Genome-wide association study identifies genomic regions associated with key reproductive traits in Korean Hanwoo cows.

BACKGROUND: Conducting genome-wide association studies (GWAS) for reproductive traits in Hanwoo cattle, including age at first calving (AFC), calving interval (CI), gestation length (GL), and number of artificial inseminations per conception (NAIPC), is of paramount significance. These analyses provided a thorough exploration of the genetic basis of these traits, facilitating the identification of key markers for targeted trait improvement. Breeders can optimize their selection strategies, leading to more efficient and sustainable breeding programs, by incorporating genetic insights. This impact extends beyond individual traits and contributes to the overall productivity and profitability of the Hanwoo beef cattle industry. Ultimately, GWAS is essential in ensuring the long-term genetic resilience and adaptability of Hanwoo cattle populations. The primary goal of this study was to identify significant single nucleotide polymorphisms (SNPs) or quantitative trait loci (QTLs) associated with the studied reproductive traits and subsequently map the underlying genes that hold promise for trait improvement. RESULTS: A genome-wide association study of reproductive traits identified 68 significant single nucleotide polymorphisms (SNPs) distributed across 29 Bos taurus autosomes (BTA). Among them, BTA14 exhibited the highest number of identified SNPs (25), whereas BTA6, BTA7, BTA8, BTA10, BTA13, BTA17, and BTA20 exhibited 8, 5, 5, 3, 8, 2, and 12 significant SNPs, respectively. Annotation of candidate genes within a 500 kb region surrounding the significant SNPs led to the identification of ten candidate genes relevant to age at first calving. These genes were: FANCG, UNC13B, TESK1, TLN1, and CREB3 on BTA8; FAM110B, UBXN2B, SDCBP, and TOX on BTA14; and MAP3K1 on BTA20. Additionally, APBA3, TCF12, and ZFR2, located on BTA7 and BTA10, were associated with the calving interval; PAX1, SGCD, and HAND1, located on BTA7 and BTA13, were linked to gestation length; and RBM47, UBE2K, and GPX8, located on BTA6 and BTA20, were linked to the number of artificial inseminations per conception in Hanwoo cows. CONCLUSIONS: The findings of this study enhance our knowledge of the genetic factors that influence reproductive traits in Hanwoo cattle populations and provide a foundation for future breeding strategies focused on improving desirable traits in beef cattle. This research offers new evidence and insights into the genetic variants and genome regions associated with reproductive traits and contributes valuable information to guide future efforts in cattle breeding.

Exploring the Role of Extracellular Vesicles in the Pathogenesis of Tuberculosis.

Tuberculosis (TB) remains a significant global health concern, necessitating accurate diagnosis and treatment monitoring. Extracellular vesicles (EVs), including exosomes, play crucial roles in disease progression, with their associated genes serving as potential biomarkers and therapeutic targets. Leveraging publicly available RNA-Seq datasets of TB patients and healthy controls (HCs), to identify differentially expressed genes (DEGs) and their associated protein-protein interaction networks and immune cell profiles, the common EV-related DEGs were identified and validated in the GSE42830 and GSE40553 datasets. We have identified nine common EV-related DEGs (SERPINA1, TNFAIP6, MAPK14, STAT1, ITGA2B, VAMP5, CTSL, CEACAM1, and PLAUR) upregulated in TB patients. Immune cell infiltration analysis revealed significant differences between TB patients and HCs, highlighting increased proportions of various immune cells in TB patients. These DEGs are involved in crucial cellular processes and pathways related to exocytosis and immune response regulation. Notably, VAMP5 exhibited excellent diagnostic performance (AUC-0.993, sensitivity-93.8%, specificity-100%), with potential as a novel biomarker for TB. The EV-related genes can serve as novel potential biomarkers that can distinguish between TB and HCs. VAMP5, which functions in exosome biogenesis and showed significant upregulation in TB, can be targeted for therapeutic interventions and treatment outcomes.

Antibiotic Resistance in Plant Pathogenic Bacteria: Recent Data and Environmental Impact of Unchecked Use and the Potential of Biocontrol Agents as an Eco-Friendly Alternative.

The economic impact of phytopathogenic bacteria on agriculture is staggering, costing billions of US dollars globally. Pseudomonas syringae is the top most phytopathogenic bacteria, having more than 60 pathovars, which cause bacteria speck in tomatoes, halo blight in beans, and so on. Although antibiotics or a combination of antibiotics are used to manage infectious diseases in plants, they are employed far less in agriculture compared to human and animal populations. Moreover, the majority of antibiotics used in plants are immediately washed away, leading to environmental damage to ecosystems and food chains. Due to the serious risk of antibiotic resistance (AR) and the potential for environmental contamination with antibiotic residues and resistance genes, the use of unchecked antibiotics against phytopathogenic bacteria is not advisable. Despite the significant concern regarding AR in the world today, there are inadequate and outdated data on the AR of phytopathogenic bacteria. This review presents recent AR data on plant pathogenic bacteria (PPB), along with their environmental impact. In light of these findings, we suggest the use of biocontrol agents as a sustainable, eco-friendly, and effective alternative to controlling phytopathogenic bacteria.

Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development.

PROteolysis TArgeting Chimera (PROTAC) is an emerging technology in chemical biology and drug discovery. This technique facilitates the complete removal of the target proteins that are "undruggable" or challenging to target through chemical molecules via the Ubiquitin-Proteasome System (UPS). PROTACs have been widely explored and outperformed not only in cancer but also in other diseases. During the past few decades, several academic institutes and pharma companies have poured more efforts into PROTAC-related technologies, setting the stage for several major degrader trial readouts in clinical phases. Despite their promising results, the formation of robust ternary orientation, off-target activity, poor permeability, and binding affinity are some of the limitations that hinder their development. Recent advancements in computational technologies have facilitated progress in the development of PROTACs. Researchers have been able to utilize these technologies to explore a wider range of E3 ligases and optimize linkers, thereby gaining a better understanding of the effectiveness and safety of PROTACs in clinical settings. In this review, we briefly explore the computational strategies reported to date for the formation of PROTAC components and discuss the key challenges and opportunities for further research in this area.

Genome-Wide Association Study to Identify QTL for Carcass Traits in Korean Hanwoo Cattle.

This study aimed to identify genetic associations with carcass traits in Hanwoo cattle using a genome-wide association study. A total of 9302 phenotypes were analyzed, and all animals were genotyped using the Illumina Bovine 50K v.3 SNP chip. Heritabilities for carcass weight (CWT), eye muscle area (EMA), backfat thickness (BF), and marbling score (MS) were estimated as 0.42, 0.36, 0.36, and 0.47, respectively, using the GBLUP model, and 0.47, 0.37, 0.36, and 0.42, respectively, using the Bayes B model. We identified 129 common SNPs using DGEBV and 118 common SNPs using GEBV on BTA6, BTA13, and BTA14, suggesting their potential association with the traits of interest. No common SNPs were found between the GBLUP and Bayes B methods when using residuals as a response variable in GWAS. The most promising candidate genes for CWT included SLIT2, PACRGL, KCNIP4, RP1, XKR4, LYN, RPS20, MOS, FAM110B, UBXN2B, CYP7A1, SDCBP, NSMAF, TOX, CA8, LAP3, FAM184B, and NCAPG. For EMA, the genes IBSP, LAP3, FAM184B, LCORL, NCAPG, SLC30A9, and BEND4 demonstrated significance. Similarly, CYP7B1, ARMC1, PDE7A, and CRH were associated with BF, while CTSZ, GNAS, VAPB, and RAB22A were associated with MS. This finding offers valuable insights into genomic regions and molecular mechanisms influencing Hanwoo carcass traits, aiding efficient breeding strategies.

Genome-Wide Association Studies for Body Conformation Traits in Korean Holstein Population.

The objective of this study was to identify quantitative trait loci (QTL) and nearby candidate genes that influence body conformation traits. Phenotypic data for 24 body conformation traits were collected from a population of 2329 Korean Holstein cattle, and all animals were genotyped using the 50 K Illumina bovine SNP chip. A total of 24 genome-wide significant SNPs associated with 24 body conformation traits were identified by genome-wide association analysis. The selection of the most promising candidate genes was based on gene ontology (GO) terms and the previously identified functions that influence various body conformation traits as determined in our study. These genes include KCNA1, RYBP, PTH1R, TMIE, and GNAI3 for body traits; ANGPT1 for rump traits; MALRD1, INHBA, and HOXA13 for feet and leg traits; and CDK1, RHOBTB1, and SLC17A1 for udder traits, respectively. These findings contribute to our understanding of the genetic basis of body conformation traits in this population and pave the way for future breeding strategies aimed at enhancing desirable traits in dairy cattle.

Genomic Predictions in Korean Hanwoo Cows: A Comparative Analysis of Genomic BLUP and Bayesian Methods for Reproductive Traits.

This study aimed to predict the accuracy of genomic estimated breeding values (GEBVs) for reproductive traits in Hanwoo cows using the GBLUP, BayesB, BayesLASSO, and BayesR methods. Accuracy estimates of GEBVs for reproductive traits were derived through fivefold cross-validation, analyzing a dataset comprising 11,348 animals and employing an Illumina Bovine 50K SNP chip. GBLUP showed an accuracy of 0.26 for AFC, while BayesB, BayesLASSO, and BayesR demonstrated values of 0.28, 0.29, and 0.29, respectively. For CI, GBLUP attained an accuracy of 0.19, whereas BayesB, BayesLASSO, and BayesR scored 0.21, 0.24, and 0.25, respectively. The accuracy for GL was uniform across GBLUP, BayesB, and BayesR at 0.31, whereas BayesLASSO showed a slightly higher accuracy of 0.33. For NAIPC, GBLUP showed an accuracy of 0.24, while BayesB, BayesLASSO, and BayesR recorded 0.22, 0.27, and 0.30, respectively. The variation in genomic prediction accuracy among methods indicated Bayesian approaches slightly outperformed GBLUP. The findings suggest that Bayesian methods, notably BayesLASSO and BayesR, offer improved predictive capabilities for reproductive traits. Future research may explore more advanced genomic approaches to enhance predictive accuracy and genetic gains in Hanwoo cattle breeding programs.

Tracing the Origin of the RSPO2 Long-Hair Allele and Epistatic Interaction between FGF5 and RSPO2 in Sapsaree Dog.

Genetic analysis of the hair-length of Sapsaree dogs, a Korean native dog breed, showed a dominant mode of inheritance for long hair. Genome-Wide Association Study (GWAS) analysis and subsequent Mendelian segregation analysis revealed an association between OXR1, RSPO2, and PKHD1L1 on chromosome 13 (CFA13). We identified the previously reported 167 bp insertion in RSPO2 3' untranslated region as a causative mutation for hair length variations. The analysis of 118 dog breeds and wolves revealed the selection signature on CFA13 in long-haired breeds. Haplotype analysis showed the association of only a few specific haplotypes to the breeds carrying the 167 bp insertion. The genetic diversity in the neighboring region linked to the insertion was higher in Sapsarees than in other Asian and European dog breeds carrying the same variation, suggesting an older history of its insertion in the Sapsaree genome than in that of the other breeds analyzed in this study. Our results show that the RSPO2 3' UTR insertion is responsible for not only the furnishing phenotype but also determining the hair length of the entire body depending on the genetic background, suggesting an epistatic interaction between FGF5 and RSPO2 influencing the hair-length phenotype in dogs.

Safety profile of D-penicillamine: a comprehensive pharmacovigilance analysis by FDA adverse event reporting system.

BACKGROUND: D-penicillamine (D-pen) is a copper-chelating drug and has immune-modulatory properties. D-pen is used to treat rheumatoid arthritis, Wilson's disease, and kidney stones (cystinuria). However, associated adverse events (AEs) of D-pen treatment are frequent and often serious. Therefore, a comprehensive assessment of the safety profile of D-pen is urgently needed. RESEARCH DESIGN AND METHODS: We identified and analyzed AEs associated with D-pen between April-1970 to July-2020 from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) databases and calculated the reported odds ratio (ROR) with 95% confidence intervals (CI) using the disproportionality analysis. RESULTS: A total of 9,150,234 AEs related to drugs were reported in the FAERS database, of which 542 were related to D-Pen. We report that D-pen was associated with dystonia (ROR: 20.52; 95%CI: 12.46-33.80), drug hypersensitivity (ROR: 5.42; 95%CI: 3.72-7.90), pancytopenia (ROR: 10.20; 95%CI: 5.61-18.56), joint swelling (ROR: 9.07; 95%CI: 5.51-14.94), renal-impairment (ROR: 6.68; 95%CI: 3.67-12.15), dysphagia (ROR: 5.05; 95%CI: 2.76-8.89), aggravation of condition (ROR: 4.16; 95%CI: 2.60-6.67), congestive cardiac failure (ROR: 4.04; 95%CI: 2.22-7.35), peripheral edema (ROR: 3.77; 95%CI: 2.17-6.55), tremor (ROR: 3.46; 95%CI: 2.00-6.01), pyrexia (ROR: 3.46; 95%CI: 2.00-6.01), and gait disturbance (ROR: 2.41; 95%CI: 1.29-4.52). CONCLUSIONS: Patients taking D-pen require close monitoring of renal function, blood counts, immunity, liver, cardiac function, and neurological function. D-pen suppresses immune system which maximizes the risk of infection.

Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders.

Neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

Proteotoxicity: A Fatal Consequence of Environmental Pollutants-Induced Impairments in Protein Clearance Machinery.

A tightly regulated protein quality control (PQC) system maintains a healthy balance between correctly folded and misfolded protein species. This PQC system work with the help of a complex network comprised of molecular chaperones and proteostasis. Any intruder, especially environmental pollutants, disrupt the PQC network and lead to PQCs disruption, thus generating damaged and infectious protein. These misfolded/unfolded proteins are linked to several diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and cataracts. Numerous studies on proteins misfolding and disruption of PQCs by environmental pollutants highlight the necessity of detailed knowledge. This review represents the PQCs network and environmental pollutants' impact on the PQC network, especially through the protein clearance system.

Neurobiology of zinc and its role in neurogenesis.

BACKGROUND: Zinc (Zn) has a diverse role in many biological processes, such as growth, immunity, anti-oxidation system, homeostatic, and repairing. It acts as a regulatory and structural catalyst ion for activities of various proteins, enzymes, and signal transcription factors, as well as cell proliferation, differentiation, and survival. The Zn ion is essential for neuronal signaling and is mainly distributed within presynaptic vesicles. Zn modulates neuronal plasticity and synaptic activity in both neonatal and adult stages. Alterations in brain Zn status results in a dozen neurological diseases including impaired brain development. Numerous researchers are working on neurogenesis, however, there is a paucity of knowledge about neurogenesis, especially in neurogenesis in adults. Neurogenesis is a multifactorial process and is regulated by many metal ions (e.g. Fe, Cu, Zn, etc.). Among them, Zn has an essential role in neurogenesis. At the molecular level, Zn controls cell cycle, apoptosis, and binding of DNA and several proteins including transcriptional and translational factors. Zn is needed for protein folding and function and Zn acts as an anti-apoptotic agent; organelle stabilizer; and an anti-inflammatory agent. Zn deficiency results in aging, neurodegenerative disease, immune deficiency, abnormal growth, cancer, and other symptoms. Prenatal deficiency of Zn results in developmental disorders in humans and animals. CONCLUSION: Both in vitro and in vivo studies have shown an association between Zn deficiency and increased risk of neurological disorders. This article reviews the existing knowledge on the role of Zn and its importance in neurogenesis.

Genetic characteristics of Korean Jeju Black cattle with high density single nucleotide polymorphisms.

OBJECTIVE: Conservation and genetic improvement of cattle breeds require information about genetic diversity and population structure of the cattle. In this study, we investigated the genetic diversity and population structure of the three cattle breeds in the Korean peninsula. METHODS: Jeju Black, Hanwoo, Holstein cattle in Korea, together with six foreign breeds were examined. Genetic diversity within the cattle breeds was analyzed with minor allele frequency (MAF), observed and expected heterozygosity (HO and HE), inbreeding coefficient (FIS) and past effective population size. Molecular variance and population structure between the nine breeds were analyzed using a model-based clustering method. Genetic distances between breeds were evaluated with Nei's genetic distance and Weir and Cockerham's FST. RESULTS: Our results revealed that Jeju Black cattle had lowest level of heterozygosity (HE = 0.21) among the studied taurine breeds, and an average MAF of 0.16. The level of inbreeding was -0.076 for Jeju Black, while -0.018 to -0.118 for the other breeds. Principle component analysis and neighbor-joining tree showed a clear separation of Jeju Black cattle from other local (Hanwoo and Japanese cattle) and taurine/indicine cattle breeds in evolutionary process, and a distinct pattern of admixture of Jeju Black cattle having no clustering with other studied populations. The FST value between Jeju Black cattle and Hanwoo was 0.106, which was lowest across the pair of breeds ranging from 0.161 to 0.274, indicating some degree of genetic closeness of Jeju Black cattle with Hanwoo. The past effective population size of Jeju Black cattle was very small, i.e. 38 in 13 generation ago, whereas 209 for Hanwoo. CONCLUSION: This study indicates genetic uniqueness of Jeju Black cattle. However, a small effective population size of Jeju Black cattle indicates the requirement for an implementation of a sustainable breeding policy to increase the population for genetic improvement and future conservation.

Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease.

: Cardiovascular diseases are one of the leading causes of death in developing countries, generally originating as coronary artery disease (CAD) or hypertension. In later stages, many CAD patients develop left ventricle dysfunction (LVD). Left ventricular ejection fraction (LVEF) is the most prevalent prognostic factor in CAD patients. LVD is a complex multifactorial condition in which the left ventricle of the heart becomes functionally impaired. Various genetic studies have correlated LVD with dilated cardiomyopathy (DCM). In recent years, enormous progress has been made in identifying the genetic causes of cardiac diseases, which has further led to a greater understanding of molecular mechanisms underlying each disease. This progress has increased the probability of establishing a specific genetic diagnosis, and thus providing new opportunities for practitioners, patients, and families to utilize this genetic information. A large number of mutations in sarcomeric genes have been discovered in cardiomyopathies. In this review, we will explore the role of the sarcomeric genes in LVD in CAD patients, which is a major cause of cardiac failure and results in heart failure.

The effectiveness of genomic selection for milk production traits of Holstein dairy cattle.

OBJECTIVE: This study was conducted to test the efficiency of genomic selection for milk production traits in a Korean Holstein cattle population. METHODS: A total of 506,481 milk production records from 293,855 animals (2,090 heads with single nucleotide polymorphism information) were used to estimate breeding value by single step best linear unbiased prediction. RESULTS: The heritability estimates for milk, fat, and protein yields in the first parity were 0.28, 0.26, and 0.23, respectively. As the parity increased, the heritability decreased for all milk production traits. The estimated generation intervals of sire for the production of bulls (LSB) and that for the production of cows (LSC) were 7.9 and 8.1 years, respectively, and the estimated generation intervals of dams for the production of bulls (LDB) and cows (LDC) were 4.9 and 4.2 years, respectively. In the overall data set, the reliability of genomic estimated breeding value (GEBV) increased by 9% on average over that of estimated breeding value (EBV), and increased by 7% in cows with test records, about 4% in bulls with progeny records, and 13% in heifers without test records. The difference in the reliability between GEBV and EBV was especially significant for the data from young bulls, i.e. 17% on average for milk (39% vs 22%), fat (39% vs 22%), and protein (37% vs 22%) yields, respectively. When selected for the milk yield using GEBV, the genetic gain increased about 7.1% over the gain with the EBV in the cows with test records, and by 2.9% in bulls with progeny records, while the genetic gain increased by about 24.2% in heifers without test records and by 35% in young bulls without progeny records. CONCLUSION: More genetic gains can be expected through the use of GEBV than EBV, and genomic selection was more effective in the selection of young bulls and heifers without test records.

Reduction of slaughter age of Hanwoo steers by early genotyping based on meat yield index.

OBJECTIVE: This study was conducted to determine early hereditary endowment to establish a short-term feeding program. METHODS: Hanwoo steers (n = 140) were equally distributed into four groups (35/group) based on genetic meat yield index (MYI) viz. the greatest, great, low, and the lowest at Jukam Hanwoo farm, Goheung. All animals were fed in group pens (5 animals/pen) with similar feed depending on the growth stage. Rice straw was provided ad libitum, whereas concentrate was fed at 5.71 kg during the growing period (6 to 13 mo) and 9.4 kg during the fattening period (13 to 28 mo). Body weight (BW) was measured at two-month intervals, whereas carcass weight was determined at slaughtering at about 31 months of age. The Affymetrix Bovine Axiom Array 640K single nucleotide polymorphism (SNP) chip was used to determine the meat quantity-related gene in the blood. RESULTS: After 6 months, the highest (p<0.05) BW was observed in the greatest MYI group (190.77 kg) and the lowest (p<0.05) in the lowest MYI group (173.51 kg). The great MYI group also showed significantly (p<0.05) higher BW than the lowest MYI group. After 16 and 24 months, the greatest MYI group had the highest BW gain (p<0.05) and were therefore slaughtered the earliest. Carcass weight was significantly (p<0.05) higher in the greatest and the great MYI groups followed by the low and the lowest MYI groups. Back-fat thickness in the greatest MYI group was highly correlated to carcass weight and marbling score. The SNP array analysis identified the carcass-weight related gene BTB-01280026 with an additive effect. The steers with the allele increasing carcass weight had heavier slaughter weight of about 12 kg. CONCLUSION: Genetic MYI is a potential tool for calf selection, which will reduce the slaughter age while simultaneously increasing carcass weight, back-fat thickness, and marbling score.

Therapeutic Advances for Huntington's Disease.

Huntington's disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

Bisphenols as a Legacy Pollutant, and Their Effects on Organ Vulnerability.

Bisphenols are widely used in the synthesis of polycarbonate plastics, epoxy resins, and thermal paper, which are used in manufacturing items of daily use. Packaged foods and drinks are the main sources of exposure to bisphenols. These chemicals affect humans and animals by disrupting the estrogen, androgen, progesterone, thyroid, and aryl hydrocarbon receptor functions. Bisphenols exert numerous harmful effects because of their interaction with receptors, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial dysfunction, and cell signal alterations. Both cohort and case-control studies have determined an association between bisphenol exposure and increased risk of cardiovascular diseases, neurological disorders, reproductive abnormalities, obesity, and diabetes. Prenatal exposure to bisphenols results in developmental disorders in animals. These chemicals also affect the immune cells and play a significant role in initiating the inflammatory response. Exposure to bisphenols exhibit age, gender, and dose-dependent effects. Even at low concentrations, bisphenols exert toxicity, and hence deserve a critical assessment of their uses. Since bisphenols have a global influence on human health, the need to discover the underlying pathways involved in all disease conditions is essential. Furthermore, it is important to promote the use of alternatives for bisphenols, thereby restricting their uses.

Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health.

The Maillard reaction is a simple but ubiquitous reaction that occurs both in vivo and ex vivo during the cooking or processing of foods under high-temperature conditions, such as baking, frying, or grilling. Glycation of proteins is a post-translational modification that forms temporary adducts, which, on further crosslinking and rearrangement, form permanent residues known as advanced glycation end products (AGEs). Cooking at high temperature results in various food products having high levels of AGEs. This review underlines the basis of AGE formation and their corresponding deleterious effects on the body. Glycated Maillard products have a direct association with the pathophysiology of some metabolic diseases, such as diabetes mellitus type 2 (DM2), acute renal failure (ARF), Alzheimer's disease, dental health, allergies, and polycystic ovary syndrome (PCOS). The most glycated and structurally abundant protein is collagen, which acts as a marker for diabetes and aging, where decreased levels indicate reduced skin elasticity. In diabetes, high levels of AGEs are associated with carotid thickening, ischemic heart disease, uremic cardiomyopathy, and kidney failure. AGEs also mimic hormones or regulate/modify their receptor mechanisms at the DNA level. In women, a high AGE diet directly correlates with high levels of androgens, anti-Müllerian hormone, insulin, and androstenedione, promoting ovarian dysfunction and/or infertility. Vitamin D3 is well-associated with the pathogenesis of PCOS and modulates steroidogenesis. It also exhibits a protective mechanism against the harmful effects of AGEs. This review elucidates and summarizes the processing of infant formula milk and the associated health hazards. Formulated according to the nutritional requirements of the newborn as a substitute for mother's milk, formula milk is a rich source of primary adducts, such as carboxy-methyl lysine, which render an infant prone to inflammation, dementia, food allergies, and other diseases. We therefore recommend that understanding this post-translational modification is the key to unlocking the mechanisms and physiology of various metabolic syndromes.

Extreme sampling design in genetic association mapping of quantitative trait loci using balanced and unbalanced case-control samples.

It is extremely expensive to conduct large sample size array- or sequencing based genome scale association studies. For a quantitative trait, an extreme case-control study design may improve the power and reduce the cost of variant calling. We investigated the performance of extreme study design when various proportions of samples are selected from the tails of phenotype distribution. Using simulations, we show that when risk genotypes become rare in the population and effect size is relatively small, it is beneficial to carry out an extreme sampling study. In particular, the number of selected cases and controls can even be unbalanced such that power is further increased, compared with a balanced selection. Our application to two data sets: methadone dose data and yearling weight data, demonstrated that similar results for full data analysis can be obtained using extreme sampling with only a fraction of the data. Using power analysis with simulated data and an experimental data application, we conclude that when full data is unavailable due to restricted budget, it is rewarding to employ an extreme sampling design in the sense that there can be immense cost reductions and qualitatively similar power as in the full data analysis.