A genomics perspective of personalized prevention and management of obesity.

This review discusses the landscape of personalized prevention and management of obesity from a nutrigenetics perspective. Focusing on macronutrient tailoring, we discuss the impact of genetic variation on responses to carbohydrate, lipid, protein, and fiber consumption. Our bioinformatic analysis of genomic variants guiding macronutrient intake revealed enrichment of pathways associated with circadian rhythm, melatonin metabolism, cholesterol and lipoprotein remodeling and PPAR signaling as potential targets of macronutrients for the management of obesity in relevant genetic backgrounds. Notably, our data-based in silico predictions suggest the potential of repurposing the SYK inhibitor fostamatinib for obesity treatment in relevant genetic profiles. In addition to dietary considerations, we address genetic variations guiding lifestyle changes in weight management, including exercise and chrononutrition. Finally, we emphasize the need for a refined understanding and expanded research into the complex genetic landscape underlying obesity and its management.

Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study.

We conducted the first genome-wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single-nucleotide polymorphisms (SNPs) reached genome-wide significance (p < 5 × 10-8 ). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36-1.76, p = 5.30 × 10-11 ; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31-1.51), p = 8.77 × 10-21 ; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16-1.35), p = 2.14 × 10-8 . We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10-43 , and rs1456315 (inside PRNCR1), p = 4.33 × 10-42 . We confirmed 35 out of 49 GWAS-identified East Asian PCa susceptibility SNPs. In addition, we identified two SNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver-operating characteristic curve for the GRS to predict PCa was 0.67 (95% CI, 0.63-0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.

Interplay of the Mediterranean diet and genetic hypertension risk on blood pressure in European adolescents: Findings from the HELENA study.

Early-life onset of high blood pressure is associated with the development of cardiovascular diseases in adulthood. In adolescents, limited evidence exists regarding the association between adherence to the Mediterranean Diet (MedDiet) and normal blood pressure (BP) levels, as well as its potential to modulate genetic predisposition to HTN. This study investigated the interaction between a MedDiet score and a recently developed HTN-genetic risk score (HTN-GRS) on blood pressure levels in a European adolescent cohort. The MedDiet score was derived from two non-consecutive 24-h dietary recalls and ranged from 0 (indicating low adherence) to 9 (indicating high adherence). Multiple linear regression models, adjusted for covariates, were employed to examine the relationship between the MedDiet score and BP z-scores and to assess the interaction effects between the MedDiet score and HTN-GRS on BP z-scores. MedDiet score showed a negative association with z-systolic BP (SBP) (ß = -0.40, p < 0.001) and z-diastolic BP (DBP) (ß = -0.29, p = 0.001). Additionally, a significant interaction effect was identified between the MedDiet score and HTN-GRS on z-SBP (ß = 0.02, p < 0.001) and z-DBP (ß = 0.02, p < 0.001). The modulatory effect of the MedDiet was more pronounced in females than in males, and HTN-GRS exhibited a stronger influence on DBP than on SBP.   Conclusion: The study suggests that higher adherence to the MedDiet is associated with reduced BP levels in adolescents and provides evidence of a genetic-diet interaction influencing BP in adolescents. What is Known: • Adherence to the Mediterranean diet may reduce BP levels. What is New: • It is the first study to assess the connection between adherence to a Mediterranean diet, a hypertension genetic risk score, and how they interact in influencing blood pressure. • It is conducted within a multicenter cohort of European adolescents.

Genome-wide polygenic risk score for major osteoporotic fractures in postmenopausal women using associated single nucleotide polymorphisms.

BACKGROUND: Osteoporosis is highly polygenic and heritable, with heritability ranging from 50 to 80%; most inherited susceptibility is associated with the cumulative effect of many common genetic variants. However, existing genetic risk scores (GRS) only provide a few percent predictive power for osteoporotic fracture. METHODS: We derived and validated a novel genome-wide polygenic score (GPS) comprised of 103,155 common genetic variants to quantify this susceptibility and tested this GPS prediction ability in an independent dataset (n = 15,776). RESULTS: Among postmenopausal women, we found a fivefold gradient in the risk of major osteoporotic fracture (MOF) (p < 0.001) and a 15.25-fold increased risk of severe osteoporosis (p < 0.001) across the GPS deciles. Compared with the remainder of the GPS distribution, the top GPS decile was associated with a 3.59-, 2.48-, 1.92-, and 1.58-fold increased risk of any fracture, MOF, hip fracture, and spine fracture, respectively. The top GPS decile also identified nearly twofold more high-risk osteoporotic patients than the top decile of conventional GRS based on 1103 conditionally independent genome-wide significant SNPs. Although the relative risk of severe osteoporosis for postmenopausal women at around 50 is relatively similar, the cumulative incident at 20-year follow-up is significantly different between the top GPS decile (13.7%) and the bottom decile (< 1%). In the subgroup analysis, the GPS transferability in non-Hispanic White is better than in other racial/ethnic groups. CONCLUSIONS: This new method to quantify inherited susceptibility to osteoporosis and osteoporotic fracture affords new opportunities for clinical prevention and risk assessment.

Bidirectional Mendelian randomization analysis of the genetic association between primary lung cancer and colorectal cancer.

BACKGROUND: With the development and popularization of low-dose chest CT technology, the diagnosis and survival rates of patients with early lung cancer (LC) have significantly improved. The occurrence of colorectal cancer (CRC) as the second primary cancer (SPC) in primary lung cancer (PLC) survivors has become an essential factor affecting the prognosis of early LC. This study explored the potential association between PLC and CRC genetically, laying a foundation for developing SPC-CRC prevention strategies after primary early LC. METHODS: Based on a two-sample bidirectional Mendelian randomization (MR) design, this study systematically screened genetic instrumental variables (IVs) based on the genome-wide association studies (GWAS) of PLC and CRC, applied inverse variance weighted (IVW) as the main method to assess the incidence association between the two cancers, and used a variety of other MR methods for supplementary analysis. Finally, the Genetic Risk Scores (GRS) method was used for secondary analysis to verify the results robustness further. RESULTS: From LC to CRC forward MR analysis, 20 genetic IVs of overall LC, 15 genetic IVs of squamous cell lung carcinoma (LUSC), and 10 genetic IVs of adenocarcinoma of the lung (LUAD) were screened. In the reverse MR analysis from CRC to LC, 47 genetic IVs for overall CRC, 37 for colon cancer, and 25 for rectal cancer were screened. The IVW method and a variety of MR methods all found that overall LC and CRC were significantly associated at the genetic level. Subgroup analysis also showed that LUSC was associated with CRC. And the results of the GRS method were consistent with those of the main analysis, confirming the robustness of the study. Our MR study found an association between LC and CRC, with an increased risk of SPC-CRC following PLC, especially LUSC. Our study provides an essential basis for the precise prevention of SPC-CRC after PLC, suggesting that we should pay more attention to the population with a history of PLC in clinical work, and pay close attention to the incidence of SPC-CRC, and carry out intervention and treatment as soon as possible.

The body mass index increases the genetic risk scores' ability to predict risk of hepatic damage in European adolescents: The HELENA study.

BACKGROUND: Hepatic disorders are often complex and multifactorial, modulated by genetic and environmental determinants. During the last years, the hepatic disease has been progressively established from early stages in life. The use of genetic risk scores (GRS) to predict the genetic susceptibility to a particular phenotype among youth has gained interest in recent years. Moreover, the alanine aminotransferase (ALT) blood biomarker is often considered as hepatic screening tool, in combination with imaging techniques. The aim of the present study was to develop an ALT-specific GRS to help in the evaluation of hepatic damage risk in European adolescents. METHODS: A total of 972 adolescents (51.3% females), aged 12.5-17.5 years, from the Healthy Lifestyle in Europe by Nutrition in Adolescence study were included in the analyses. The sample incorporated adolescents in all body mass index (BMI) categories and was divided considering healthy/unhealthy ALT levels, using sex-specific cut-off points. From 1212 a priori ALT-related single nucleotide polymorphisms (SNPs) extracted from candidate gene selection, a first screening of 234 SNPs univariately associated was established, selecting seven significant SNPs (p < .05) in the multivariate model. An unweighted GRS (uGRS) was developed by summing the number of reference alleles, and a weighted GRS (wGRS), by multiplying each allele to its estimated coefficient. RESULTS: The uGRS and wGRS were significantly associated with ALT (p < .001). The area under curve was obtained integrating BMI as clinical factor, improving the predictive ability for uGRS (.7039) and wGRS (.7035), using 10-fold internal cross-validation. CONCLUSIONS: Considering BMI status, both GRSs could contribute as complementary tools to help in the early diagnosis of hepatic damage risk in European adolescents.

Development of a genetic risk score for obesity predisposition evaluation.

Obesity is a major public health issue resulting from an interaction between genetic and environmental factors. Genetic risk scores (GRSs) are useful to summarize the effects of many genetic variants on obesity risk. In this study, we aimed to assess the association of previously well-studied genetic variants with obesity and develop a genetic risk score to anticipate the risk of obesity development in the Iranian population. Among 968 participants, 599 (61.88%) were obese, and 369 (38.12%) were considered control samples. After genotyping, an initial screening of 16 variants associated with body mass index (BMI) was performed utilizing a general linear model (p < 0.25), and seven genetic variants were selected. The association of these variants with obesity was examined using a multivariate logistic regression model (p < 0.05), and finally, five variants were found to be significantly associated with obesity. Two gene score models (weighted and unweighted), including these five loci, were constructed. To compare the discriminative power of the models, the area under the curve was calculated using tenfold internal cross-validation. Among the studied variants, ADRB3 rs4994, FTO rs9939609, ADRB2 rs1042714, IL6 rs1800795, and MTHFR rs1801133 polymorphisms were significantly associated with obesity in the Iranian population. Both of the constructed models were significantly associated with BMI (p < 0.05) and the area under the mean curve of the weighted GRS and unweighted GRS were 70.22% ± 0.05 and 70.19% ± 0.05, respectively. Both GRSs proved to predict obesity and could potentially be utilized as genetic tools to assess the obesity predisposition in the Iranian population. Also, among the studied variants, ADRB3 rs4994 and FTO rs9939609 polymorphisms have the highest impacts on the risk of obesity.

Interaction of HnRNP F with the guanine-rich segments in viral antigenomic RNA enhances porcine reproductive and respiratory syndrome virus-2 replication.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein (HnRNP) F is a member of HnRNP family proteins that participate in splicing of cellular newly synthesized mRNAs by specifically recognizing tandem guanine-tracts (G-tracts) RNA sequences. Whether HnRNP F could recognize viral-derived tandem G-tracts and affect virus replication remain poorly defined. METHODS: The effect of HnRNP F on porcine reproductive and respiratory syndrome virus (PRRSV) propagation was evaluated by real-time PCR, western blotting, and plaque-forming unit assay. The association between HnRNP F and PRRSV guanine-rich segments (GRS) were analyzed by RNA pulldown and RNA immunoprecipitation. The expression pattern of HnRNP F was investigated by western blotting and nuclear and cytoplasmic fractionation. RESULTS: Knockdown of endogenous HnRNP F effectively blocks the synthesis of viral RNA and nucleocapsid (N) protein. Conversely, overexpression of porcine HnRNP F has the opposite effect. Moreover, RNA pulldown and RNA immunoprecipitation assays reveal that the qRMM1 and qRRM2 domains of HnRNP F recognize the GRS in PRRSV antigenomic RNA. Finally, HnRNP F is redistributed into the cytoplasm and forms a complex with guanine-quadruplex (G4) helicase DHX36 during PRRSV infection. CONCLUSIONS: These findings elucidate the potential functions of HnRNP F in regulating the proliferation of PRRSV and contribute to a better molecular understanding of host-PRRSV interactions.

Optimized Distributed Generalized Reed-Solomon Coding with Space-Time Block Coded Spatial Modulation.

We present a well-known generalized Reed-Solomon (GRS) code incorporated with space-time block coded spatial modulation (STBC-SM) for wireless networks, which is capable of enjoying coded cooperation between the source and the relay. In the proposed distributed GRS-coded STBC-SM (DGRSC-STBC-SM) scheme, the source and relay nodes use distinct GRS codes. At the relay, we employ the concept of information selection to choose the message symbols from the source for further encoding. Thus, the codewords jointly constructed by the source and relay are generated at the destination. For achieving the best codeword set at the destination, we propose an optimal algorithm at the relay to select partial symbols from the source. To reduce the computational complexity, we propose a more practical algorithm with low complexity. Monte Carlo simulation results show that the proposed scheme using the low-complexity algorithm can achieve near-optimal error performance. Furthermore, our proposed scheme provides better error performance than its corresponding coded non-cooperative counterpart and the existing Reed-Solomon coded cooperative SM (RSCC-SM) scheme under identical conditions.

Effects of a New Antithrombotic Drug GRS, a Soluble Guanylate Cyclase Stimulator, on Endothelial Dysfunction in Rats with Myocardial Infarction.

New antithrombotic drug GRS, a soluble guanylate cyclase stimulator, after repeated administration in a dose of 10 mg/kg alleviates the symptoms of endothelial dysfunction in rats with myocardial infarction; it restores antiplatelet activity of the blood vessel wall and vasodilatory function of the endothelium without producing significant effect on endothelium-independent vasodilation. GRS also has direct antiaggregant and antihypertensive effects in therapeutic doses. The obtained data suggest that GRS can be therapeutically useful in patients with cardiovascular diseases accompanied by endothelial dysfunction.

Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience.

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.

Adult-onset diabetes in Middle Eastern immigrants to Sweden: Novel subgroups and diabetic complications-The All New Diabetes in Scania cohort diabetic complications and ethnicity.

BACKGROUND: Middle Eastern immigrants to Europe represent a high risk population for type 2 diabetes. We compared prevalence of novel subgroups and assessed risk of diabetic macro- and microvascular complications between diabetes patients of Middle Eastern and European origin. METHODS: This study included newly diagnosed diabetes patients born in Sweden (N = 10641) or Iraq (N = 286), previously included in the All New Diabetes in Scania cohort. The study was conducted between January 2008 and August 2016. Patients were followed to April 2017. Incidence rates in diabetic macro- and microvascular complications were assessed using cox-regression adjusting for the confounding effect of age at onset, sex, anthropometrics, glomerular filtration rate (eGFR) and HbA1c. FINDINGS: In Iraqi immigrants versus native Swedes, severe insulin-deficient diabetes was almost twice as common (27.9 vs. 16.2% p < 0.001) but severe insulin-resistant diabetes was less prevalent. Patients born in Iraq had higher risk of coronary events (hazard ratio [HR] 1.84, 95% CI 1.06-3.12) but considerably lower risk of chronic kidney disease (CKD) than Swedes (HR 0.19; 0.05-0.76). The lower risk in Iraqi immigrants was partially attributed to better eGFR. Genetic risk scores (GRS) showed more genetic variants associated with poor insulin secretion but lower risk of insulin resistance in the Iraqi than native Swedish group. INTERPRETATION: People with diabetes, born in the Middle East present with a more insulin-deficient phenotype and genotype than native Swedes. They have a higher risk of coronary events but lower risk of CKD. Ethnic differences should be considered in the preventive work towards diabetes and its complications.

The Utility of Genetic Risk Score to Improve Performance of FRAX for Fracture Prediction in US Postmenopausal Women.

The ability of the fracture risk assessment tool (FRAX) in discriminating fracture and non-fracture in postmenopausal women remains suboptimal. Adding a genetic profile may improve the performance of FRAX. Three genetic risk scores (GRSs) (GRS_fracture, GRS_BMD, GRS_eBMD) were calculated for each participant in the Women's Health Initiative Study (n = 23,981), based on the summary statistics of three comprehensive osteoporosis-related genome-wide association studies (GWAS). The primary outcomes were incident major osteoporotic fracture (MOF) and hip fracture (HF). The association between each GRS and fracture risk were evaluated in separate Cox Proportional Hazard models, with FRAX clinical risk factors adjusted for. The discrimination ability of each model was assessed using Area Under the Curve (AUC). The predictive improvement attributable to each GRSs was assessed using the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI). GRS_BMD and GRS_eBMD were significantly associated with MOF and HF risk, independent of the base FRAX risk factors. Compare to the base FRAX model, the models with GRS_fracture, GRS_BMD, and GRS_eBMD improved the reclassification of MOF by 0.5% (95% CI, 0.2% to 0.9%, p = p < .01), 0.3% (95% CI, 0.1% to 0.6%, p = 0.01), and 2.1% (95% CI, 0.3% to 2.8%, p < .01), respectively. Similar results were also observed when using HF as an outcome. Our study suggested that the addition of genetic profiles provide limited improvements in the reclassification of FRAX for MOF and HF.

Polygenic risk score is a predictor of adenomatous polyps at screening colonoscopy.

BACKGROUND: Single nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. METHODS: We randomly selected 1769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of < 0.5, 0.5-1.5, and > 1.5 were categorized as low, average and elevated risk. RESULTS: Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, p < 0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p < 0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p-trend < 0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p < 0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps. CONCLUSIONS: GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.

Differential expression of major genes involved in the biosynthesis of aliphatic glucosinolates in intergeneric Baemoochae (Brassicaceae) and its parents during development.

KEY MESSAGE: Thus study found the temporal and spatial relationship between production of aliphatic glucosinolate compounds and the expression profile of glucosinolate-related genes during growth and development in radish, Chinese cabbage, and their intergeneric hybrid baemoochae plants. Glucosinolates (GSLs) are one of major bioactive compounds in Brassicaceae plants. GSLs play a role in defense against microbes as well as chemo-preventative activity against cancer, which draw attentions from plant scientists. We investigated the temporal relationship between production of aliphatic Glucosinolate (GSLs) compounds and the expression profile of GSL related genes during growth and development in radish, Chinese cabbage, and their intergeneric hybrid, baemoochae. Over the complete life cycle, Glucoraphasatin (GRH) and glucoraphanin (GRE) predominated in radish, whereas gluconapin (GNP), glucobrassicanapin (GBN), and glucoraphanin (GRA) abounded in Chinese cabbage. Baemoochae contained intermediate levels of all GSLs studied, indicating inheritance from both radish and Chinese cabbage. Expression patterns of BCAT4, CYP79F1, CYP83A1, UGT74B1, GRS1, FMOgs-ox1, and AOP2 genes showed a correlation to their corresponding encoded proteins in radish, Chinese cabbage, and baemoochae. Interestingly, there is a sharp change in gene expression pattern involved in side chain modification, particularly GRS1, FMOgs-ox1, and AOP2, among these plants during the vegetative and reproductive stage. For instance, the GRS1 was strongly expressed during leaf development, while both of FMOgs-ox1 and AOP2 was manifested high in floral tissues. Furthermore, expression of GRS1 gene which is responsible for GRH production was predominantly expressed in leaf tissues of radish and baemoochae, whereas it was only slightly detected in Chinese cabbage root tissue, explaining why radish has an abundance of GRH compared to other Brassica plants. Altogether, our comprehensive and comparative data proved that aliphatic GSLs biosynthesis is dynamically and precisely regulated in a tissue- and development-dependent manner in Brassicaceae family members.

Multi-Locus Models to Address Hb F Variability in Portuguese ß-Thalassemia Carriers.

Hb F production is under the influence of major quantitative trait loci (QTL). The present study aims: i) to replicate the association with Hb F for representative genetic variants in the three major Hb F QTLs in a Portuguese sample of ß-thalassemia (ß-thal) carriers; and ii) to test different genetic multi-locus models to account for the genetic component of Hb F variation. A population sample of 79 Portuguese ß-thal carriers (39 males, 40 females), aged between 2 to 70 years old, were genotyped for polymorphisms in the locus control region (LCR)-5' hypersensitive site 4 (5'HS4) rs16912979, XmnI-HBG2 rs7482144, BCL11A rs1427407 and HMIP rs66650371, using standard biomolecular procedures. Univariate linear regression models were used to test for genetic associations with Hb F. The minor alleles of the individual variants BCL11A rs1427407 (T) (0.165), HMIP rs66650371 (3 bp del) (0.247) and XmnI-HBG2 rs7482144 (T) (0.196), were found to be significantly associated with increased levels of Hb F (p = 0.029, p = 0.002 and p = 0.0004, respectively), explaining about 6.0, 12.0 and 15.0% of Hb F variation, respectively. In a multiple linear regression approach, the three loci accounted for about 30.0% of Hb F variance. Two genetic risk scores (GRS), rationalizing the number of minor alleles into a single genetic variable, explained about 30.0 and 32.0% of the Hb F variation. In conclusion, we replicated in ß-thal carriers previously reported associations with Hb F. Multi-locus models combining three representative variants of Hb F influencing QTLs can explain a larger amount of Hb F variability.

Induction of Glucoraphasatin Biosynthesis Genes by MYB29 in Radish (Raphanus sativus L.) Roots.

Glucoraphasatin (GRH) is a specific aliphatic glucosinolate (GSL) that is only abundant in radish (Raphanus sativus L.). The gene expression regulating GRH biosynthesis in radish is still poorly understood. We employed a total of 59 radish accessions to analyze GSL profiles and showed that GRH was specific and predominant among the aliphatic GSLs in radish roots. We selected five accessions roots with high, moderate and low GSL biosynthesis, respectively, to conduct a comparative transcriptome analysis and the qRT-PCR of the biosynthesis genes for aliphatic GSLs. In this study, among all the accessions tested, roots with the accession RA157-74 had a high GRH content and showed a significant expression of the aliphatic GSL biosynthesis genes. We defined the genes involved in the GRH biosynthesis process and found that they were regulated by a transcription factor (RSG00789) at the MYB29 locus in radish roots. We found 13 aliphatic GSL biosynthesis genes regulated by the RSG00789 gene in the GRH biosynthesis pathway.

Metabolism of a New Antiaggregant, Indolinone Derivative.

Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs.

Nanotechnology as a tool to overcome the bariatric surgery malabsorption.

Obesity is a metabolic disease that affects all ages; it is considered life-threatening condition as it leads to fatal complications such as; cardiovascular diseases and diabetes. The therapeutic options include; life-style modifications, pharmacotherapy intervention, and surgical intervention. Bariatric surgery (BS) is considered as the most effective option among the others for its rapid weight loss, maintaining the lost mass, and improving the quality of life of the patients. Nevertheless, BS leads to severe changes in the bioavailability of medications, especially for chronic diseases, which may reach to limit where the patient's life endangers. Recently, pharmaceutical formulations had developed several methods to improve the drug bioavailability of drugs though the implying of nanotechnology. Nonotechnology is responsible for reducing the size of the drugs to the nano range (<1000 nm), which increase the drug surface area, dissolution, absorption, and, most importantly, the bioavailability of these drugs. It is believed that BS malabsorption and drugs bioavailability problems can be solved using nanotechnology for its advantages in overcoming BS complications.

Concept and benchmarks for assessing narrow-sense validity of genetic risk score values.

BACKGROUND: While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped. METHODS: We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up. RESULTS: GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10-3 , P = 1 × 10-3 , and P = 1.5 × 10-13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3-0.79, 0.8-1.19, 1.2-1.49, 1.5-1.99, 2-2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. CONCLUSION: Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.