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Current Protocols in Protein Science Dec 2020While native proteins cover diverse structural spaces and achieve various biological events, not many of them can directly serve human needs. One reason is that the...
While native proteins cover diverse structural spaces and achieve various biological events, not many of them can directly serve human needs. One reason is that the native proteins usually contain idiosyncrasies evolved for their native functions but disfavoring engineering requirements. To overcome this issue, one strategy is to create de novo proteins which are designed to possess improved stability, high environmental tolerance, and enhanced engineering potential. Compared to other protein engineering strategies, in silico design of de novo proteins has significantly expanded the protein structural and sequence spaces, reduced wet lab workload, and incorporated engineered features in a guided and efficient manner. In the Baker laboratory we have been applying a design pipeline that uses the blueprint builder to design different folds of de novo proteins, and have successfully obtained libraries of de novo proteins with improved stability and engineering potential. In this article, we will use the design of de novo β-barrel proteins as an example to describe the principles and basic procedures of the blueprint builder-based design pipeline. © 2020 Wiley Periodicals LLC. Basic Protocol 1: The construction of blueprints Alternate Protocol: Build blueprints based on existing protein .pdb files Basic Protocol 2: De novo protein design pipeline using the blueprint builder.
Topics: Computer Simulation; Humans; Protein Conformation; Protein Engineering
PubMed: 33320432
DOI: 10.1002/cpps.116 -
The Plant Journal : For Cell and... Aug 2022De novo genes are derived from non-coding sequences, and they can play essential roles in organisms. Cultivated peanut (Arachis hypogaea) is a major oil and protein crop...
De novo genes are derived from non-coding sequences, and they can play essential roles in organisms. Cultivated peanut (Arachis hypogaea) is a major oil and protein crop derived from a cross between Arachis duranensis and Arachis ipaensis. However, few de novo genes have been documented in Arachis. Here, we identified 381 de novo genes in A. hypogaea cv. Tifrunner based on comparison with five closely related Arachis species. There are distinct differences in gene expression patterns and gene structures between conserved and de novo genes. The identified de novo genes originated from ancestral sequence regions associated with metabolic and biosynthetic processes, and they were subsequently integrated into existing regulatory networks. De novo paralogs and homoeologs were identified in A. hypogaea cv. Tifrunner. De novo paralogs and homoeologs with conserved expression have mismatching cis-acting elements under normal growth conditions. De novo genes potentially have pluripotent functions in responses to biotic stresses as well as in growth and development based on quantitative trait locus data. This work provides a foundation for future research examining gene birth processes and gene function in Arachis and related taxa.
Topics: Arachis; Evolution, Molecular; Quantitative Trait Loci
PubMed: 35748398
DOI: 10.1111/tpj.15875 -
World Journal of Clinical Cases Dec 2022As operative techniques and mortality rates of pancreatectomy have improved, there has been a shift in focus to maintaining and improving the nutritional status of these...
BACKGROUND
As operative techniques and mortality rates of pancreatectomy have improved, there has been a shift in focus to maintaining and improving the nutritional status of these patients as we continue to learn more about post-operative complications. Although pancreatic endocrine and exocrine insufficiencies are known complications of pancreatectomy, increased longevity of these patients has also led to a higher incidence of fatty liver disease which differs from traditional fatty liver disease given the lack of metabolic syndrome.
AIM
To identify and summarize patterns and risk factors of post-pancreatectomy fatty liver disease to guide future management.
METHODS
We performed a database search on PubMed selecting papers published between 2001 and 2022 in the English language. PubMed was last accessed 1 June 2022.
RESULTS
Various factors influence the development of fatty liver including indication for surgery (benign malignant), type of pancreatectomy, amount of pancreas remnant, and peri-operative nutritional status. With an incidence rate up to 75%, non-alcoholic fatty liver disease (NAFLD) can develop within 12 mo after pancreatectomy and various risk factors have been established including pancreatic resection line and remnant pancreas volume, peri-operative malnutrition and weight loss, pancreatic exocrine insufficiency (EPI), malignancy as the indication for surgery, and postmenopausal status.
CONCLUSION
Since majority of risk factors leads to EPI and malnutrition, peri-operative focus on nutrition and enzymes replacement is key in preventing and treating NAFLD after pancreatectomy.
PubMed: 36569000
DOI: 10.12998/wjcc.v10.i35.12946 -
Life (Basel, Switzerland) Mar 2021De novo protein design is a powerful methodology used to study natural functions in an artificial-protein context. Since its inception, it has been used to reproduce a... (Review)
Review
De novo protein design is a powerful methodology used to study natural functions in an artificial-protein context. Since its inception, it has been used to reproduce a plethora of reactions and uncover biophysical principles that are often difficult to extract from direct studies of natural proteins. Natural proteins are capable of assuming a variety of different structures and subsequently binding ligands at impressively high levels of both specificity and affinity. Here, we will review recent examples of de novo design studies on binding reactions for small molecules, nucleic acids, and the formation of protein-protein interactions. We will then discuss some new structural advances in the field. Finally, we will discuss some advancements in computational modeling and design approaches and provide an overview of some modern algorithmic tools being used to design these proteins.
PubMed: 33802210
DOI: 10.3390/life11030225 -
APMIS : Acta Pathologica,... Apr 2023Liver transplant recipients receive immunosuppressive treatment to avoid organ rejection, increasing the risk of developing de novo cancer after transplantation. We...
Liver transplant recipients receive immunosuppressive treatment to avoid organ rejection, increasing the risk of developing de novo cancer after transplantation. We investigated the cumulative incidence of de novo cancer in a cohort of Danish liver transplant recipients. The study was a retrospective cohort study of adult liver transplant recipients transplanted at Rigshospitalet, Copenhagen, Denmark, between January 1, 2010, and December 31, 2019. De novo cancer was defined as cancer arising at least 30 days after liver transplantation, excluding relapses from prior cancers and donor-derived cancers. We determined the incidence of de novo cancer in the cohort using the Aalen-Johansen estimator, with death and retransplantation as competing risks. We included 389 liver transplant recipients and identified 47 recipients (12%) with de novo cancer after liver transplantation, including 25 recipients with non-melanoma skin cancers. The cumulative incidences at 5 years after liver transplantation for all cancers and non-skin cancers were 10.7% and 4.9%, respectively. De novo cancer after liver transplantation is relatively common, with the majority being non-melanoma skin cancer. Future studies of sufficient size are needed to identify risk factors for de novo cancer after liver transplantation.
Topics: Adult; Humans; Liver Transplantation; Retrospective Studies; Neoplasms; Risk Factors; Immunosuppressive Agents; Incidence
PubMed: 36680559
DOI: 10.1111/apm.13296 -
Journal of Neurosurgery Jul 2018De novo aneurysms are rare entities periodically discovered during follow-up imaging. Little is known regarding the frequency with which these lesions form or the time... (Review)
Review
OBJECTIVE
De novo aneurysms are rare entities periodically discovered during follow-up imaging. Little is known regarding the frequency with which these lesions form or the time course. This systematic review and meta-analysis was undertaken to estimate the incidence of de novo aneurysms and to determine risk factors for aneurysm formation.
METHODS
The authors searched multiple databases for studies of patients with unruptured and ruptured aneurysms describing the rate of de novo aneurysm formation. The primary outcome was incidence of de novo aneurysm formation. A meta-analysis was performed using a random-effects model. The authors examined the associations of multiple aneurysms, prior subarachnoid hemorrhage, smoking, sex, age at presentation, and hypertension with de novo aneurysm formation.
RESULTS
The meta-analysis included 14,968 aneurysm patients who received imaging follow-up from 35 studies. The overall incidence of de novo aneurysm formation was 2% (95% CI 2%-3%) over a mean follow-up time of 8.3 years. The estimated incidence density was 0.3%/patient-year. There was no statistically significant difference in rates of de novo aneurysm formation between patients who had ruptured aneurysms and those with unruptured aneurysms. In 8 studies, 11.2% of de novo aneurysms were found in patients with ≤ 5 years of follow-up and 88.8% were found at > 5 years. The mean time to rupture for de novo aneurysms was 10 years.
CONCLUSIONS
This systematic review demonstrates that formation of de novo aneurysms is rare. Overall, routine screening for de novo aneurysms is likely to be of low yield and could be performed at time intervals of at least 5 to 10 years.
PubMed: 29979115
DOI: 10.3171/2018.1.JNS172450 -
European Journal of Human Genetics :... Jan 2021By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus...
By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.
Topics: Adolescent; Adult; Child; Female; Gene Frequency; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Mutation, Missense; Polymorphism, Single Nucleotide; Promoter Regions, Genetic
PubMed: 32724065
DOI: 10.1038/s41431-020-0698-5 -
Liver Transplantation : Official... Jan 2004De novo malignancies are one of the current problems in patients with organ transplantation. The incidence has been considered to be higher as a result of increases of... (Review)
Review
De novo malignancies are one of the current problems in patients with organ transplantation. The incidence has been considered to be higher as a result of increases of oncogenic viruses in immunosuppressed organ recipients. Published reports have shown increased incidence of de novo tumors such as malignant lymphomas and cutaneous neoplasms but decreased incidence of breast cancer. A variety of factors affect de novo breast cancer development in organ recipients, including immunosuppression, viruses, and underlying disease. The aims of this review are to evaluate the incidence and management of patients with de novo breast cancer by giving the University of Pittsburgh's data, and to evaluate the incidence of de novo breast cancer in published reports in light of an age-adjusted rate. According to age-adjusted rates presented by the National Cancer Institute's Surveillance, Epidemiology and End Results data, we found increased incidence rate of de novo breast cancer in the previously published series. The University of Pittsburgh's incidence rate of de novo breast cancer was determined in a fashion similar to that for the Surveillance, Epidemiology and End Results data. Eighty-three percent of all patients were diagnosed at early stages, and it appeared to take longer for de novo breast cancer to develop in patients treated with tacrolimus than in patients treated with cyclosporine. In conclusion, surgical treatment of breast cancer in liver recipients is the same as treatment of breast cancer in patients without transplantation. However, the effects of chemotherapy, radiotherapy, and/or tamoxifen remain unclear in transplanted patients and need to be evaluated in larger studies.
Topics: Breast Neoplasms; Female; Humans; Immunosuppressive Agents; Incidence; Killer Cells, Natural; Liver Transplantation; Postoperative Complications; SEER Program
PubMed: 14755771
DOI: 10.1002/lt.20025 -
F1000Research 2017Nanopore technology provides a novel approach to DNA sequencing that yields long, label-free reads of constant quality. The first commercial implementation of this... (Review)
Review
Nanopore technology provides a novel approach to DNA sequencing that yields long, label-free reads of constant quality. The first commercial implementation of this approach, the MinION, has shown promise in various sequencing applications. This review gives an up-to-date overview of the MinION's utility as a sequencing device. It is argued that the MinION may allow for portable and affordable sequencing of even complex genomes in the near future, despite the currently error-prone nature of its reads. Through continuous updates to the MinION hardware and the development of new assembly pipelines, both sequencing accuracy and assembly quality have already risen rapidly. However, this fast pace of development has also lead to a lack of overview of the expanding landscape of analysis tools, as performance evaluations are outdated quickly. As the MinION is approaching a state of maturity, its user community would benefit from a thorough comparative benchmarking effort of de novo assembly pipelines in the near future. An earlier version of this article can be found on bioRxiv.
PubMed: 29375809
DOI: 10.12688/f1000research.12012.2 -
Computational and Structural... 2022Various deep learning-based architectures for molecular generation have been proposed for drug design. The flourish of the molecular generation methods and...
Various deep learning-based architectures for molecular generation have been proposed for drug design. The flourish of the molecular generation methods and applications has created a great demand for the visualization and functional profiling for the generated molecules. An increasing number of publicly available chemogenomic databases sets good foundations and creates good opportunities for comprehensive profiling of the de novo library. In this paper, we present DenovoProfiling, a webserver dedicated to library visualization and functional profiling. Currently, DenovoProfiling contains six modules: (1) identification & visualization module for chemical structure visualization and identify the reported structures, (2) chemical space module for chemical space exploration using similarity maps, principal components analysis (PCA), drug-like properties distribution, and scaffold-based clustering, (3) ADMET prediction module for predicting the ADMET properties of the molecules, (4) molecular alignment module for three dimensional molecular shape analysis, (5) drugs mapping module for identifying structural similar drugs, and (6) target & pathway module for identifying the reported targets and corresponding functional pathways. DenovoProfiling could provide structural identification, chemical space exploration, drug mapping, and target & pathway information. The comprehensive annotated information could give users a clear picture of their library and could guide the further selection of candidates for chemical synthesis and biological confirmation. DenovoProfiling is freely available at http://denovoprofiling.xielab.net.
PubMed: 36016718
DOI: 10.1016/j.csbj.2022.07.045