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Nature Genetics Aug 2023Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point...
Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.
Topics: Humans; Multifactorial Inheritance; Quantitative Trait Loci; Genome-Wide Association Study; Genetic Predisposition to Disease; Phenotype; Polymorphism, Single Nucleotide
PubMed: 37443254
DOI: 10.1038/s41588-023-01443-6 -
Rheumatology (Oxford, England) Jan 2024Calprotectin (CLP) is a calcium-binding protein produced by neutrophils and monocytes in the course of inflammation. Today, the role of faecal CLP in chronic IBD is well... (Review)
Review
Calprotectin (CLP) is a calcium-binding protein produced by neutrophils and monocytes in the course of inflammation. Today, the role of faecal CLP in chronic IBD is well known, but in recent years attention has shifted towards circulating CLP. In fact, this molecule can be measured in different biological fluids: blood, saliva and urine, using different analytic methods that are described in this review. Furthermore, different data confirm the relevant role of serum CLP in autoimmune diseases. In this review we will highlight the correlation between high levels of circulating CLP and specific autoantibodies of major autoimmune pathologies paving the way to the employment of CLP measurement as useful biomarker for monitoring outcome in different pathologies.
Topics: Humans; Leukocyte L1 Antigen Complex; Inflammation; Biomarkers; Feces; Neutrophils; Inflammatory Bowel Diseases
PubMed: 37603715
DOI: 10.1093/rheumatology/kead405 -
Nature Communications Jan 2024To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in... (Meta-Analysis)
Meta-Analysis
To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.
Topics: Humans; Thyroid Gland; Thyroxine; Genome-Wide Association Study; Triiodothyronine; Thyrotropin
PubMed: 38291025
DOI: 10.1038/s41467-024-44701-9 -
Cardiovascular Diabetology Sep 2023Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated...
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease.
METHODS
The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes.
RESULTS
In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes.
CONCLUSION
Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets.
TRIAL REGISTRATION
The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).
Topics: Aged; Humans; Diabetes Mellitus, Type 2; C-Reactive Protein; Arachidonic Acid; Carotid Artery Diseases; Plaque, Atherosclerotic; Inflammation; Atherosclerosis
PubMed: 37710315
DOI: 10.1186/s12933-023-01979-1 -
Molecules (Basel, Switzerland) Nov 2023This review discusses the significance of natural deep eutectic solvents (NaDESs) as a promising green extraction technology. It employs the consolidated meta-analytic... (Review)
Review
This review discusses the significance of natural deep eutectic solvents (NaDESs) as a promising green extraction technology. It employs the consolidated meta-analytic approach theory methodology, using the Web of Science and Scopus databases to analyze 2091 articles as the basis of the review. This review explores NaDESs by examining their properties, challenges, and limitations. It underscores the broad applications of NaDESs, some of which remain unexplored, with a focus on their roles as solvents and preservatives. NaDESs' connections with nanocarriers and their use in the food, cosmetics, and pharmaceutical sectors are highlighted. This article suggests that biomimicry could inspire researchers to develop technologies that are less harmful to the human body by emulating natural processes. This approach challenges the notion that green science is inferior. This review presents numerous successful studies and applications of NaDESs, concluding that they represent a viable and promising avenue for research in the field of green chemistry.
PubMed: 38005377
DOI: 10.3390/molecules28227653 -
Cell Reports Methods Dec 2023Glycomics, the comprehensive profiling of all glycan structures in samples, is rapidly expanding to enable insights into physiology and disease mechanisms. However,...
Glycomics, the comprehensive profiling of all glycan structures in samples, is rapidly expanding to enable insights into physiology and disease mechanisms. However, glycan structure complexity and glycomics data interpretation present challenges, especially for differential expression analysis. Here, we present a framework for differential glycomics expression analysis. Our methodology encompasses specialized and domain-informed methods for data normalization and imputation, glycan motif extraction and quantification, differential expression analysis, motif enrichment analysis, time series analysis, and meta-analytic capabilities, synthesizing results across multiple studies. All methods are integrated into our open-source glycowork package, facilitating performant workflows and user-friendly access. We demonstrate these methods using dedicated simulations and glycomics datasets of N-, O-, lipid-linked, and free glycans. Differential expression tests here focus on human datasets and cancer vs. healthy tissue comparisons. Our rigorous approach allows for robust, reliable, and comprehensive differential expression analyses in glycomics, contributing to advancing glycomics research and its translation to clinical and diagnostic applications.
Topics: Humans; Glycomics; Polysaccharides
PubMed: 37992708
DOI: 10.1016/j.crmeth.2023.100652 -
Sensors (Basel, Switzerland) Aug 2023Green Chemistry is a vital and crucial instrument in achieving pollution control, and it plays an important role in helping society reach the Sustainable Development...
Green Chemistry is a vital and crucial instrument in achieving pollution control, and it plays an important role in helping society reach the Sustainable Development Goals (SDGs). NIR (near-infrared spectroscopy) has been utilized as an alternate technique for molecular identification, making the process faster and less expensive. Near-infrared diffuse reflectance spectroscopy and Machine Learning (ML) algorithms were utilized in this study to construct identification and classification models of bacteria such as , , and . Furthermore, divide these bacteria into Gram-negative and Gram-positive groups. The green and quick approach was created by combining NIR spectroscopy with a diffuse reflectance accessory. Using infrared spectral data and ML techniques such as principal component analysis (PCA), hierarchical cluster analysis (HCA) and K-Nearest Neighbor (KNN), It was feasible to accomplish the identification and classification of four bacteria and classify these bacteria into two groups: Gram-positive and Gram-negative, with 100% accuracy. We may conclude that our study has a high potential for bacterial identification and classification, as well as being consistent with global policies of sustainable development and green analytical chemistry.
Topics: Spectroscopy, Near-Infrared; Algorithms; Bacteria; Chemistry, Analytic; Escherichia coli; Machine Learning
PubMed: 37687792
DOI: 10.3390/s23177336 -
Journal of Medical Screening Dec 2023A rolling circle amplification (RCA) based commercial methodology using cell-free (cf)DNA to screen for common trisomies became available in 2018. Relevant publications...
OBJECTIVE
A rolling circle amplification (RCA) based commercial methodology using cell-free (cf)DNA to screen for common trisomies became available in 2018. Relevant publications documented high detection but with a higher than expected 1% false positive rate. Preliminary evidence suggested assay variability was an issue. A multi-center collaboration was created to explore this further and examine whether subsequent manufacturer changes were effective.
METHODS
Three academic (four devices) and two commercial (two devices) laboratories provided run date, chromosome 21, 18, and 13 run-specific standard deviations, number of samples run, and reagent lot identifications. Temporal trends and between-site/device consistency were explored. Proportions of run standard deviations exceeding pre-specified caps of 0.4%, 0.4% and 0.6% were computed.
RESULTS
Overall, 661 RCA runs between April 2019 and July 30, 2022 tested 39,756 samples. In the first 24, subsequent 9, and final 7 months, proportions of capped chromosome 21 runs dropped from 39% to 22% to 6.0%; for chromosome 18, rates were 76%, 36%, and 4.0%. Few chromosome 13 runs were capped using the original 0.60%, but capping at 0.50%, rates were 28%, 16%, and 7.6%. Final rates occurred after reformulated reagents and imaging software modifications were fully implemented across all devices. Revised detection and false positive rates are estimated at 98.4% and 0.3%, respectively. After repeat testing, failure rates may be as low as 0.3%.
CONCLUSION
Current RCA-based screening performance estimates are equivalent to those reported for other methods, but with a lower test failure rate after repeat testing.
Topics: Pregnancy; Female; Humans; Cell-Free Nucleic Acids; Early Detection of Cancer; Prenatal Diagnosis; Trisomy
PubMed: 37194254
DOI: 10.1177/09691413231173315 -
Scientific Reports Jul 2023Nanomaterials feature exceptional, one-of-a-kind qualities that might be used in electronics, medicine, and other industries. Two-dimensional nanomaterials called...
Nanomaterials feature exceptional, one-of-a-kind qualities that might be used in electronics, medicine, and other industries. Two-dimensional nanomaterials called borophene have a variety of intriguing characteristics, which helped them to leave an indelible impression in the fields of chemistry, material science, nanotechnology, and condensed matter physics. The concept of modelling the structure of a molecule or chemical network to a chemical graph and then quantitatively analysing them with the aid of topological descriptors was a major advance in the fields of mathematics and chemistry, with a wide range of applications. M-polynomial approach is a very versatile and quick method for computing the degree-based descriptors of chemical graphs or networks. The degree-based descriptors of the [Formula: see text]-Borophene nanosheet are established in this study utilising the M-polynomial technique. A program code that enables to generate the M-polynomial of any chemical structure was developed in Java platform and the same is displayed. At the conclusion, the numerical and graphical comparison based on the identified analytic expressions is also provided. Additionally, the QSPR analysis was also carried out and the outcoms are presented therein.
PubMed: 37491369
DOI: 10.1038/s41598-023-37637-5 -
Reproductive Biology and Endocrinology... Oct 2023With advanced maternal age, abnormalities during oocyte meiosis increase significantly. Aneuploidy is an important reason for the reduction in the quality of aged...
BACKGROUND
With advanced maternal age, abnormalities during oocyte meiosis increase significantly. Aneuploidy is an important reason for the reduction in the quality of aged oocytes. However, the molecular mechanism of aneuploidy in aged oocytes is far from understood. Histone acetyltransferase 1 (HAT1) has been reported to be essential for mammalian development and genome stability, and involved in multiple organ aging. Whether HAT1 is involved in ovarian aging and the detailed mechanisms remain to be elucidated.
METHODS
The level of HAT1 in aged mice ovaries was detected by immunohistochemical and immunoblotting. To explore the function of HAT1 in the process of mouse oocyte maturation, we used Anacardic Acid (AA) and small interfering RNAs (siRNA) to culture cumulus-oocyte complexes (COCs) from ICR female mice in vitro and gathered statistics of germinal vesicle breakdown (GVBD), the first polar body extrusion (PBE), meiotic defects, aneuploidy, 2-cell embryos formation, and blastocyst formation rate. Moreover, the human granulosa cell (GC)-like line KGN cells were used to investigate the mechanisms of HAT1 in this progress.
RESULTS
HAT1 was highly expressed in ovarian granulosa cells (GCs) from young mice and the expression of HAT1 was significantly decreased in aged GCs. AA and siRNAs mediated inhibition of HAT1 in GCs decreased the PBE rate, and increased meiotic defects and aneuploidy in oocytes. Further studies showed that HAT1 could acetylate Forkhead box transcription factor O1 (FoxO1), leading to the translocation of FoxO1 into the nucleus. Resultantly, the translocation of acetylated FoxO1 increased the expression of amphiregulin (AREG) in GCs, which plays a significant role in oocyte meiosis.
CONCLUSION
The present study suggests that decreased expression of HAT1 in GCs is a potential reason corresponding to oocyte age-related meiotic defects and provides a potential therapeutic target for clinical intervention to reduce aneuploid oocytes.
Topics: Animals; Female; Humans; Mice; Aneuploidy; Granulosa Cells; Histone Acetyltransferases; Mammals; Meiosis; Mice, Inbred ICR; Oocytes
PubMed: 37907924
DOI: 10.1186/s12958-023-01147-w