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Nature Communications Dec 2023De novo peptide sequencing, which does not rely on a comprehensive target sequence database, provides us with a way to identify novel peptides from tandem mass spectra....
De novo peptide sequencing, which does not rely on a comprehensive target sequence database, provides us with a way to identify novel peptides from tandem mass spectra. However, current de novo sequencing algorithms suffer from low accuracy and coverage, which hinders their application in proteomics. In this paper, we present PepNet, a fully convolutional neural network for high accuracy de novo peptide sequencing. PepNet takes an MS/MS spectrum (represented as a high-dimensional vector) as input, and outputs the optimal peptide sequence along with its confidence score. The PepNet model is trained using a total of 3 million high-energy collisional dissociation MS/MS spectra from multiple human peptide spectral libraries. Evaluation results show that PepNet significantly outperforms current best-performing de novo sequencing algorithms (e.g. PointNovo and DeepNovo) in both peptide-level accuracy and positional-level accuracy. PepNet can sequence a large fraction of spectra that were not identified by database search engines, and thus could be used as a complementary tool to database search engines for peptide identification in proteomics. In addition, PepNet runs around 3x and 7x faster than PointNovo and DeepNovo on GPUs, respectively, thus being more suitable for the analysis of large-scale proteomics data.
Topics: Humans; Tandem Mass Spectrometry; Sequence Analysis, Protein; Peptides; Amino Acid Sequence; Neural Networks, Computer; Algorithms; Peptide Library
PubMed: 38042873
DOI: 10.1038/s41467-023-43010-x -
BioRxiv : the Preprint Server For... Dec 2023The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules...
The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low μM, in a predictable manner. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free-energy calculations performed directly on the designed models are in excellent agreement with the experimentally measured affinities, suggesting that the de novo design of small-molecule-binding proteins with tuned interaction energies is now feasible entirely from computation. We expect these methods to open many opportunities in biomedicine, including rapid sensor development, antidote design, and drug delivery vehicles.
PubMed: 38187746
DOI: 10.1101/2023.12.23.573178 -
European Journal of Heart Failure Feb 2024Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in... (Observational Study)
Observational Study
AIMS
Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS.
METHODS AND RESULTS
In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005).
CONCLUSION
In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this.
Topics: Humans; Heart Failure; Hospital Mortality; Prognosis; Shock, Cardiogenic
PubMed: 37940139
DOI: 10.1002/ejhf.3082 -
Current Opinion in Structural Biology Jun 2024Engineering new molecules with desirable functions and properties has the potential to extend our ability to engineer proteins beyond what nature has so far evolved.... (Review)
Review
Engineering new molecules with desirable functions and properties has the potential to extend our ability to engineer proteins beyond what nature has so far evolved. Advances in the so-called 'de novo' design problem have recently been brought forward by developments in artificial intelligence. Generative architectures, such as language models and diffusion processes, seem adept at generating novel, yet realistic proteins that display desirable properties and perform specified functions. State-of-the-art design protocols now achieve experimental success rates nearing 20%, thus widening the access to de novo designed proteins. Despite extensive progress, there are clear field-wide challenges, for example, in determining the best in silico metrics to prioritise designs for experimental testing, and in designing proteins that can undergo large conformational changes or be regulated by post-translational modifications. With an increase in the number of models being developed, this review provides a framework to understand how these tools fit into the overall process of de novo protein design. Throughout, we highlight the power of incorporating biochemical knowledge to improve performance and interpretability.
Topics: Artificial Intelligence; Proteins; Protein Engineering; Models, Molecular; Protein Conformation
PubMed: 38663170
DOI: 10.1016/j.sbi.2024.102794 -
Molecular Cancer Research : MCR Jan 2024Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is...
UNLABELLED
Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis.
IMPLICATIONS
SCLC tumors preferentially utilize either the de novo or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Purines; Purine Nucleotides; Hypoxanthine Phosphoribosyltransferase; Lung Neoplasms
PubMed: 37773022
DOI: 10.1158/1541-7786.MCR-23-0386 -
International Journal of Biological... Apr 2024Silk, especially spider and insect silk, is a highly versatile biomaterial with potential applications in biomedicine, materials science, and biomimetic engineering. The... (Review)
Review
Silk, especially spider and insect silk, is a highly versatile biomaterial with potential applications in biomedicine, materials science, and biomimetic engineering. The primary structure of silk proteins is the basis for the mechanical properties of silk fibers. Biotechnologies such as single-molecule sequencing have facilitated an increasing number of reports on new silk genes and assembled silk proteins. Therefore, this review aims to provide a comprehensive overview of the recent advances in representative spider and insect silk proteins, focusing on identification methods, sequence characteristics, and de novo design and assembly. The review discusses three identification methods for silk genes: polymerase chain reaction (PCR)-based sequencing, PCR-free cloning and sequencing, and whole-genome sequencing. Moreover, it reveals the main spider and insect silk proteins and their sequences. Subsequent de novo assembly of artificial silk is covered and future research directions in the field of silk proteins, including new silk genes, customizable artificial silk, and the expansion of silk production and applications are discussed. This review provides a basis for the genetic aspects of silk production and the potential applications of artificial silk in material science and biomedical engineering.
Topics: Animals; Silk; Spiders; Biotechnology; Insect Proteins; Biomedical Engineering; Recombinant Proteins
PubMed: 38417762
DOI: 10.1016/j.ijbiomac.2024.130444 -
Inflammatory Bowel Diseases Oct 2023Children who undergo ileal pouch anal anastomosis (IPAA) surgery for refractory ulcerative colitis (UC) may ultimately develop a Crohn's disease (CD) phenotype. This de...
Children who undergo ileal pouch anal anastomosis (IPAA) surgery for refractory ulcerative colitis (UC) may ultimately develop a Crohn's disease (CD) phenotype. This de novo CD is open to broad interpretation and misattribution, and its manifestation in children is poorly understood. The surgically altered environment of the ileal pouch is at risk of a spectrum of ileal pouch disorders, which have limited description in children. In this issue of Inflammatory Bowel Diseases, a multicenter, retrospective study of children with UC who underwent IPAA and developed de novo CD highlights the challenges and opportunities of ileal pouch characterization in children.
PubMed: 37815461
DOI: 10.1093/ibd/izad231 -
Heliyon May 2024Colpocleisis is one of traditional surgical procedures for elderly and frail women with advanced pelvic organ prolapse. The occurrence of de novo urinary incontinence...
BACKGROUND
Colpocleisis is one of traditional surgical procedures for elderly and frail women with advanced pelvic organ prolapse. The occurrence of de novo urinary incontinence following colpocleisis was considered to impair the postoperative quality of life. The incidence of de novo urinary incontinence after colpocleisis has been reported to be ranging from 6.6 % to 27 %. There was an absence of prospective large-sample study to investigate the accurate incidence of de novo urinary incontinence following colpocleisis and the impact on the quality of life till now.
PURPOSE
s The primary objective was to report the incidence of de novo urinary incontinence after colpocleisis. The second objectives were to evaluate the long-term quality of life in patients with de novo urinary incontinence, and to conduct detailed pre- and post-operative evaluations of lower urinary tract symptoms.
METHODS
This prospective study included 253 patients with symptomatic pelvic organ prolapse who underwent colpocleisis between 2009 and 2021. De novo urinary incontinence was defined as the occurrence of urinary incontinence 3 months postoperatively. All patients were required to complete the Urinary Distress Inventory questionnaire and the Urinary Impact Questionnaire for the evaluation of patients' quality of life, and the Patient Global Impression of Improvement questionnaire for the evaluation of patients' satisfaction.
RESULTS
245 patients (245/253, 96·8 %) completed the 3-month follow-up, and were included in the final analysis. The incidence of de novo urinary incontinence was 5.4 % (10/185). There was no significant difference in the Urinary Distress Inventory -6 scores (22.50 vs. 10.30, = 0.276) or the subjective satisfaction rate (100 % vs. 98.9 %, = 0.250) between the patients with or without de novo urinary incontinence at the long-term follow-up. The incidence of voiding difficulty was significantly reduced after colpocleisis (27.8 % vs. 0.0 %, < 0.001). The patients' quality of life indicated by Urinary Distress Inventory-6 and Urinary Impact Questionnaire-7 scores were significantly improved postoperatively (26.27 vs. 13.39, and 19.13 vs. 6.05, < 0.05).
CONCLUSION
The incidence of de novo urinary incontinence after colpocleisis was very low. Patients' quality of life, and low urinary tract symptoms were significantly improved after colpocleisis.
PubMed: 38813205
DOI: 10.1016/j.heliyon.2024.e30805 -
Archives of Biochemistry and Biophysics Feb 2024In the early 2000s, the concept of "unstructured biology" has emerged to be an important field in protein science by generating various new research directions. Many... (Review)
Review
In the early 2000s, the concept of "unstructured biology" has emerged to be an important field in protein science by generating various new research directions. Many novel strategies and methods have been developed that are focused on effectively identifying/predicting intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs), identifying their potential functions, disorder based drug design etc. Due to the range of functions of IDPs/IDPRs and their involvement in various debilitating diseases they are of contemporary interest to the scientific community. Recent researches are focused on designing/redesigning specific IDPs/IDPRs de novo. These de novo design/redesigns of IDPs/IDPRs are carried out by altering compositional biases and specific sequence patterning parameters. The main focus of these researches is to influence specific molecular functions, phase behavior, cellular phenotypes etc. In this review, we first provide the differences of natively folded and natively unfolded or IDPs with respect to their potential energy landscapes. Here, we provide current understandings on the different computational design strategies and methods that have been utilized in de novo design and redesigns of IDPs and IDPRs. Finally, we conclude the review by discussing the challenges that have been faced during the computational design/design attempts of IDPs/IDPRs.
Topics: Intrinsically Disordered Proteins; Protein Conformation; Models, Molecular; Drug Design
PubMed: 38097100
DOI: 10.1016/j.abb.2023.109857 -
Transplant International : Official... 2023Although the association between post-transplant malignancy (PTM) and immunosuppressive therapy after organ transplantation has been studied, an integrated review of PTM...
Although the association between post-transplant malignancy (PTM) and immunosuppressive therapy after organ transplantation has been studied, an integrated review of PTM after lung transplantation is lacking. We investigated the incidence and types of PTM and its impact on survival following double lung transplantation (DLT). The incidence and type of PTM as well as the annual and cumulative risks of each malignancy after DLT were analyzed. The overall survival (OS) of recipients with or without PTM was compared by the Kaplan-Meier survival method and landmark analysis. There were 5,629 cases (23.52%) with 27 types of PTMs and incidences and OS varied according to the types of PTMs. The recipients with PTM showed a significantly longer OS than those without PTM ( < 0.001). However, while the recipients with PTM showed significantly better OS at 3, and 5 years ( < 0.001, = 0.007), it was worse at the 10-year landmark time ( = 0.013). And the single PTM group showed a worse OS rate than the multiple PTM group ( < 0.001). This comprehensive report on PTM following DLT can help understand the risks and timing of PTM to improve the implementation of screening and treatment.
Topics: Lung Transplantation; Incidence; Risk; Immunosuppression Therapy; Neoplasms; Humans; Male; Adult; Middle Aged
PubMed: 37663524
DOI: 10.3389/ti.2023.11552