrocystic epithelial cell lines with a focus on their chemical compositions by LC-MS/MS. Cell lines were treated with pomegranate juice extracts in different doses at selected time intervals (24th, 48th, and 72nd hour). Afterwards, WST-1 cell proliferation assay was performed to investigate the cytotoxicity of the extracts. Accordingly, all extracts decreased the cell viability of MCF-7 breast cancer cell lines and had no cytotoxic effect on the cell viability of MCF-10A cell lines. Among eight extracts, P7 (Izmir 1513), which was rich in anthocyanins such as cyanidin chloride (69.76 ± 8.02 µg/g extract), cyanidin-3-O-glucoside (903.66 ± 101.89 µg/g extract), and punicalagin (992.09 ± 174.53 µg/g extract), was found to demonstrate the strongest cytotoxic activity on MCF-7 breast cancer cell lines by decreasing the cell viability in half at 24th hour with an IC50 value of 49.08 µg/ml. PRACTICAL APPLICATIONS: Eight commercially valuable pomegranate (Punica granatum) cultivars from Turkey were examined. Pelargonidin, cyanidin, cyanidin-3-O-gl, callistephin, and delphinidin-3-O-gl were quantified. Two cultivars (P1 and P3) showed comparatively higher antioxidant effects. A cultivar (P7) showed strongest cytotoxic activity against MCF-7 breast cancer cell line. The cultivars have potential to be used as natural antioxidant and anticancer agents.

Monogenic Childhood Diabetes: Dissecting Clinical Heterogeneity by Next-Generation Sequencing in Maturity-Onset Diabetes of the Young.

Diabetes is a common disorder with a heterogeneous clinical presentation and an enormous burden on health care worldwide. About 1-6% of patients with diabetes suffer from maturity-onset diabetes of the young (MODY), the most common form of monogenic diabetes with autosomal dominant inheritance. MODY is genetically and clinically heterogeneous and caused by genetic variations in pancreatic ß-cell development and insulin secretion. We report here new findings from targeted next-generation sequencing (NGS) of 13 MODY-related genes. A sample of 22 unrelated pediatric patients with MODY and 13 unrelated healthy controls were recruited from a Turkish population. Targeted NGS was performed with Miseq 4000 (Illumina) to identify genetic variations in 13 MODY-related genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11. The NGS data were analyzed adhering to the Genome Analysis ToolKit (GATK) best practices pipeline, and variant filtering and annotation were performed. In the patient sample, we identified 43 MODY-specific genetic variations that were not present in the control group, including 11 missense mutations and 4 synonymous mutations. Importantly, and to the best of our knowledge, the missense mutations NEUROD1 p.D202E, KFL11 p.R461Q, BLK p.G248R, and KCNJ11 p.S385F were first associated with MODY in the present study. These findings contribute to the worldwide knowledge base on MODY and molecular correlates of clinical heterogeneity in monogenic childhood diabetes. Further comparative population genetics and functional genomics studies are called for, with an eye to discovery of novel diagnostics and personalized medicine in MODY. Because MODY is often misdiagnosed as type 1 or type 2 diabetes mellitus, advances in MODY diagnostics with NGS stand to benefit diabetes overall clinical care as well.

Atomistic Modeling of Peptide Aggregation and ß-Sheet Structuring in Corn Zein for Viscoelasticity.

The structure-function relationships of plant-based proteins that give rise to desirable texture attributes in order to mimic meat products are generally unknown. In particular, it is not clear how to engineer viscoelasticity to impart cohesiveness and proper mouthfeel; however, it is known that intermolecular ß-sheet structures have the potential to enhance the viscoelastic property. Here, we investigated the propensity of selected peptide segments within common corn α-zein variants to maintain stable aggregates and ß-sheet structures. Simulations on dimer systems showed that stability was influenced by the initial orientation and the presence of contiguous small hydrophobic residues. Simulations using eight-peptide ß-sheet oligomers revealed that peptide sequences without proline had higher levels of ß-sheet structuring. Additionally, we identified that sequences with a dimer hydrogen-bonding density of >22% tended to have a larger percent ß-sheet conformation. These results contribute to understanding how the viscoelasticity of zein can be increased for use in plant-based meat analogues.

Peroxisome Proliferator-Activated Receptor Gamma Pro12Ala/C161T Genotypes and Risky Haplotype Altering Risk of Breast Cancer: A Turkish Case-Control Study.

Breast cancer (BC) has a high incidence rate among women worldwide, and the mechanisms and etiology of this disease are not yet fully understood. The peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor that plays important roles in energy metabolism and cellular differentiation, is also suggested to be effective in cancer development. However, the results of studies investigating the cancer association with PPARgamma are inconsistent, creating a need for further investigation of the effects of this transcription factor on BC risk. We have examined the Pro12Ala-(rs1801282) and C161T-(rs3856806) polymorphisms of the PPARgamma gene in Turkish patients with BC in this case-control study. A total of 95 women diagnosed with BC as cases and 119 controls were genotyped for PPARgamma polymorphisms by polymerase chain reaction and restriction fragment length polymorphism techniques. The ProPro genotype and T161 allele were associated with an increased risk of BC comparing with the Ala12 allele and CC161 genotype, respectively (p < 0.001). The multivariate regression analysis confirmed that the ProPro genotype (p < 0.011), T161 allele (p < 0.001), smoking (p = 0.019), and advanced age (> 60 years) (p = 0.007) are risk factors for breast cancer. We also found that the PPARgamma Pro12Ala and C161T polymorphisms were in linkage disequilibrium (D':0.511, r2:0.099). It was determined that carrying ProPro-T161 risky PPARgamma haplotype was associated with a higher risk of BC compared to protective Ala12-CC161 haplotype (p < 0.01, OR:7.797, 95% CI:3.521-17.263). We concluded that PPARgamma Pro12Ala and C161T polymorphisms are associated with increased BC risk, and ProPro-T161 risky haplotype, which is in linkage disequilibrium, increases this effect.

Local aromatase activity alterations in breast cancer tissues: A potential way of decision support for clinicians.

BACKGROUND AND AIMS: It is becoming evident that local estrogen exposure is important in postmenopausal breast cancer patients. The microenvironment is established by breast stromal cells based on communication with tumor cells that is essential to cancer development, invasion, and metastasis. Here we investigated aromatase activity levels in both tumor and matched stromal tissues by showing their impact on the manufacturing of local estrogen and tumor progression in cases of invasive ductal carcinoma (IDC). METHODS: Tumor (T) and tumor-associated stroma (TAS) neighboring tissues were acquired from each postmenopausal patient, diagnosed with IDC, and categorized as luminal A (n = 20). The control group was formed from tumor-free breast tissue samples (N, n = 12). A microsomal-based technique was created to compare breast tissue aromatase activities using liquid chromatography - mass spectrometry. FINDINGS: We observed that the TAS tissues have the highest aromatase activities (p < 0.05). High progesterone receptor (PR) intensity levels were found to be decreasing the activity level in these tissues significantly (p < 0.05). Tumor tissue specific aromatase activity levels of postmenopausal patients' were tend to be lower compared to healthy premenopausal subjects' (3 fold, p < 0.001). In addition low activity in tumor tissues were associated with low grade and late stage cancers. CONCLUSIONS: Early detection and personalized therapy is essential for postmenopausal breast cancer patients. Together, our in-house tandem mass spectrometry technique has the potential for further development and standardization for the measurement of aromatase activity and may assist clinicians decide on therapy policies for postmenopausal IDC patients which could be an invaluable asset for precise and specific evaluation.

Investigation of DFNB4 SLC26A4 mutation in patients with enlarged vestibular aquaduct.

OBJECTIVES: Mutations of the SLC26A4 gene causing enlarged vestibular aqueduct (EVA) syndrome have not yet been fully elucidated. The study aimed to investigate SLC26A4 mutations in patients with EVA syndrome in the Turkish population. Identifying these mutations may play an essential role in determining the prognosis, follow-up, and management options of these patients. METHODS: Whole exome sequencing and/or Sanger sequencing of SLC26A4 in 22 patients with sensorineural hearing loss associated with isolated EVA without inner ear anomalies, and 22 controls were performed. RESULTS: Twenty-two patients and 22 control subjects were included in the study. The onset of hearing loss was pre-lingual in 15 patients, and post-lingual in 7. The mean (standard deviation) vestibular aqueduct width of the patients was 3.23 mm (1.28). Twenty SLC26A4 variants, 15 of them unique, were identified in 22 patients. Among them, seven variants were heterozygous, and 13 were homozygous. The variants p.E37X (c.109G > T), p.Y27H (c.79T > C), p.C706Y (c.2117G > A) have not been previously reported. CONCLUSION: The detection of rare and previously unreported mutations in our study showed that studies with a larger number of patients with EVA might reveal more role of the SLC26A4 gene. Besides, to understand the etiopathogenesis of the disease, other related genes also should be investigated.

[Investigation of metabolic effects of CETP gene rs289714 variation in coronary artery patients: A case-control study]. / Koroner arter hastalarinda CETP geni rs289714 varyasyonunun metabolik etkilerinin arastirilmasi: Olgu-kontrol çalismasi.

OBJECTIVE: The aim of this study was to investigate the effects of the CETP gene rs289714 polymorphism on the serum lipid profile and other metabolic parameters in Turkish patients with coronary artery disease (CAD). METHODS: The CETP rs289714 variant was examined in 104 patients with CAD and 77 controls using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The CETP rs289714 genotype and allele distribution was not statistically different between the groups (p>0.05). The body mass index (BMI) values in men with CAD were higher in patients with the G allele compared with those carrying the AA genotype (p=0.05). Logistic regression analysis showed that the G allele in male CAD patients was a risk factor for a BMI of ≥ 27 kg/m2 (odds ratio: 0.269, 95% confidence interval: 0.075­0.966; p=0.044). The G allele in female patients was associated with lower HDL-C levels than the AA genotype (p=0.049). CONCLUSION: The results suggest that the CETP rs289714 polymorphism may cause risk for the development of CAD due to its effects on high-density lipoprotein cholesterol values in female patients and BMI in male patients.