Replication Errors Research Articles

DNA damage signalling histone H2AX is required for tumour growth

Cancer most frequently develops in self-renewal tissues that are the target of genetic alterations due to mutagens or intrinsic DNA replication errors. Histone γH2AX has a critical role in the cellular DNA repair pathway cascade and contributes to genomic stability. However, the role of γH2AX in the ontology of cancer is unclear. We have investigated this issue in the epidermis, a self-renewal epithelium continuously exposed to genetic hazard and replication stress. Silencing H2AX caused cell cycle hyperactivation, impaired DNA repair and epidermal hyperplasia in the skin. However, mutagen-induced carcinogenesis was strikingly reduced in the absence of H2AX. KO tumours appeared significantly later than controls and were fewer, smaller and more benign. The stem cell marker Δp63 drastically diminished in the KO epidermis. We conclude that H2AX is required for tissue-making during both homoeostasis and tumourigenesis, possibly by contributing to the control and repair of stem cells. Therefore, although H2AX is thought to act as a tumour suppressor and our results show that it contributes to homeostasis, they also indicate that it is required for the development of cancer.

An immunogenetic basis for lung cancer risk.

Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.

Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors

Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.

Cold atmospheric plasma stabilizes mismatch repair for effective, uniform treatment of diverse colorectal cancer cell types

Mismatch Repair (MMR) mechanisms play a pivotal role in rectifying DNA replication errors and maintaining the stability of DNA microsatellite structure. Colorectal cancer (CRC) can be characterized into microsatellite stability (MSS) and microsatellite instability (MSI) subtypes based on the functionality of MMR. MSI CRC notably exhibits enhanced chemotherapy resistance, attributable to diminished MMR-related protein expression. Cold atmospheric plasma (CAP) has emerged as a promising treatment modality, demonstrating efficacy in inducing apoptosis in various cancer cells. However, the therapeutic impact of CAP on MSI colorectal cancer, and the underlying mechanisms remain elusive. In this study, we investigated the effects of CAP on MSI (MC38, HCT116, and LOVO) and MSS (CT26 and HT29) CRC cell lines. We are probing into the products of CAP treatment. Our findings indicate that CAP treatment induces comparable effects on apoptosis, reactive oxygen species (ROS), and reactive nitrogen species (RNS), as well as the expression of apoptosis-related proteins in both MSI and MSS cells. Mechanistically, CAP treatment led to an elevation in the expression of mismatch repair proteins (MLH1 and MSH2), particularly in MSI cells, which notably have been proven to facilitate the activation of apoptosis-related proteins. Collectively, our study reveals that CAP enhances apoptotic signaling and induces apoptosis in MSI colorectal cancer cells by upregulating the expression of MMR-related proteins, thereby reinforcing MMR stabilization.

NMR measurements of transient low-populated tautomeric and anionic Watson-Crick-like G·T/U in RNA:DNA hybrids: implications for the fidelity of transcription and CRISPR/Cas9 gene editing.

Many biochemical processes use the Watson-Crick geometry to distinguish correct from incorrect base pairing. However, on rare occasions, mismatches such as G·T/U can transiently adopt Watson-Crick-like conformations through tautomerization or ionization of the bases, giving rise to replicative and translational errors. The propensities to form Watson-Crick-like mismatches in RNA:DNA hybrids remain unknown, making it unclear whether they can also contribute to errors during processes such as transcription and CRISPR/Cas editing. Here, using NMR R1ρ experiments, we show that dG·rU and dT·rG mismatches in two RNA:DNA hybrids transiently form tautomeric (Genol·T/U $ \mathbin{\lower.3ex\hbox{$\buildrel\textstyle\rightarrow\over {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}}$}}$ G·Tenol/Uenol) and anionic (G·T-/U-) Watson-Crick-like conformations. The tautomerization dynamics were like those measured in A-RNA and B-DNA duplexes. However, anionic dG·rU- formed with a ten-fold higher propensity relative to dT-·rG and dG·dT- and this could be attributed to the lower pKa (ΔpKa ∼0.4-0.9) of U versus T. Our findings suggest plausible roles for Watson-Crick-like G·T/U mismatches in transcriptional errors and CRISPR/Cas9 off-target gene editing, uncover a crucial difference between the chemical dynamics of G·U versus G·T, and indicate that anionic Watson-Crick-like G·U- could play a significant role evading Watson-Crick fidelity checkpoints in RNA:DNA hybrids and RNA duplexes.

Mutational signature dynamics indicate SARS-CoV-2's evolutionary capacity is driven by host antiviral molecules.

The COVID-19 pandemic has been characterised by sequential variant-specific waves shaped by viral, individual human and population factors. SARS-CoV-2 variants are defined by their unique combinations of mutations and there has been a clear adaptation to more efficient human infection since the emergence of this new human coronavirus in late 2019. Here, we use machine learning models to identify shared signatures, i.e., common underlying mutational processes and link these to the subset of mutations that define the variants of concern (VOCs). First, we examined the global SARS-CoV-2 genomes and associated metadata to determine how viral properties and public health measures have influenced the magnitude of waves, as measured by the number of infection cases, in different geographic locations using regression models. This analysis showed that, as expected, both public health measures and virus properties were associated with the waves of regional SARS-CoV-2 reported infection numbers and this impact varies geographically. We attribute this to intrinsic differences such as vaccine coverage, testing and sequencing capacity and the effectiveness of government stringency. To assess underlying evolutionary change, we used non-negative matrix factorisation and observed three distinct mutational signatures, unique in their substitution patterns and exposures from the SARS-CoV-2 genomes. Signatures 1, 2 and 3 were biased to C→T, T→C/A→G and G→T point mutations. We hypothesise assignments of these mutational signatures to the host antiviral molecules APOBEC, ADAR and ROS respectively. We observe a shift amidst the pandemic in relative mutational signature activity from predominantly Signature 1 changes to an increasingly high proportion of changes consistent with Signature 2. This could represent changes in how the virus and the host immune response interact and indicates how SARS-CoV-2 may continue to generate variation in the future. Linkage of the detected mutational signatures to the VOC-defining amino acids substitutions indicates the majority of SARS-CoV-2's evolutionary capacity is likely to be associated with the action of host antiviral molecules rather than virus replication errors.

Antagonistic interactions safeguard mitotic propagation of genetic and epigenetic information in zebrafish

The stability of cellular phenotypes in developing organisms depends on error-free transmission of epigenetic and genetic information during mitosis. Methylation of cytosine residues in genomic DNA is a key epigenetic mark that modulates gene expression and prevents genome instability. Here, we report on a genetic test of the relationship between DNA replication and methylation in the context of the developing vertebrate organism instead of cell lines. Our analysis is based on the identification of hypomorphic alleles of dnmt1, encoding the DNA maintenance methylase Dnmt1, and pole1, encoding the catalytic subunit of leading-strand DNA polymerase epsilon holoenzyme (Pole). Homozygous dnmt1 mutants exhibit genome-wide DNA hypomethylation, whereas the pole1 mutation is associated with increased DNA methylation levels. In dnmt1/pole1 double-mutant zebrafish larvae, DNA methylation levels are restored to near normal values, associated with partial rescue of mutant-associated transcriptional changes and phenotypes. Hence, a balancing antagonism between DNA replication and maintenance methylation buffers against replicative errors contributing to the robustness of vertebrate development.

Template switching between the leading and lagging strands at replication forks generates inverted copy number variants through hairpin-capped extrachromosomal DNA.

Inherited and germ-line de novo copy number variants (CNVs) are increasingly found to be correlated with human developmental and cancerous phenotypes. Several models for template switching during replication have been proposed to explain the generation of these gross chromosomal rearrangements. We proposed a model of template switching (ODIRA-origin dependent inverted repeat amplification) in which simultaneous ligation of the leading and lagging strands at diverging replication forks could generate segmental inverted triplications through an extrachromosomal inverted circular intermediate. Here, we created a genetic assay using split-ura3 cassettes to trap the proposed inverted intermediate. However, instead of recovering circular inverted intermediates, we found inverted linear chromosomal fragments ending in native telomeres-suggesting that a template switch had occurred at the centromere-proximal fork of a replication bubble. As telomeric inverted hairpin fragments can also be created through double strand breaks we tested whether replication errors or repair of double stranded DNA breaks were the most likely initiating event. The results from CRISPR/Cas9 cleavage experiments and growth in the replication inhibitor hydroxyurea indicate that it is a replication error, not a double stranded break that creates the inverted junctions. Since inverted amplicons of the SUL1 gene occur during long-term growth in sulfate-limited chemostats, we sequenced evolved populations to look for evidence of linear intermediates formed by an error in replication. All of the data are compatible with a two-step version of the ODIRA model in which sequential template switching at short inverted repeats between the leading and lagging strands at a replication fork, followed by integration via homologous recombination, generates inverted interstitial triplications.

Delineation Errors Caused by Replication and Expansion Operations in Monaco.

This study aims to investigate the errors in structure volume and shape caused by the replication, expansion, and merging operations of the Monaco system and analyze their influence on dosimetry evaluation. A retrospective collection of 30 patients undergoing radiotherapy was utilized. Cylinders with radii of 5, 10, and 30 mm were delineated in computerized tomography (CT) images from 10 patients with thoracic and abdominal issues, and the Margins function in Monaco was used to expand the margins by 0, 3, 5, and 10 mm in 2D mode. In 10 patients with vertebral metastases, the Margins function was utilized to replicate and merge targets, and the Copy Structure function was employed to replicate targets. Cross-CT replication was performed for the targets of 10 patients with nasopharyngeal carcinoma. The deviation between the processed structure volume and the ideal value was compared. The difference in the maximum dose (Dmax) before and after lens replication was evaluated in 10 patients undergoing whole-brain radiotherapy. Monaco's Margins function increased the volume of the processed structure during the copying procedure. The margin error was equivalent to expanding the structure by 0.3-0.4 mm, and a margin error of 0.3-0.4 mm was produced in each expansion instance. The volume deviation for a cylinder with a radius of 5 mm was 12.99%. The Merge function of Margins copied substructures and merged them. The Copy Structure function did not alter the structure during copying, but the volume was reduced by less than 1% after copying across CT. Dmax after lens replication was higher than that before replication, with a median difference of 31.3 cGy for the left lenses. Monaco's Margins function introduces errors in organ replication, expansion, and merging, resulting in incorrect dose assessment. Physicians should be mindful of the potential effects when utilizing them.

An aviation accident report data-driven approach to scenario design for a centrifuge-based dynamic flight simulator

The use of flight simulators in investigating an aviation incident or accident related to human errors has been identified as an important part of a strategy to improve safety. This study aimed to replicate a real flight of the MiG-29 aircraft using a centrifuge-based dynamic flight simulator and to determine the simulator’s accuracy in recreating in-flight aircraft performance. A 60-second recording of the real flight of the MiG-29 aircraft, captured by the flight data recorder, was chosen for replication in the HTC-07 human training centrifuge simulator. To evaluate how accurately the simulator replicates the performance of the aircraft, the linear accelerations and angular velocities acting on a pilot during the real flight were compared with those during the replication of that flight in the simulator. The fit of these parameters was assessed using the root mean square percentage error (RMSPE) and the correlation coefficient (r). The highest replication accuracy was achieved for the vertical component of the linear acceleration (RMSPE=2068; r=0.98), while the worst result was obtained for the longitudinal component (RMSPE=14205; r=0.31). Inaccuracies were much more pronounced for the angular velocity. The roll angular velocity had the lowest replication error (RMSPE=12640). However, its correlation with the recorded velocity during the real flight was very weak (r=-0.02). Despite some inaccuracies in replicating other components of the acceleration and angular velocity vectors, the HTC-07 simulator seems valuable for investigating aviation incidents or accidents related to human factors.

A retrospective analysis of spontaneous chromosomal aberrations in human lymphocyte cultures of individuals from Bosnia and Herzegovina

Spontaneous chromosomal aberrations are structural or numerical changes of chromosomes that occur naturally, without exposure to external genotoxic factors. They are not inherited, occur randomly in the karyotype, and do not have direct clinical significance. However, they can affect genomic instability and disease predisposition. They can result from DNA replication or repair processes errors, and typically are observed in cells that are actively dividing. Spontaneous chromosomal aberrations may arise due to the natural chromosomal instability and can be elevated in individuals exposed to mutagens. We analyzed frequencies of spontaneous chromosomal aberrations in 137 individuals subjected to karyotype analysis at the Laboratory for Cytogenetics and Genotoxicology, University of Sarajevo – Institute for Genetic Engineering and Biotechnology, during 2008-2023. Whole blood samples were cultivated for 72 hours with the thymidine added in the 48th hour. Metaphases were arrested by colcemid 60 minutes before harvesting. GTG banding was performed and slides were analyzed under 1000x magnification in accordance with An International System for Human Cytogenetic Nomenclature and E.C.A. Cytogenetic Guidelines and Quality Assurance. Constitutionally aberrant karyotypes were found in 2.92% of analysed individuals as well as altered karyotypes considered as normal chromosomal variants. In the total of 3092 analyzed metaphases, 20 spontaneous chromosomal aberrations were found in 13 individuals. This study contributes to the limited knowledge of the cytogenetic status of the Bosnian and Herzegovinian population. Further monitoring of spontaneous chromosomal aberrations incidences is recommended.

Match-play, training workloads and sensorimotor and neuromuscular performance of elite young soccer players

Purpose: The purpose of this study was to assess sensorimotor and neuromuscular performance capabilities over an in-season microcycle in early-career professional soccer players and to examine the relationship with training and match-play workload. Methods: Sensorimotor and neuromuscular performance capabilities (isometric knee extensor: force replication error, peak force, electromechanical delay, rate of force development) of 12 professional soccer players were assessed over a 7-day period. Training and match-play workload was also recorded over the same period for each player (high-intensity running distance). Fluctuations in sensorimotor and neuromuscular performance and workload variables were analysed. Results: There was evidence of fluctuations in sensorimotor and neuromuscular performance capability over the microcycle that reached statistical (p < .005) and practical (18.1% [baseline-to-peak]) significance alongside heterogeneity in training and match workload (264% [coefficient of variation], p < .0005). Some temporal congruence among fluctuating patterns of intra-microcycle training and match-play load and concomitant electromechanical delay performance was noted (p < .005). Asynchronous responses were observed for peak force, but rate of force development and force replication error capabilities were unchanged during the microcycle. Conclusion: While some neuromuscular performance capabilities fluctuate over an in-season microcycle and are influenced partially by high-intensity running workload, sensorimotor performance capabilities were unchanged during the microcycle.

The impact of global warming on the signature virulence gene, thermolabile hemolysin, of Vibrio parahaemolyticus.

Global warming is increasing human exposure to pathogens and has already had an impact on human health. Vibrio parahaemolyticus, a major pathogen causing foodborne illness, accumulates in numerous aquatic organisms and can be affected by environmental stressors such as increased replication errors or DNA damage resulting in point mutations. This could lead to an elevation in the mutation rate, which influences the expansion of Vibrio spp. habitats and the spread of associated diseases. In this study, a total of 241 strains were isolated from aquatic products imported or exported through China Customs between 2005 and 2010. The whole genomes of those strains were sequenced, revealing a highly significant level of genetic diversity. Our analysis identified 27 new sequence types (STs) ranging from ST2950 to ST2976. The global temperature trend since 1950 affects the thermolabile hemolysin gene (tlh) found in all Vibrio parahaemolyticus leading to mutant sites exhibiting similar trends as temperatures rise; seven high-frequency mutation hotspots (A180G, T552G, G657T, T858C, C1062T, A1137G, and T1179C) were identified along with two clinically specific sites (T259C and A951T) that may indicate adaptation over time due to climate change, leading to increased virulence potential for this bacterial species. These results provide insight into the genetics of Vibrio parahaemolyticus and provide a reference for subsequent research, identification, and monitoring efforts related to its spread. IMPORTANCE In this study, Vibrio parahaemolyticus strains were collected from a large number of aquatic products globally and found that temperature has an impact on the virulence of these bacteria. As global temperatures rise, mutations in a gene marker called thermolabile hemolysin (tlh) also increase. This suggests that environmental isolates adapt to the warming environment and become more pathogenic. The findings can help in developing tools to analyze and monitor these bacteria as well as assess any link between climate change and vibrio-associated diseases, which could be used for forecasting outbreaks associated with them.

Signification and Application of Mutator and Antimutator Phenotype-Induced Genetic Variations in Evolutionary Adaptation and Cancer Therapeutics.

Mutations present a dichotomy in their implications for cellular processes. They primarily arise from DNA replication errors or damage repair processes induced by environmental challenges. Cumulative mutations underlie genetic variations and drive evolution, yet also contribute to degenerative diseases such as cancer and aging. The mutator phenotype elucidates the heightened mutation rates observed in malignant tumors. Evolutionary adaptation, analogous to bacterial and eukaryotic systems, manifests through mutator phenotypes during changing environmental conditions, highlighting the delicate balance between advantageous mutations and their potentially detrimental consequences. Leveraging the genetic tractability of Saccharomyces cerevisiae offers unique insights into mutator phenotypes and genome instability akin to human cancers. Innovative reporter assays in yeast model organisms enable the detection of diverse genome alterations, aiding a comprehensive analysis of mutator phenotypes. Despite significant advancements, our understanding of the intricate mechanisms governing spontaneous mutation rates and preserving genetic integrity remains incomplete. This review outlines various cellular pathways affecting mutation rates and explores the role of mutator genes and mutation-derived phenotypes, particularly prevalent in malignant tumor cells. An in-depth comprehension of mutator and antimutator activities in yeast and higher eukaryotes holds promise for effective cancer control strategies.

Aberrant Repair of 8-Oxoguanine in Short DNA Bulges.

The presence of DNA damage can increase the likelihood of DNA replication errors and promote mutations. In particular, pauses of DNA polymerase at the site of damage can lead to polymerase slippage and the formation of 1-2-nucleotide bulges. Repair of such structures using an undamaged DNA template leads to small deletions. One of the most abundant oxidative DNA lesions, 8-oxoguanine (oxoG), was shown to induce small deletions, but the mechanism of this phenomenon is currently unknown. We studied the aberrant repair of oxoG located in one- and two-nucleotide bulges by the Escherichia coli and human base excision repair systems. Our results indicate that the repair in such substrates can serve as a mechanism for fixing small deletions in bacteria but not in humans.

Diversity of short linear interaction motifs in SARS-CoV-2 nucleocapsid protein.

Short linear motifs (SLiMs) are 3-10 amino acid long binding motifs in intrinsically disordered protein regions (IDRs) that serve as ubiquitous protein-protein interaction modules in eukaryotic cells. Through molecular mimicry, viruses hijack these sequence motifs to control host cellular processes. It is thought that the small size of SLiMs and the high mutation frequencies of viral IDRs allow rapid host adaptation. However, a salient characteristic of RNA viruses, due to high replication errors, is their obligate existence as mutant swarms. Taking advantage of the uniquely large genomic database of SARS-CoV-2, here, we analyze the role of sequence diversity in the presentation of SLiMs, focusing on the highly abundant, multi-functional nucleocapsid protein. We find that motif mimicry is a highly dynamic process that produces an abundance of motifs transiently present in subsets of mutant species. This diversity allows the virus to efficiently explore eukaryotic motifs and evolve the host-virus interface.

Heteroplasmy and Individual Mitogene Pools: Characteristics and Potential Roles in Ecological Studies.

The mitochondrial genome (mitogenome or mtDNA), the extrachromosomal genome, is a multicopy circular DNA with high mutation rates due to replication and repair errors. A mitochondrion, cell, tissue, organ, or an individual body may hold multiple variants, both inherited and developed over a lifetime, which make up individual mitogene pools. This phenomenon is also called mtDNA heteroplasmy. MtDNA variants influence cellular and tissular functions and are consequently subjected to selection. Although it has long been recognized that only inheritable germline heteroplasmies have evolutionary significance, non-inheritable somatic heteroplasmies have been overlooked since they directly affect individual fitness and thus indirectly affect the fate of heritable germline variants. This review focuses on the characteristics, dynamics, and functions of mtDNA heteroplasmy and proposes the concept of individual mitogene pools to discuss individual genetic diversity from multiple angles. We provide a unique perspective on the relationship between individual genetic diversity and heritable genetic diversity and guide how the individual mitogene pool with novel genetic markers can be applied to ecological research.

Separating Measurement Error and Signal in Environmental Data: Use of Replicates to Address Uncertainty.

Measurement uncertainty has long been a concern in the characterizing and interpreting environmental and toxicological measurements. We compared statistical analysis approaches when there are replicates: a Naı̈ve approach that omits replicates, a Hybrid approach that inappropriately treats replicates as independent samples, and a Measurement Error Model (MEM) approach in a random effects analysis of variance (ANOVA) model that appropriately incorporates replicates. A simulation study assessed the effects of sample size and levels of replication, signal variance, and measurement error on estimates from the three statistical approaches. MEM results were superior overall with confidence intervals for the observed mean narrower on average than those from the Naı̈ve approach, giving improved characterization. The MEM approach also featured an unparalleled advantage in estimating signal and measurement error variance separately, directly addressing measurement uncertainty. These MEM estimates were approximately unbiased on average with more replication and larger sample sizes. Case studies illustrated analyzing normally distributed arsenic and log-normally distributed chromium concentrations in tap water and calculating MEM confidence intervals for the true, latent signal mean and latent signal geometric mean (i.e., with measurement error removed). MEM estimates are valuable for study planning; we used simulation to compare various sample sizes and levels of replication.

Exercise-induced fatigue affects knee proprioceptive acuity and quadriceps neuromuscular function more in patients with ACL reconstruction or meniscus surgery than in healthy individuals.

To observe how knee proprioceptive acuity and quadriceps neuromuscular function change during and after repeated isokinetic knee-extension exercise in patients with anterior cruciate ligament reconstruction (ACLR) or meniscus surgery. Patients with ACLR or meniscus surgery and matched controls (n = 19 in each group) performed knee-flexion replication at 15° and 75°, and quadriceps peak torque (PT), central activation ratio (CAR) and rate of torque development (RTD) at baseline and immediately after every five sets of isokinetic knee-extension exercise (times 1-5). Compared to the baseline, the ACLR and control groups displayed errors in knee-flexion replication at 75° only at time 5 (115.9-155.6%; p ≤ 0.04, d ≥ 0.97), whereas the meniscus surgery group exhibited errors at all time points (142.5-265.6%; p ≤ 0.0003, d ≥ 1.4). Significant percentage reductions in quadriceps CAR were observed between times 4 and 5 in the ACLR group (-5.8%; p = 0.0002, d = 0.96), but not in the meniscus surgery (-1.4%; n.s.) and control (0.1%; n.s.) groups. Significant percentage reductions in quadriceps RTD were observed between times 4 and 5 in the ACLR (-24.2%; p = 0.007, d = 0.99) and meniscus surgery (-23.0%; p = 0.01, d = 0.85) groups, but not in the control group (-0.2%; n.s.). Patients with ACLR or meniscus surgery displayed a greater loss in knee proprioceptive acuity and quadriceps neuromuscular function during and after exercise than healthy individuals. Evidence-based interventions to enhance exercise-induced fatigue resistance should be implemented following ACLR or meniscus surgery, aiming to prevent proprioceptive and neuromuscular changes within the knee joint and quadriceps. III.

A Semi-Static Replication Method for Bermudan Swaptions under an Affine Multi-Factor Model

We present a semi-static replication algorithm for Bermudan swaptions under an affine, multi-factor term structure model. In contrast to dynamic replication, which needs to be continuously updated as the market moves, a semi-static replication needs to be rebalanced on just a finite number of instances. We show that the exotic derivative can be decomposed into a portfolio of vanilla discount bond options, which mirrors its value as the market moves and can be priced in closed form. This paves the way toward the efficient numerical simulation of xVA, market, and credit risk metrics for which forward valuation is the key ingredient. The static portfolio composition is obtained by regressing the target option’s value using an interpretable, artificial neural network. Leveraging the universal approximation power of neural networks, we prove that the replication error can be arbitrarily small for a sufficiently large portfolio. A direct, a lower bound, and an upper bound estimator for the Bermudan swaption price are inferred from the replication algorithm. Additionally, closed-form error margins to the price statistics are determined. We practically study the accuracy and convergence of the method through several numerical experiments. The results indicate that the semi-static replication approaches the LSM benchmark with basis point accuracy and provides tight, efficient error bounds. For in-model simulations, the semi-static replication outperforms a traditional dynamic hedge.