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Nature Biotechnology Feb 2024Information in proteins flows from sequence to structure to function, with each step causally driven by the preceding one. Protein design is founded on inverting this... (Review)
Review
Information in proteins flows from sequence to structure to function, with each step causally driven by the preceding one. Protein design is founded on inverting this process: specify a desired function, design a structure executing this function, and find a sequence that folds into this structure. This 'central dogma' underlies nearly all de novo protein-design efforts. Our ability to accomplish these tasks depends on our understanding of protein folding and function and our ability to capture this understanding in computational methods. In recent years, deep learning-derived approaches for efficient and accurate structure modeling and enrichment of successful designs have enabled progression beyond the design of protein structures and towards the design of functional proteins. We examine these advances in the broader context of classical de novo protein design and consider implications for future challenges to come, including fundamental capabilities such as sequence and structure co-design and conformational control considering flexibility, and functional objectives such as antibody and enzyme design.
Topics: Protein Engineering; Proteins; Protein Folding
PubMed: 38361073
DOI: 10.1038/s41587-024-02133-2 -
Scientific Reports Apr 2024People correct for movement errors when acquiring new motor skills (de novo learning) or adapting well-known movements (motor adaptation). While de novo learning...
People correct for movement errors when acquiring new motor skills (de novo learning) or adapting well-known movements (motor adaptation). While de novo learning establishes new control policies, adaptation modifies existing ones, and previous work have distinguished behavioral and underlying brain mechanisms for each motor learning type. However, it is still unclear whether learning in each type interferes with the other. In study 1, we use a within-subjects design where participants train with both 30° visuomotor rotation and mirror reversal perturbations, to compare adaptation and de novo learning respectively. We find no perturbation order effects, and find no evidence for differences in learning rates and asymptotes for both perturbations. Explicit instructions also provide an advantage during early learning in both perturbations. However, mirror reversal learning shows larger inter-participant variability and slower movement initiation. Furthermore, we only observe reach aftereffects following rotation training. In study 2, we incorporate the mirror reversal in a browser-based task, to investigate under-studied de novo learning mechanisms like retention and generalization. Learning persists across three or more days, substantially transfers to the untrained hand, and to targets on both sides of the mirror axis. Our results extend insights for distinguishing motor skill acquisition from adapting well-known movements.
Topics: Humans; Psychomotor Performance; Generalization, Psychological; Motor Skills; Movement; Reversal Learning; Adaptation, Physiological
PubMed: 38632252
DOI: 10.1038/s41598-024-59445-1 -
BMC Genomics Sep 2023The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal...
The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history. Here we reported the application of long-read sequencing for direct haplotyping in a female patient with de novo PKD1 c.11,526 G > C mutation and successfully established the high-risk haplotype. Together with targeted short-read sequencing of SNPs for the couple and embryos, the carrier status for embryos was identified. A healthy baby was born without the PKD1 pathogenic mutation. Our PGT-M strategy based on long-read sequencing for direct haplotyping combined with targeted SNP haplotype can be widely applied to other monogenic disease carriers with de novo mutation.
Topics: Female; Humans; Infant; Genetic Testing; Haplotypes; Mutation; Polycystic Kidney, Autosomal Dominant; Polymorphism, Single Nucleotide; Preimplantation Diagnosis
PubMed: 37667185
DOI: 10.1186/s12864-023-09593-x -
Genome Research Sep 2023Assisted reproductive technologies (ARTs), including in vitro maturation and fertilization (IVF), are increasingly used in human and animal reproduction. Whether these...
Assisted reproductive technologies (ARTs), including in vitro maturation and fertilization (IVF), are increasingly used in human and animal reproduction. Whether these technologies directly affect the rate of de novo mutation (DNM), and to what extent, has been a matter of debate. Here we take advantage of domestic cattle, characterized by complex pedigrees that are ideally suited to detect DNMs and by the systematic use of ART, to study the rate of de novo structural variation (dnSV) in this species and how it is impacted by IVF. By exploiting features of associated de novo point mutations (dnPMs) and dnSVs in clustered DNMs, we provide strong evidence that (1) IVF increases the rate of dnSV approximately fivefold, and (2) the corresponding mutations occur during the very early stages of embryonic development (one- and two-cell stage), yet primarily affect the paternal genome.
Topics: Pregnancy; Female; Animals; Cattle; Humans; Mutation; Family; Pedigree; Embryonic Development; Genome, Human
PubMed: 37793781
DOI: 10.1101/gr.277884.123 -
MSphere Oct 2023The ability to use 16S rRNA gene sequence data to train machine learning classification models offers the opportunity to diagnose patients based on the composition of...
The ability to use 16S rRNA gene sequence data to train machine learning classification models offers the opportunity to diagnose patients based on the composition of their microbiome. In some applications, the taxonomic resolution that provides the best models may require the use of operational taxonomic units (OTUs) whose composition changes when new data are added. We previously developed a new reference-based approach, OptiFit, that fits new sequence data to existing OTUs without changing the composition of the original OTUs. While OptiFit produces OTUs that are as high quality as OTUs, it is unclear whether this method for fitting new sequence data into existing OTUs will impact the performance of classification models relative to models trained and tested only using OTUs. We used OptiFit to cluster sequences into existing OTUs and evaluated model performance in classifying a dataset containing samples from patients with and without colonic screen relevant neoplasia (SRN). We compared the performance of this model to standard methods including and database-reference-based clustering. We found that using OptiFit performed as well or better in classifying SRNs. OptiFit can streamline the process of classifying new samples by avoiding the need to retrain models using reclustered sequences. IMPORTANCE There is great potential for using microbiome data to aid in diagnosis. A challenge with operational taxonomic unit (OTU)-based classification models is that 16S rRNA gene sequences are often assigned to OTUs based on similarity to other sequences in the dataset. If data are generated from new patients, the old and new sequences must be reclustered to OTUs and the classification model retrained. Yet there is a desire to have a single, validated model that can be widely deployed. To overcome this obstacle, we applied the OptiFit clustering algorithm to fit new sequence data to existing OTUs allowing for reuse of the model. A random forest model implemented using OptiFit performed as well as the traditional reassign and retrain approach. This result shows that it is possible to train and apply machine learning models based on OTU relative abundance data that do not require retraining or the use of a reference database.
Topics: Humans; Sequence Analysis, DNA; RNA, Ribosomal, 16S; Metagenomics; Algorithms; Microbiota
PubMed: 37615431
DOI: 10.1128/msphere.00336-23 -
CNS Neuroscience & Therapeutics Mar 2024Can we better understand the unique mechanisms of de novo abilities in light of our current knowledge of the psychological and neuroscientific literature on creativity?... (Review)
Review
Can we better understand the unique mechanisms of de novo abilities in light of our current knowledge of the psychological and neuroscientific literature on creativity? This review outlines the state-of-the-art in the neuroscience of creativity and points out crucial aspects that still demand further exploration, such as brain plasticity. The progressive development of current neuroscience research on creativity presents a multitude of prospects and potentials for furnishing efficacious therapy in the context of health and illness. Therefore, we discuss directions for future studies, identifying a focus on pinpointing the neglected beneficial practices for creative therapy. We emphasize the neglected neuroscience perspective of creativity on health and disease and how creative therapy could offer limitless possibilities to improve our well-being and give hope to patients with neurodegenerative diseases to compensate for their brain injuries and cognitive impairments by expressing their hidden creativity.
Topics: Humans; Creativity; Neurosciences; Cognitive Dysfunction
PubMed: 37305955
DOI: 10.1111/cns.14266 -
Current Problems in Cardiology Sep 2023Contemporary literature reveals a range of cardiac complications in patients who receive the percutaneous coronary intervention (PCI) for chronic total occlusion (CTO).... (Meta-Analysis)
Meta-Analysis Review
Comparison of Percutaneous Coronary Intervention-Related Adverse Cardiac Outcomes in Patients With in-stent vs de novo Chronic Total Occlusion: A Systematic Review and Meta-Analysis.
Contemporary literature reveals a range of cardiac complications in patients who receive the percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). This study compared the adverse cardiac outcomes and procedural/technical success rates between the patients groups of in-stent (IS) CTO PCI and de novo CTO PCI. This systematic review and meta-analysis compared odds for primary (all-cause mortality, MACE, cardiac death post PCI, stroke) and secondary (bleeding requiring blood transfusion, ischemia-driven target-vessel revascularization, PCI procedural success, PCI technical success, and target-vessel MI) endpoints between 2734 patients who received PCI for IS CTO and 17,808 for de novo CTO. Odds ratios for outcome variables were calculated within 95% confidence intervals (CIs) via the Mantel-Haenszel method. The pooled analysis was undertaken for observational (retrospective/prospective) single- and multicentered studies published between January 2005 and December 2021. We found 57% higher, 166% higher, 129% higher, and 57% lower odds for MACE (OR: 1.57, 95% CI 1.31, 1.89, P < 0.001), ischemia-driven target-vessel revascularization (OR: 2.66, 95% CI 2.01, 3.53, P < 0.001), target-vessel myocardial infarction (MI) (OR: 2.29, 95% CI 1.70, 3.10, P < 0.001), and bleeding requiring blood transfusion (OR: 0.43, 95% CI 0.19, 1.00, P = 0.05), respectively, in patients with IS CTO PCI as compared to that of the de novo CTO PCI. No statistically significant differences between the study groups were recorded for the other primary/secondary outcome variables. The findings from this study indicated a high predisposition for MACE, ischemia-driven target-vessel revascularization, target vessel MI, and a lower incidence of bleeding episodes among IS CTO PCI patients as compared to those with de novo CTO PCI. The prognostic outcomes in CTO PCI cases require further investigation with randomized controlled trials.
Topics: Humans; Treatment Outcome; Coronary Occlusion; Percutaneous Coronary Intervention; Retrospective Studies; Prospective Studies; Risk Factors; Time Factors; Stents; Myocardial Infarction; Chronic Disease
PubMed: 37178988
DOI: 10.1016/j.cpcardiol.2023.101797 -
Cancer Jul 2024This study was conducted to better characterize the epidemiology, clinical outcomes, and current treatment patterns of de novo oligometastatic hormone-sensitive prostate...
BACKGROUND
This study was conducted to better characterize the epidemiology, clinical outcomes, and current treatment patterns of de novo oligometastatic hormone-sensitive prostate cancer (omHSPC) in the United States Veterans Affairs Health Care System.
METHODS
In this observational retrospective cohort study, 400 de novo metastatic hormone-sensitive PC (mHSPC) patients diagnosed from January 2015 to December 2020 (follow-up through December 2021) were randomly selected. omHSPC was defined as five or less total metastases (excluding liver) by conventional imaging. Kaplan-Meier methods estimated overall survival (OS) and castration-resistant prostate cancer (CRPC)-free survival from mHSPC diagnosis date and a log-rank test compared these outcomes by oligometastatic status.
RESULTS
Twenty percent (79 of 400) of de novo mHSPC patients were oligometastatic. Most baseline characteristics were similar by oligometastatic status; however, men with non-omHSPC had higher median prostate-specific antigen at diagnosis (151.7) than omHSPC (44.1). First-line (1L) novel hormonal therapy was similar between groups (20%); 1L chemotherapy was lower in omHSPC (5%) versus non-omHSPC (14%). More omHSPC patients received metastasis-directed therapy/prostate radiation therapy (14%) versus non-omHSPC (2%). Median OS and CRPC-free survival (in months) were higher in omHSPC versus non-omHSPC (44.4; 95% confidence interval [CI], 33.9-not estimated vs. 26.2; 95% CI, 20.5-32.5, p = .0089 and 27.6; 95% CI, 22.1-37.2 vs. 15.3; 95% CI, 12.8-17.9, p = .0049), respectively.
CONCLUSIONS
Approximately 20% of de novo mHSPC were oligometastatic, and OS was significantly longer in omHSPC versus non-omHSPC. Although potentially "curative" therapy use was higher in omHSPC versus non-omHSPC, the percentages were still relatively low. Future studies are warranted given potential for prolonged responses with multimodal therapy inclusive of systemic and local therapies.
PubMed: 38950063
DOI: 10.1002/cncr.35466 -
PloS One 2024Patterns of single nucleotide polymorphisms (SNPs) in eukaryotic DNA are traditionally attributed to selective pressure, drift, identity descent, or related...
Patterns of single nucleotide polymorphisms (SNPs) in eukaryotic DNA are traditionally attributed to selective pressure, drift, identity descent, or related factors-without accounting for ways in which bias during de novo SNP formation, itself, might contribute. A functional and phenotypic analysis based on evolutionary resilience of DNA points to decreased numbers of non-synonymous SNPs in human and other genomes, with a predominant component of SNP depletion in the human gene pool caused by robust preferences during de novo SNP formation (rather than selective constraint). Ramifications of these findings are broad, belie a number of concepts regarding human evolution, and point to a novel interpretation of evolving DNA across diverse species.
Topics: Polymorphism, Single Nucleotide; Humans; Evolution, Molecular; Genome, Human; Animals; Genome; Genomics
PubMed: 38753830
DOI: 10.1371/journal.pone.0303257 -
Frontiers in Genetics 2024Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong...
Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong clinical heterogeneity. Genetic factors play an important role in ASD, but about 75% of ASD cases have an undetermined genetic risk. We extensively investigated an ASD cohort made of 102 families from the Middle Eastern population of Qatar. First, we investigated the copy number variations (CNV) contribution using genome-wide SNP arrays. Next, we employed Next Generation Sequencing (NGS) to identify or inherited variants contributing to the ASD etiology and its associated comorbid conditions in families with complete trios (affected child and the parents). Our analysis revealed 16 CNV regions located in genomic regions implicated in ASD. The analysis of the 88 ASD cases identified 41 genes in 39 ASD subjects with de novo (n = 24) or inherited variants (n = 22). We identified three novel variants in new candidate genes for ASD (, , and ). Also, we have identified 15 variants in genes that were previously implicated in ASD or related neurodevelopmental disorders (, , , , , , , , , , , , , and ). Additionally, we defined eight novel recessive variants (, , , , , and ), four of which were X-linked. Despite the ASD multifactorial etiology that hinders ASD genetic risk discovery, the number of identified novel or known putative ASD genetic variants was appreciable. Nevertheless, this study represents the first comprehensive characterization of ASD genetic risk in Qatar's Middle Eastern population.
PubMed: 38572415
DOI: 10.3389/fgene.2024.1363849