-
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 -
Molecular Genetics & Genomic Medicine Mar 2019Osteogenesis imperfecta (OI) is a rare genetic bone fragility disorder. In the current study, differences between the genotypes and phenotypes of de novo and inherited...
BACKGROUND
Osteogenesis imperfecta (OI) is a rare genetic bone fragility disorder. In the current study, differences between the genotypes and phenotypes of de novo and inherited collagen-related OI were investigated.
METHODS
A comparative analysis was performed of the genotypes and phenotypes of 146 unrelated inherited and de novo collagen I OI cases from Estonia, Ukraine, and Vietnam. Mutational analysis of the subjects and all available parents were performed with Sanger sequencing.
RESULTS
Results showed that 56.16% of the OI cases were caused by de novo pathogenic variants. The proportion of OI types OI1, OI4, and OI3 among subjects with inherited OI was 45.31%, 46.88%, and 7.81%, respectively. Among subjects with de novo OI, the proportions of OI types (OI1, OI4, and OI3) were almost equal. Both inherited and de novo OI pathogenic variants occurred more often in the COL1A1 gene than in the COL1A2. The majority of de novo cases were missense pathogenic variants, whereas inherited OI was mostly caused by loss of function pathogenic variants.
CONCLUSION
In summary, there were significant differences between the phenotypes and genotypes of subjects with de novo and inherited OI. These findings may promote the further understanding of OI etiology, and assist with diagnostics procedures, as well as with family planning.
Topics: Adolescent; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Humans; Male; Mutation; Osteogenesis Imperfecta
PubMed: 30675999
DOI: 10.1002/mgg3.559 -
Frontiers in Plant Science 2023Plants, unlike animals, possess a unique developmental plasticity, that allows them to adapt to changing environmental conditions. A fundamental aspect of this... (Review)
Review
Plants, unlike animals, possess a unique developmental plasticity, that allows them to adapt to changing environmental conditions. A fundamental aspect of this plasticity is their ability to undergo postembryonic organogenesis. This requires the presence of regulators that trigger and mediate specific spatiotemporal changes in developmental programs. The phytohormone cytokinin has been known as a principal regulator of plant development for more than six decades. In shoot organogenesis and shoot regeneration, cytokinins are the prime candidates for the signal that determines shoot identity. Both processes of shoot apical meristem development are accompanied by changes in gene expression, cell fate reprogramming, and the switching-on of the shoot-specific homeodomain regulator, WUSCHEL. Current understanding about the role of cytokinins in the shoot regeneration will be discussed.
PubMed: 37662179
DOI: 10.3389/fpls.2023.1239133 -
Breast (Edinburgh, Scotland) Oct 2023Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current...
OBJECTIVES
Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current situation is helpful for the clinical cognition and decision-making.
METHODS
We retrospectively analyzed the clinical and survival information of de novo stage IV breast cancer with BM between 2015 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable logistic and Cox regression analyses were performed to identify predictors of BM and factors associated with all-cause mortality in de novo stage IV breast cancer, respectively. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests.
RESULTS
Our cohort consisted of 1366 patients with BM in de novo stage IV breast cancer, with an incidence of 8.38% in patients with metastatic disease to any distant site. Incidence was highest among patients with metastatic disease with HR-HER2+ (12.95%) and HR-HER2- (13.40%) subtypes. The higher the number of extracranial metastases, the higher the BM incidence. The median OS was 12.0 (95%CI: 10.426-13.574) months in BM group; it was longest in HR + HER2+ (19.0[95%CI: 11.793-26.207] months), and shortest in HR-HER2- (7.0 [95%CI:5.354-8.646] months). Marital status, subtype, and abundance of metastatic sites influenced morbidity and OS of BM in de novo stage IV breast cancer.
CONCLUSIONS
Population-based estimates of the incidence and prognosis for patients with BM in de novo stage IV breast cancer were closely associated with subtype and metastatic burden. These findings may be helpful in developing diagnostic strategies, especially for brain screening.
Topics: Humans; Female; Breast Neoplasms; Retrospective Studies; Brain Neoplasms; Brain; Cognition; Prognosis; Neoplasm Metastasis
PubMed: 37499376
DOI: 10.1016/j.breast.2023.07.005 -
European Journal of Medical Genetics Apr 2020To investigate whether increased parental age is associated with an increased risk for de novo copy number variant (CNV) formation in offspring.
PURPOSE
To investigate whether increased parental age is associated with an increased risk for de novo copy number variant (CNV) formation in offspring.
METHODS
CNV calls from 2323 individuals referred to Signature Genomic Laboratories for clinical microarray-based comparative genomic hybridization were investigated; 17% of the samples were prenatal and 83% were postnatal. The de novo CNV data were further split into de novo CNVs bound by low copy repeats (LCRs) and those not bound by LCRs.
RESULTS
No association was found between CNV occurrence and paternal age in both the prenatal (p = 0.6795) and postnatal (p = 0.1741) cohorts. Maternal age was significantly higher with de novo CNV occurrence in our postnatal cohort (p = 0.0126), an effect which may be driven by formation of de novo CNVs that are bound by LCRs (p = 0.0026). Furthermore, a significant positive correlation was observed between maternal age and de novo CNVs (Point-Biserial R = 0.0503, p = 0.0152).
CONCLUSIONS
This large-scale study did not find any evidence for the influence of increased paternal age on de novo CNV formation, while increased maternal age appeared to increase risk for de novo, non-complex CNV occurrence in offspring with intellectual disability/developmental delay. Further studies and continued technological advances will help yield more information on the risk factors for de novo CNVs.
Topics: Adult; DNA Copy Number Variations; Fathers; Female; Humans; Infant, Newborn; Male; Mothers; Parents
PubMed: 31883480
DOI: 10.1016/j.ejmg.2019.103829 -
Interventional Neuroradiology : Journal... Aug 2022Intracranial dural arteriovenous fistulas (dAVF) account for nearly 10-15% of all arteriovenous malformations. Although the majority of dAVF are effectively cured after...
Intracranial dural arteriovenous fistulas (dAVF) account for nearly 10-15% of all arteriovenous malformations. Although the majority of dAVF are effectively cured after endovascular intervention, there are cases of dAVFs that may recur after radiographic cure. We present the case of a 69-year-old female with de novo formation of three dAVFs in different anatomic locations after successive endovascular treatments. The patient's initial dAVF was identified in the right posterior frontal convexity region and obliterated with transarterial and transvenous embolization. The patient returned eight years later due to left-sided pulsatile tinnitus and a new dAVF in the left greater sphenoid wing region was seen on angiography. This was treated with transvenous embolization with complete resolution. One year later, she developed left sided pulsatile tinnitus again and was found to have a left carotid-cavernous dAVF. This is the first case report to our knowledge of the formation of three de novo dAVFs over multiple years in distinct anatomical locations. We also review the literature regarding de novo dAVFs after endovascular treatment which includes 16 cases. De novo dAVF formation is likely due to numerous factors including changes in venous flow and aberrant vascular development. It is important to further understand the relationship between endovascular treatment and recurrent dAVF formation to prevent subsequent malformations.
PubMed: 35924383
DOI: 10.1177/15910199221118517 -
Genes Mar 2022Most genetic variants are rare and specific to the population, highlighting the importance of characterizing local population genetic diversity. Many countries have...
Most genetic variants are rare and specific to the population, highlighting the importance of characterizing local population genetic diversity. Many countries have initiated population-based whole-genome sequencing (WGS) studies. Genomic variation within Lithuanian families are not available in the public databases. Here, we describe initial findings of a high-coverage (an average of 36.27×) whole genome sequencing for 25 trios of the Lithuanian population. Each genome on average carried approximately 4,701,473 (±28,255) variants, where 80.6% (3,787,626) were single nucleotide polymorphisms (SNPs), and the rest 19.4% were indels. An average of 12.45% was novel according to dbSNP (build 150). The WGS structural variation (SV) analysis identified on average 9133 (±85.10) SVs, of which 95.85% were novel. De novo single nucleotide variation (SNV) analysis identified 4417 variants, where 1.1% de novo SNVs were exonic, 43.9% intronic, 51.9% intergenic, and the rest 3.13% in UTR or downstream sequence. Three potential pathogenic de novo variants in the , , and genes were identified. Our findings provide useful information on local human population genomic variation, especially for de novo variants, and will be a valuable resource for further genetic studies, and medical implications.
Topics: Genome, Human; Humans; INDEL Mutation; Lithuania; Polymorphism, Single Nucleotide; Whole Genome Sequencing
PubMed: 35456375
DOI: 10.3390/genes13040569 -
Journal of Neurosurgery Feb 2019Incidence rates of de novo aneurysm formation and recurrence after clip ligation remain controversial. In this meta-analysis, the authors provide data on pooled annual... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Incidence rates of de novo aneurysm formation and recurrence after clip ligation remain controversial. In this meta-analysis, the authors provide data on pooled annual incidence rates and the association of patient characteristics with time to formation of de novo aneurysms and time to recurrence after clipping.
METHODS
A search of the literature up to June 15, 2016, on PubMed and a systematic review were performed. The association of age, aneurysm rupture status, aneurysm multiplicity, and anatomical location with time to recurrence or formation of de novo aneurysm was estimated using multivariable Cox proportional-hazards models. Kaplan-Meier estimates (event-free survival curves) are shown. Pooled annualized incidence rates of recurrent and de novo aneurysms were estimated using Poisson regression. Proportions of aneurysms and average follow-up times are displayed as bubble plots with LOESS smoothers weighted for study size.
RESULTS
Of the 7606 articles screened, 92 were included in the study. Case reports on 101 patients with recurrent aneurysms and 132 patients with de novo aneurysms were analyzed. Long-term follow-up studies on de novo aneurysm formation included 13,723 patients with 101,378 patient-years of follow-up; studies on aneurysm recurrence included 5922 patients with 31,055 patient-years of follow-up. Mean time to recurrence was 12.9 ± 6.6 years (mean ± standard deviation), and mean time to de novo formation was 9.3 ± 6.1 years. No association with sex, aneurysm location, and initial rupture could be shown. De novo aneurysms occurred later in patients with multiplicity of aneurysms at diagnosis (HR 0.63, p = 0.03) and in patients with increasing age (HR per 10 yrs 0.88, p = 0.06). Pooled annualized incidence rates were 0.35% for de novo aneurysms and 0.13% for recurrent aneurysms.
CONCLUSIONS
Despite low reported annual incidence rates, the cumulative risk of 9.6%-22% for aneurysm recurrence or de novo formation 20 years after clip ligation warrants lifelong follow-up. Screening at 5, 10, and 20 years would detect 30.8% (95% CI 23.3%-37.6%), 64.2% (95% CI 55.9%-70.9%), and 95.9% (95% CI 90.9%-97.9%) of de novo aneurysms. Screening for recurrent aneurysms at 10, 15, and 20 years would detect 36.6% (95% CI 26.5%-45.4%), 65.3% (95% CI 54.7%-73.5%), and 95.1% (95% CI 85.8%-96.6%) of lesions.
Topics: Humans; Incidence; Intracranial Aneurysm; Kaplan-Meier Estimate; Ligation; Postoperative Complications; Proportional Hazards Models; Recurrence
PubMed: 30797217
DOI: 10.3171/2018.10.JNS181281 -
Incidence and Management of De Novo Lower Urinary Tract Symptoms After Pelvic Organ Prolapse Repair.Current Urology Reports Sep 2017Pelvic organ prolapse (POP) is a significant problem with many options for surgical correction. Following prolapse surgery, de novo lower urinary tract symptoms (LUTS)... (Review)
Review
PURPOSE OF REVIEW
Pelvic organ prolapse (POP) is a significant problem with many options for surgical correction. Following prolapse surgery, de novo lower urinary tract symptoms (LUTS) are not uncommon. We review the current literature on de novo lower urinary tract symptoms following POP repair and discuss the role of urodynamics in the evaluation of the prolapse patient.
RECENT FINDINGS
Patients with occult stress urinary incontinence (SUI) appear to be at higher risk of developing de novo SUI after POP repair. Prolapse reduction in patients undergoing urodynamic evaluation is important. Different types of POP repair influence rates of de novo SUI. Also, prophylactic anti-incontinence procedures at time of POP repair appear to lower the incidence of de novo SUI, but at the cost of increased risk of complications and morbidity. Pre-existing overactive bladder (OAB) symptoms may either improve or persist, and de novo OAB can develop. The specific role of urodynamic study testing for POP is still being determined. Increasingly, women are seeking surgical treatment for POP. Aside from complications related to surgery in general, proper patient counseling is important regarding the risk of development of de novo voiding problems following surgery. Despite a growing body of literature looking at de novo voiding symptoms after prolapse repair, more studies are still needed.
Topics: Aged; Female; Humans; Incidence; Lower Urinary Tract Symptoms; Middle Aged; Pelvic Organ Prolapse; Postoperative Complications; Risk Factors; Urinary Bladder, Overactive; Urinary Incontinence, Stress; Urodynamics; Urologic Surgical Procedures
PubMed: 28900856
DOI: 10.1007/s11934-017-0732-5 -
Breast Cancer Research and Treatment Nov 2022This study evaluated whether patients with de novo metastatic breast cancer (MBC) have superior outcomes compared to those with recurrent MBC in a contemporary treatment...
PURPOSE
This study evaluated whether patients with de novo metastatic breast cancer (MBC) have superior outcomes compared to those with recurrent MBC in a contemporary treatment era and examined factors related to outcome differentials.
METHODS
Using an institutional database, we examined patient and tumor characteristics, treatment response, and outcome among 232 patients with de novo and 612 patients with recurrent MBC diagnosed between 2011 and 2017.
RESULTS
De novo MBC had 9-month (m) longer overall survival (OS) than recurrent MBC (36.4 vs 27.4 m, p < 0.001). Contributions to this difference included nearly twofold more HER2-positive (29.3% vs 15.2%) and significantly fewer triple-negative breast cancers (20.3% vs 32.4%, both p < 0.001) in de novo compared with recurrent MBC cohorts. Stratified by clinical subtype, progression-free survival (PFS) on first-line therapy was significantly longer in de novo MBC in all but the triple-negative subtype, 25.5 vs 11.6 m (p < 0.001) among 390 patients with hormone receptor-positive, HER2-negative, 11.4 vs 5.4 m (p = 0.002) among 142 patients with HER2-positive, and 4.0 vs 3.0 m (p = 0.121) among 162 with triple-negative MBC. In multivariable analysis, de novo status remained independently associated with improved OS (hazard ratio 0.63, 95% CI 0.49-0.80), regardless of subtype and other features.
CONCLUSION
Patients with de novo MBC have better outcomes than those with recurrent MBC. Differences in clinical subtype and response to therapy in the metastatic setting contribute to, but do not fully explain, this difference. Longer PFS to first-line therapy in de novo MBC suggests biologic differences compared to recurrent MBC, which may be intrinsic or due to acquired resistance from treatment for prior localized breast cancer in recurrent disease.
Topics: Biological Products; Breast Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Prognosis; Receptor, ErbB-2
PubMed: 36008651
DOI: 10.1007/s10549-022-06700-6