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Current Opinion in Hematology May 2024Lipids play vital roles in platelet structure, signaling, and metabolism. In addition to capturing exogenous lipids, platelets possess the capacity for de novo...
PURPOSE OF REVIEW
Lipids play vital roles in platelet structure, signaling, and metabolism. In addition to capturing exogenous lipids, platelets possess the capacity for de novo lipogenesis, regulated by acetyl-coA carboxylase 1 (ACC1). This review aims to cover the critical roles of platelet de novo lipogenesis and lipidome in platelet production, function, and diseases.
RECENT FINDINGS
Upon platelet activation, approximately 20% of the platelet lipidome undergoes significant modifications, primarily affecting arachidonic acid-containing species. Multiple studies emphasize the impact of de novo lipogenesis, with ACC1 as key player, on platelet functions. Mouse models suggest the importance of the AMPK-ACC1 axis in regulating platelet membrane arachidonic acid content, associated with TXA2 secretion, and thrombus formation. In human platelets, ACC1 inhibition leads to reduced platelet reactivity. Remodeling of the platelet lipidome, alongside with de novo lipogenesis, is also crucial for platelet biogenesis. Disruptions in the platelet lipidome are observed in various pathological conditions, including cardiovascular and inflammatory diseases, with associations between these alterations and shifts in platelet reactivity highlighted.
SUMMARY
The platelet lipidome, partially regulated by ACC-driven de novo lipogenesis, is indispensable for platelet production and function. It is implicated in various pathological conditions involving platelets.
PubMed: 38727017
DOI: 10.1097/MOH.0000000000000820 -
Annals of Translational Medicine May 2021With the exponential increase of worldwide obesity, the number of bariatric surgery (BaS) procedures have equally risen. The surgical management of obesity has been... (Review)
Review
With the exponential increase of worldwide obesity, the number of bariatric surgery (BaS) procedures have equally risen. The surgical management of obesity has been widely established as the standard of care for sustained weight reduction, resolution, and improvement of associated comorbidities. However, BaS itself can have postoperative deleterious effects, including gastroesophageal reflux disease (GERD) and upper gastrointestinal motility disorders. The modified anatomy resulting from BaS, due to either a restrictive or hypoabsorptive component, gives this disorder a multifactorial etiology. The overall management of GERD should focus on three primordial approaches: Non-surgical, endoluminal, and surgical. Even in the absence of GERD following primary or secondary BaS, said disorder should be closely monitored and therapy should be catered in a case-by-case approach. Consequently, treatment strategies have been developed on this principle as to adequately resolve GERD. Despite the presence of multiple and suitable treatment modalities, the operating surgeon should perform them in the best interest of the patient. Short-, medium-, and long-term outcomes should be taken into consideration prior to proceed with any type of preferred management option. This article herein presents an update on the surgical management of GERD following BaS and current practical innovations.
PubMed: 34164533
DOI: 10.21037/atm-20-5890 -
Current Topics in Medicinal Chemistry 2022The artificial intelligence (AI)-assisted design of drug candidates with novel structures and desired properties has received significant attention in the recent past,... (Review)
Review
BACKGROUND
The artificial intelligence (AI)-assisted design of drug candidates with novel structures and desired properties has received significant attention in the recent past, so related areas of forward prediction that aim to discover chemical matters worth synthesizing and further experimental investigation.
OBJECTIVES
The purpose behind developing AI-driven models is to explore the broader chemical space and suggest new drug candidate scaffolds with promising therapeutic value. Moreover, it is anticipated that such AI-based models may not only significantly reduce the cost and time but also decrease the attrition rate of drug candidates that fail to reach the desirable endpoints at the final stages of drug development. In an attempt to develop AI-based models for de novo drug design, numerous methods have been proposed by various study groups by applying machine learning and deep learning algorithms to chemical datasets. However, there are many challenges in obtaining accurate predictions, and real breakthroughs in de novo drug design are still scarce.
METHODS
In this review, we explore the recent trends in developing AI-based models for de novo drug design to assess the current status, challenges, and opportunities in the field.
CONCLUSION
The consistently improved AI algorithms and the abundance of curated training chemical data indicate that AI-based de novo drug design should perform better than the current models. Improvements in the performance are warranted to obtain better outcomes in the form of potential drug candidates, which can perform well in in vivo conditions, especially in the case of more complex diseases.
Topics: Artificial Intelligence; Machine Learning; Algorithms; Drug Design; Drug Development
PubMed: 36263480
DOI: 10.2174/1568026623666221017143244 -
Research and Reports in Urology 2021Pubovaginal sling is an efficient and safe procedure for stress urinary incontinence without the complications of synthetic sling. Urine retention and de novo urgency...
INTRODUCTION
Pubovaginal sling is an efficient and safe procedure for stress urinary incontinence without the complications of synthetic sling. Urine retention and de novo urgency are bothersome aftermath of this procedure. We aim to identify potential risk factors for de novo urgency after autologous pubovaginal sling.
METHODS
From 2013 to 2016, 347 patients underwent autologous pubovaginal sling. Age, BMI, pelvic irradiation, use of anticholinergic medication, previous vaginal related surgical histories, "over-tight" technique, and concomitant surgeries were examined for potential risk factors. De novo urgency/urge incontinence was defined as treatment (medication, botulinum toxin injection, sacral neuromodulation) for urge postoperatively and was not noted before surgery. Chi-square and fisher's exact tests were used as statistical analysis.
RESULTS
A total of 109 patients underwent autologous rectus fascia pubovaginal sling, after excluding status post urethral diverticulectomy, concomitant diverticulectomy, and concomitant abdominal surgery. Twenty-three (21.1%) patients were treated for de novo urge/urge incontinence, 18 (78.2%) with anticholinergic, 4 (17.3%) with botox injection and 2 (8.69%) with sacral neuromodulation. None but prior pelvic organ prolapse surgery was associated with developing de novo urge/urge incontinence (p=0.026).
DISCUSSION
Patients with prior pelvic organ prolapse surgery were more likely to be at risk of de novo urgency after autologous pubovaginal sling. This study provided more information for preoperative consultation for patients undergoing incontinence surgery.
PubMed: 34422706
DOI: 10.2147/RRU.S321955 -
Genes Sep 2021The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number... (Review)
Review
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of variants in CDH. This review gives an overview of the known disease-causing variants in CDH patients.
Topics: Aneuploidy; Chromosome Aberrations; DNA Copy Number Variations; Hernias, Diaphragmatic, Congenital; Humans; Mutation
PubMed: 34573387
DOI: 10.3390/genes12091405 -
Molecular Biology and Evolution Mar 2023As the accuracy and throughput of nanopore sequencing improve, it is increasingly common to perform long-read first de novo genome assemblies followed by polishing with...
As the accuracy and throughput of nanopore sequencing improve, it is increasingly common to perform long-read first de novo genome assemblies followed by polishing with accurate short reads. We briefly introduce FMLRC2, the successor to the original FM-index Long Read Corrector (FMLRC), and illustrate its performance as a fast and accurate de novo assembly polisher for both bacterial and eukaryotic genomes.
Topics: Sequence Analysis, DNA; Eukaryota; Nanopores; Bacteria; Genome, Bacterial; High-Throughput Nucleotide Sequencing
PubMed: 36869750
DOI: 10.1093/molbev/msad048 -
Current Opinion in Chemical Biology Jun 2020Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use... (Review)
Review
Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use naturally existing proteins as a starting point, and therefore, are intrinsically limited to small alterations of a protein's natural structure and function. Conversely, computational de novo protein design is free of such limitation, and can produce a virtually infinite number of novel protein sequences, folds, and functions. Recently, we used de novo protein engineering to create Neoleukin-2/15 (Neo-2/15), a protein mimetic of the function of both interleukin-2 (IL-2) and interleukin-15 (IL-15). To our knowledge, Neo-2/15 is the first de novo protein with immunotherapeutic activity, and in murine cancer models, it has demonstrated enhanced therapeutic potency and reduced toxicity compared to IL-2. De novo protein design is already showcasing its tremendous potential for driving the next wave of protein-based therapeutics that are explicitly engineered to treat disease.
Topics: Amino Acid Sequence; Animals; Immunotherapy; Interleukin-15; Interleukin-2; Mice; Models, Molecular; Neoplasms; Neoplasms, Experimental; Protein Binding; Protein Conformation; Protein Engineering; Structure-Activity Relationship
PubMed: 32371023
DOI: 10.1016/j.cbpa.2020.02.002 -
Frontiers in Physiology 2022Embryonic-to-neonatal development in chicken is characterized by high rates of lipid oxidation in the late-term embryonic liver and high rates of lipogenesis in the...
Embryonic-to-neonatal development in chicken is characterized by high rates of lipid oxidation in the late-term embryonic liver and high rates of lipogenesis in the neonatal liver. This rapid remodeling of hepatic mitochondrial and cytoplasmic networks occurs without symptoms of hepatocellular stress. Our objective was to characterize the metabolic phenotype of the embryonic and neonatal liver and explore whether these metabolic signatures are preserved in primary cultured hepatocytes. Plasma and liver metabolites were profiled using mass spectrometry based metabolomics on embryonic day 18 (ed18) and neonatal day 3 (nd3). Hepatocytes from ed18 and nd3 were isolated and cultured, and treated with insulin, glucagon, growth hormone and corticosterone to define hormonal responsiveness and determine their impacts on mitochondrial metabolism and lipogenesis. Metabolic profiling illustrated the clear transition from the embryonic liver relying on lipid oxidation to the neonatal liver upregulating lipogenesis. This metabolic phenotype was conserved in the isolated hepatocytes from the embryos and the neonates. Cultured hepatocytes from the neonatal liver also maintained a robust response to insulin and glucagon, as evidenced by their contradictory effects on lipid oxidation and lipogenesis. In summary, primary hepatocytes from the embryonic and neonatal chicken could be a valuable tool to investigate mechanisms regulating hepatic mitochondrial metabolism and lipogenesis.
PubMed: 35530509
DOI: 10.3389/fphys.2022.870451 -
Cytogenetic and Genome Research 2020During gametogenesis, the human genome can acquire various de novo rearrangements. Most constitutional genomic rearrangements are created through 1 of the 4 well-known... (Review)
Review
During gametogenesis, the human genome can acquire various de novo rearrangements. Most constitutional genomic rearrangements are created through 1 of the 4 well-known mechanisms, i.e., nonallelic homologous recombination, erroneous repair after double-strand DNA breaks, replication errors, and retrotransposition. However, recent studies have identified 2 types of extremely complex rearrangements that cannot be simply explained by these mechanisms. The first type consists of chaotic structural changes in 1 or a few chromosomes that result from "chromoanagenesis (an umbrella term that covers chromothripsis, chromoanasynthesis, and chromoplexy)." The other type is large independent rearrangements in multiple chromosomes indicative of "transient multifocal genomic crisis." Germline chromoanagenesis (chromothripsis) likely occurs predominantly during spermatogenesis or postzygotic embryogenesis, while multifocal genomic crisis appears to be limited to a specific time window during oogenesis and early embryogenesis or during spermatogenesis. This review article introduces the current understanding of the molecular basis of de novo rearrangements in the germline.
Topics: Chromothripsis; Embryonic Development; Germ-Line Mutation; Humans; Oogenesis; Recombination, Genetic; Spermatogenesis
PubMed: 32396893
DOI: 10.1159/000507837 -
Frontiers in Immunology 2022To examine the production time, type, and MFI of post-transplantation HLA antibodies, and their effects on haplo-HSCT outcomes, we retrospectively included 116 patients...
To examine the production time, type, and MFI of post-transplantation HLA antibodies, and their effects on haplo-HSCT outcomes, we retrospectively included 116 patients who were negative for pre-existing HLA antibodies. In total, 322 serum samples from pre-transplantation to post-transplantation were dynamically tested by Luminex and single-antigen bead reagents. Patients were divided into: HLA antibody persistently negative group (group 1), the HLA antibody transiently positive group (group 2), the HLA antibody non-persistently positive group (group 3), and the HLA antibody persistently positive group (group 4). Group 4 included DSA+non-DSA (NDSA) (group 4a) and NDSA (group 4b) groups. The detection rate of HLA antibodies was 75.9% (88/116). The median MFI for HLA antibodies was 2439 (1033-20162). The incidence of II-IV aGvHD was higher in group 2 than in group 1 (52.6% vs 17.9%, P < 0.01); in group 4a than in group 1 (87.5% vs 17.9%, P < 0.001); and in group 4a than in group 4b (87.5% vs 40.0%, P = 0.001). The DFS (37.5% vs 85.7%, P < 0.01) and OS (37.5% vs 85.7%, P < 0.01) of group 4a were lower than those of group 1. The DFS (48.0% vs 85.7%, P < 0.01) and OS (56.0% vs 85.7%, P = 0.03) of group 4b were lower than those of group 1. Multivariate analysis showed that HLA antibody being transiently positive (HR: 5.30; 95% CI: 1.71-16.42, P = 0.01) and persistently positive (HR: 5.67; 95% CI: 2.00-16.08, P < 0.01) were both associated with a higher incidence of II-IV aGvHD. Persistently positive HLA antibodies were a risk factor for reduced DFS (HR: 6.57; 95% CI: 2.08-20.70, P < 0.01) and OS (HR: 5.51; 95% CI: 1.73-17.53, P < 0.01). DSA and NDSA can be detected since 15 days after haplo-HSCT in patients without pre-existing HLA antibodies, and affect aGvHD, DFS, and OS. Haplo-HSCT patients must be monitored for HLA antibodies changes for appropriate preventive clinical management, and we recommend that 1-month post-transplantation is the best test time point.
Topics: Humans; Retrospective Studies; Hematologic Neoplasms; Antibodies; Risk Factors; Hematopoietic Stem Cell Transplantation
PubMed: 36532004
DOI: 10.3389/fimmu.2022.1047200