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Nature Reviews. Genetics Sep 2016The study of de novo protein-coding genes is maturing from the ad hoc reporting of individual cases to the systematic analysis of extensive genomic data from several... (Review)
Review
The study of de novo protein-coding genes is maturing from the ad hoc reporting of individual cases to the systematic analysis of extensive genomic data from several species. We identify three key challenges for this emerging field: understanding how best to identify de novo genes, how they arise and why they spread. We highlight the intellectual challenges of understanding how a de novo gene becomes integrated into pre-existing functions and becomes essential. We suggest that, as with protein sequence evolution, antagonistic co-evolution may be key to de novo gene evolution, particularly for new essential genes and new cancer-associated genes.
Topics: Evolution, Molecular; Genomics; Humans; Open Reading Frames; Phylogeny; Proteins
PubMed: 27452112
DOI: 10.1038/nrg.2016.78 -
Frontiers in Genetics 2023Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1,...
Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1, are commonly associated with ID. The aim of this study was to identify novel gene variants in Chinese individuals with ID and evaluate the pathogenicity of the detected variants. Whole exome sequencing (WES) was performed on 113 patients diagnosed with ID. In the study, two variants in were identified. Sanger sequencing was used to confirm these variants. Minigene assays were used to verify whether the intronic variant in influenced the normal splicing of mRNA. Two heterozygous pathogenic variants in c.333del and c.664-2A>G, were identified in two ID patients separately. The c.333del variant has been reported previously as a finding in a child with ID, while the c.664-2A>G variant was novel intronic variant, which has not been reported in the literature. Functional studies showed that c.664-2A>G could cause aberrant splicing, resulting in exon 7 skipping and a 16bp deletion within exon 7. We identified two pathogenic heterozygous variants in in two patients with ID, among which the c.664-2A>G variant was a novel pathogenic variant. Our findings further enrich the variant spectrum of the gene and provide a research basis for the genetic diagnosis of ID.
PubMed: 37928246
DOI: 10.3389/fgene.2023.1270175 -
Methods in Molecular Biology (Clifton,... 2022In the latest years, the application of deep generative models to suggest virtual compounds is becoming a new and powerful tool in drug discovery projects. The idea... (Review)
Review
In the latest years, the application of deep generative models to suggest virtual compounds is becoming a new and powerful tool in drug discovery projects. The idea behind this review is to offer an updated view on de novo design approaches based on artificial intelligent (AI) algorithms, with a particular focus on ligand-based methods. We start this review by reporting a brief overview of the most relevant de novo design approaches developed before the use of AI techniques. We then describe the nowadays most common neural network architectures employed in ligand-based de novo design, together with an up-to-date list of more than 100 deep generative models found in the literature (2017-2020). In order to show how deep generative approaches are applied into drug discovery context, we report all the now available studies in which generated compounds have been synthetized and their biological activity tested. Finally, we discuss what we envisage as beneficial future directions for further application of deep generative models in de novo drug design.
Topics: Artificial Intelligence; Deep Learning; Drug Design; Ligands; Neural Networks, Computer
PubMed: 34731474
DOI: 10.1007/978-1-0716-1787-8_12 -
PloS One 2014The evolution of sequestration (uptake and accumulation) relative to de novo biosynthesis of chemical defense compounds is poorly understood, as is the interplay between...
The evolution of sequestration (uptake and accumulation) relative to de novo biosynthesis of chemical defense compounds is poorly understood, as is the interplay between these two strategies. The Burnet moth Zygaena filipendulae (Lepidoptera) and its food-plant Lotus corniculatus (Fabaceae) poses an exemplary case study of these questions, as Z. filipendulae belongs to the only insect family known to both de novo biosynthesize and sequester the same defense compounds directly from its food-plant. Z. filipendulae and L. corniculatus both contain the two cyanogenic glucosides linamarin and lotaustralin, which are defense compounds that can be hydrolyzed to liberate toxic hydrogen cyanide. The overall amounts and ratios of linamarin and lotaustralin in Z. filipendulae are tightly regulated, and only to a low extent reflect the ratio in the ingested food-plant. We demonstrate that Z. filipendulae adjusts the de novo biosynthesis of CNglcs by regulation at both the transcriptional and protein level depending on food plant composition. Ultimately this ensures that the larva saves energy and nitrogen while maintaining an effective defense system to fend off predators. By using in situ PCR and immunolocalization, the biosynthetic pathway was resolved to the larval fat body and integument, which infers rapid replenishment of defense compounds following an encounter with a predator. Our study supports the hypothesis that de novo biosynthesis of CNglcs in Z. filipendulae preceded the ability to sequester, and facilitated a food-plant switch to cyanogenic plants, after which sequestration could evolve. Preservation of de novo biosynthesis allows fine-tuning of the amount and composition of CNglcs in Z. filipendulae.
Topics: Animals; Fabaceae; Glucosides; Glycosides; Larva; Lepidoptera; Lotus; Moths; Nitriles
PubMed: 25299618
DOI: 10.1371/journal.pone.0108745 -
Breast Cancer Research and Treatment Apr 2021To examine patterns of de-novo metastases (mets) and association with breast cancer-specific mortality across subtypes and racial groups.
PURPOSE
To examine patterns of de-novo metastases (mets) and association with breast cancer-specific mortality across subtypes and racial groups.
METHODS
Non-Hispanic (NH) Black and NH-White patients ages 40 years and older with primary breast cancer (BC) between 2010 and 2015 were examined. Multilevel logistic regression and Cox proportional hazards models were used to assess (1) odds of de-novo mets to specific sites by subtype, and (2) association of subtype with risk of BC mortality among patients with de-novo mets by race.
RESULTS
A total of 204,941 BC patients were included in analysis. The most common de-novo mets site was to the bone, and overall prevalence of de-novo mets was higher among NH-Black (6.4%) versus NH-White (4.1%) patients. The odds of de-novo mets to any site were lower for TNBC (OR 0.68, 95% CI 0.62-0.73) and HR+/HER2- (OR 0.50, 95% CI 0.47-0.53) subtypes, but higher for HR-/HER2+ (OR 1.16, 95% CI 1.06-1.28) relative to HR+/HER2+ . De-novo mets to the brain only was associated with the highest mortality risk across all subtypes, ranging from a 13-fold increase (hazard ratio 13.45, 95% CI 5.03-35.96) for HR-/HER2+ to a 39-fold increase (hazard ratio 39.04, 95% CI 26.2-58.14) for HR+/HER2-.
CONCLUSION
Site and fatality of de-novo mets vary by subtype and by race. This information may help improve risk stratification and post-diagnostic surveillance to ultimately reduce BC mortality.
Topics: Adult; Black or African American; Breast Neoplasms; Ethnicity; Female; Humans; Receptors, Estrogen; Receptors, Progesterone
PubMed: 33175313
DOI: 10.1007/s10549-020-06007-4 -
Proteins Jun 2024Understanding the emergence and structural characteristics of de novo and random proteins is crucial for unraveling protein evolution and designing novel enzymes....
Understanding the emergence and structural characteristics of de novo and random proteins is crucial for unraveling protein evolution and designing novel enzymes. However, experimental determination of their structures remains challenging. Recent advancements in protein structure prediction, particularly with AlphaFold2 (AF2), have expanded our knowledge of protein structures, but their applicability to de novo and random proteins is unclear. In this study, we investigate the structural predictions and confidence scores of AF2 and protein language model-based predictor ESMFold for de novo and conserved proteins from Drosophila and a dataset of comparable random proteins. We find that the structural predictions for de novo and random proteins differ significantly from conserved proteins. Interestingly, a positive correlation between disorder and confidence scores (pLDDT) is observed for de novo and random proteins, in contrast to the negative correlation observed for conserved proteins. Furthermore, the performance of structure predictors for de novo and random proteins is hampered by the lack of sequence identity. We also observe fluctuating median predicted disorder among different sequence length quartiles for random proteins, suggesting an influence of sequence length on disorder predictions. In conclusion, while structure predictors provide initial insights into the structural composition of de novo and random proteins, their accuracy and applicability to such proteins remain limited. Experimental determination of their structures is necessary for a comprehensive understanding. The positive correlation between disorder and pLDDT could imply a potential for conditional folding and transient binding interactions of de novo and random proteins.
Topics: Animals; Protein Folding; Conserved Sequence; Drosophila Proteins; Databases, Protein; Models, Molecular; Computational Biology; Proteins; Intrinsically Disordered Proteins; Protein Conformation; Amino Acid Sequence; Algorithms; Drosophila
PubMed: 38226524
DOI: 10.1002/prot.26652 -
Biology Jan 2023Protein therapeutics have been widely used to treat hematological disorders. With the advent of de novo protein design, protein therapeutics are not limited to... (Review)
Review
Protein therapeutics have been widely used to treat hematological disorders. With the advent of de novo protein design, protein therapeutics are not limited to ameliorating natural proteins but also produce novel protein sequences, folds, and functions with shapes and functions customized to bind to the therapeutic targets. De novo protein techniques have been widely used biomedically to design novel diagnostic and therapeutic drugs, novel vaccines, and novel biological materials. In addition, de novo protein design has provided new options for treating hematological disorders. Scientists have designed protein switches called Colocalization-dependent Latching Orthogonal Cage-Key pRoteins (Co-LOCKR) that perform computations on the surface of cells. De novo designed molecules exhibit a better capacity than the currently available tyrosine kinase inhibitors in chronic myeloid leukemia therapy. De novo designed protein neoleukin-2/15 enhances chimeric antigen receptor T-cell activity. This new technique has great biomedical potential, especially in exploring new treatment methods for hematological disorders. This review discusses the development of de novo protein design and its biological applications, with emphasis on the treatment of hematological disorders.
PubMed: 36829445
DOI: 10.3390/biology12020166 -
Proceedings of the National Academy of... Oct 2022De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test...
De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test for our understanding of the underlying physical principles of protein folding and may lead to the development of proteins with unmatched functional characteristics. The first fundamental challenge of de novo design is to devise "designable" structural templates leading to sequences that will adopt the predicted fold. Here, we built on the TopoBuilder (TB) de novo design method, to automatically assemble structural templates with native-like features starting from string descriptors that capture the overall topology of proteins. Our framework eliminates the dependency of hand-crafted and fold-specific rules through an iterative, data-driven approach that extracts geometrical parameters from structural tertiary motifs. We evaluated the TopoBuilder framework by designing sequences for a set of five protein folds and experimental characterization revealed that several sequences were folded and stable in solution. The TopoBuilder de novo design framework will be broadly useful to guide the generation of artificial proteins with customized geometries, enabling the exploration of the protein universe.
Topics: Models, Molecular; Protein Engineering; Protein Folding; Proteins
PubMed: 36252041
DOI: 10.1073/pnas.2206111119 -
European Journal of Gastroenterology &... Mar 2021Nonalcoholic fatty liver disease (NAFLD) is a long-term complication after liver transplantation. Our aims were to determine de-novo-NAFLD at 5-year post-liver...
BACKGROUND AND AIMS
Nonalcoholic fatty liver disease (NAFLD) is a long-term complication after liver transplantation. Our aims were to determine de-novo-NAFLD at 5-year post-liver transplantation and identify predictive risk factors.
METHODS
This was a retrospective analysis of de-novo-NAFLD at 5-year post-liver transplantation. NAFLD was defined as the radiological evidence of steatosis. Data from transplanted patients between November 2001 and May 2014 were collected. Noninvasive fibrosis scores were calculated. Predictors of de-novo NAFLD and survival were assessed by multivariate analyses and Kaplan-Meier method.
RESULTS
A total of 252 liver transplantations were evaluated after applying exclusion criteria, (78.6% men) with 54.9 years old (SD ± 9.5). Prevalence of de-novo NAFLD at 5-year post-liver transplantation was 36.1%. Cardiovascular events were presented in 19.88% and 23.08% of non-NAFLD and NAFLD patients, (P = 0.58). On multivariate analysis, male sex (OR, 5.40; P = 0.001), obesity (OR, 3.72; P = 0.017), metabolic syndrome (OR, 4.69; P < 0.001) and de-novo diabetes (OR, 2.79; P = 0.018), were predictive. Significant fibrosis (≥F2) was presented in 58-86%. The mean survival in NAFLD and control group was 166.3 and 173.6 months, respectively (P = 0 0.50).
CONCLUSION
De-novo NAFLD at fifth-year post-liver transplantation is frequently and associated with cardiovascular comorbidity. Male sex, obesity, de-novo diabetes and metabolic syndrome were factors associated with de-novo NAFLD. A significant proportion of patients had advanced fibrosis. This group trends toward worse patients' survival.
Topics: Female; Humans; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Prevalence; Retrospective Studies; Risk Factors
PubMed: 32317584
DOI: 10.1097/MEG.0000000000001736 -
World Journal of Hepatology May 2015Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between... (Review)
Review
Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.
PubMed: 25954477
DOI: 10.4254/wjh.v7.i7.942