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At least 1,297 records · Page 72

Techno‐Economic Analysis of Additively‐Manufactured Wind Turbine Blade Tips That Enable Technology Integration

The Additively‐Manufactured, System‐Integrated Tip (AMSIT) project is leveraging the flexibility of 3D printing to integrate several technologies in a wind turbine blade tip, while reducing the levelized cost of electricity (LCOE) produced. The design integration is demonstrated for a 200‐kW–scale turbine with 13‐m blades, with the outer 15% of the blade replaced with a 3D‐printed design. Aerodynamic performance is enhanced without increasing swept area through inclusion of a winglet and surface texturing, both challenging for traditional manufacturing. Longevity and durability are improved through integrated lightning and leading edge erosion protection. Increased power, reduced repair frequency, and ease of repair through blade modularity all contribute to reduced LCOE. The analysis is also extended to modern MW‐scale designs to estimate the impact of the technology at scale, demonstrating the potential to reduce LCOE significantly for modern onshore turbines, with even higher potential savings offshore.

3D printing↗

A Systematic Review of Protocols for the Three-Dimensional Morphologic Assessment of Abdominal Aortic Aneurysms Using Computed Tomographic Angiography

The morphology of infrarenal abdominal aortic aneurysms (AAAs) directly influences the perioperative outcome and long-term durability of endovascular aneurysm repair. A variety of methods have been proposed for the characterization of AAA morphology using reconstructed three-dimensional (3D) computed tomography (CT) images. At present, there is lack of consensus as to which of these methods is most applicable to clinical practice or research. The purpose of this review was to evaluate existing protocols that used 3D CT images in the assessment of various aspects of AAA morphology. An electronic search was performed, from January 1996 to the end of October 2010, using the Embase and Medline databases. The literature review conformed to PRISMA statement standards. The literature search identified 604 articles, of which 31 studies met inclusion criteria. Only 15 of 31 studies objectively assessed reproducibility. Existing published protocols were insufficient to define a single evidence-based methodology for preoperative assessment of AAA morphology. Further development and expert consensus are required to establish a standardized and validated protocol to determine precisely how morphology relates to outcomes after endovascular aneurysm repair.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Current Status of Endovascular Preservation of the Internal Iliac Artery with Iliac Branch Devices (IBD)

Endovascular aneurysm repair (EVAR) has become the most utilized treatment for abdominal aortic aneurysms (AAA), but the presence of common iliac dilatation or aneurysm may prevent the achievement of effective distal seal and fixation. Ideal repair in these cases should involve both effective preservation of the pelvic circulation and durable exclusion of the AAA. Unilateral or bilateral internal iliac artery (IIA) preservation with iliac branch devices (IBD) is safe, feasible and effective with technical and clinical outcomes comparable to standard EVAR. The versatility of current devices has allowed extended application to complex cases, but must be considered carefully in difficult anatomies. Pending long-term durability results and formal cost-effectiveness appraisals, IBD implantation has several advantages to anatomically eligible patients as compared with other available open or endovascular/hybrid solutions for IIA preservation during EVAR for aortoiliac aneurysms.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Surgical wound fluids from patients treated with intraoperative radiotherapy induce radiobiological response in breast cancer cells

Breast cancer is the most common cancer occurring in women. The standard of breast cancer treatment is based on breast-conserving surgery with administration of adjuvant whole breast radiotherapy. Research shows that in-breast relapse is most likely to occur in the tumour bed, i.e. around the scar. Intraoperative radiotherapy (IORT), in which radiation is delivered to the tumour bed, reduces the risk of local recurrence not only through direct cell killing, but also through modification of local microenvironment. Additionally IORT modifies the composition and biological activity of surgical wound fluid. Since many researchers show that radiation damage is mediated through factors secreted to the environment by irradiated cells, we hypothesized that this radiation-induced bystander effect is partly responsible for the change observed in surgical wound fluids. We collected conditioned medium from irradiated breast cancer cells (CM) and surgical wound fluids from patients who underwent IORT (RT-WF) and from patients after breast-conserving surgery alone (WF). We incubated two breast cancer cell lines (MCF-7 and MDA-MB-468) with WF, RT-WF, CM or WF + CM and measured radiobiological response of cells. We measured the level of double-strand breaks, induction of apoptosis and the changes in expression of genes related to DNA damage repair. We observed that stimulation with RT-WF and with WF + CM-induced double-strand breaks and increased expression of DNA damage repair-related genes, which was not observed after stimulation with WF. These results suggest that IOERT induces secretion of bystander factors mediating the genotoxic effect of ionizing radiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Optimizing power system restoration with damaged communications

Utility procedures for power system blackstart and restoration typically assume that energization decisions can be reliably communicated across the grid. In reality, the communications and control network would likely also be affected in power outages, such as those caused by extreme weather events or cyber-attacks. This paper studies the effect of damage to the power system communications and control infrastructure on restoration operations following a blackout. We model the communications infrastructure as a graph, overlaying the power grid, and imposing the requirement that every energized element in the power grid be observable from a control center. We expand on a specialized branch-and-bound algorithm from the literature to optimize the restoration process and devise an initialization heuristic and a rounding heuristic to improve solution speed. We perform numerical experiments on synthetic systems for Illinois and Texas with outages based on a solar flare or hurricane. We compare the results of our specialized branch-and-bound algorithm to the results from (i) the initialization heuristic alone, (ii) a variation of this heuristic that we use as a baseline, and (iii) the restoration optimization for the power system without communications constraints. Here, we find that damage to the communications infrastructure significantly increases the time required to re-energize the grid. Moreover, by simultaneously optimizing communications repairs and grid energization decisions, we are able to re-energize the grid significantly faster than if communications repairs and energization decisions were made independently or with partial coordination, motivating improvements to current industry practice.

97 MATHEMATICS AND COMPUTING↗

Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection

Each year thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. Overall, these studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.

60 APPLIED LIFE SCIENCES↗

In-situ qualification and physics-based process design for aerosol jet printing via spatially correlated light scattering measurements

Aerosol jet printing is a contactless, digital, and additive technique broadly used for manufacturing flexible, hybrid, and conformal electronics. However, batch-to-batch variability has hindered widespread industry adoption and scaling to production volumes. Recently, light scattering measurements have emerged as a tool to measure aerosol volume fraction – a key parameter determining deposition rate – and have proven an effective feedback source for closed loop control on timescales ranging from minutes to hours. Here, the efficacy of light scattering measurements as a tool for in-situ qualification over shorter time durations is explored. To be the linear relationship between light scattering measurements and deposition rate was validated at 500 ms time intervals, allowing deposition rate to be mapped to positional coordinates and providing a new data stream to drive quality control assessments. Because light scattering measurements are indicative of a physical process parameter, they were substituted into equations for resistance and sheet resistance, resulting in predictions nominally within 10% of measured values for sets of printed devices. Finally, to highlight a more active utility, light scattering measurements were employed in a print repair framework, successfully repairing prints with randomly induced defects to within 5% of the measured resistance of a control set.

36 MATERIALS SCIENCE↗

Cold spray technology in nuclear energy applications: A review of recent advances

Cold spray technology is a promising solid-state, powder-based deposition methods for fabrication of coatings, near-net-shape manufacturing, and component repair. In recent years, this technology has been investigated for many applications in the nuclear energy sector. For example, it has been explored for the deposition of coatings of corrosion and oxidation materials on zirconium-alloys fuel claddings in light water reactors (LWR) for achieving more accident-tolerant fuel (ATF) cladding. Other examples of its use for nuclear energy applications include coatings for enhancements in wear resistance and heat transfer, near-net shape manufacturing of next-generation fuel claddings of oxide dispersion-strengthened (ODS) steels, and for mitigation and repair of potential chloride induced stress corrosion cracking in used fuel storage canister systems. This work reviews published literature on the application of cold spray process for nuclear energy applications, while pointing to gaps that have yet to be addressed.

36 MATERIALS SCIENCE↗

Site-specific surface reactivity on MgO for atomic layer deposition via selective hydration

Atomic layer deposition (ALD) is a powerful technique for thin film synthesis, offering atomic-scale precision and conformality. While ALD of MgO has been widely studied for applications in energy storage and microelectronics, its potential as surface on which deposition may be selective and defects repaired remains underexplored. Here, we present a combined theoretical and experimental investigation of MgO surface hydration and its implications for targeted ALD growth using water and dimethyl aluminum isopropoxide (DMAI) as reactants. We perform density functional theory (DFT) calculations to examine molecular and dissociative H 2 O adsorption on MgO (100) terraces and step-edge sites, including pristine surfaces and those with Mg/O vacancies. Reaction Gibbs free energies are calculated under various conditions to quantify surface reactivity. Our findings reveal facet- and defect-dependent hydration behaviors that align with experimental ALD growth trends on MgO (100). This study provides a molecular-level understanding of MgO surface chemistry critical for optimizing ALD processes for thin film growth and defect repair.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Nukbone® promotes proliferation and osteoblastic differentiation of mesenchymal stem cells from human amniotic membrane

Highlights: •Nukbone showed to be a good scaffold for adhesion, proliferation and differentiation of stem cells. •Nukbone induced osteoblastic differentiation of human mesenchymal stem cells. •Results showed that Nukbone offer an excellent option for bone tissue regeneration due to properties. -- Abstract: Bovine bone matrix Nukbone® (NKB) is an osseous tissue-engineering biomaterial that retains its mineral and organic phases and its natural bone topography and has been used as a xenoimplant for bone regeneration in clinics. There are not studies regarding its influence of the NKB in the behavior of cells during the repairing processes. The aim of this research is to demonstrate that NKB has an osteoinductive effect in human mesenchymal stem cells from amniotic membrane (AM-hMSCs). Results indicated that NKB favors the AM-hMSCs adhesion and proliferation up to 7 days in culture as shown by the scanning electron microscopy and proliferation measures using an alamarBlue assay. Furthermore, as demonstrated by reverse transcriptase polymerase chain reaction, it was detected that two gene expression markers of osteoblastic differentiation: the core binding factor and osteocalcin were higher for AM-hMSCs co-cultured with NKB in comparison with cultivated cells in absence of the biomaterial. As the results indicate, NKB possess the capability for inducing successfully the osteoblastic differentiation of AM-hMSC, so that, NKB is an excellent xenoimplant option for repairing bone tissue defects.

60 APPLIED LIFE SCIENCES↗

Asparagine 326 in the extremely C-terminal region of XRCC4 is essential for the cell survival after irradiation

XRCC4 is one of the crucial proteins in the repair of DNA double-strand break (DSB) through non-homologous end-joining (NHEJ). As XRCC4 consists of 336 amino acids, N-terminal 200 amino acids include domains for dimerization and for association with DNA ligase IV and XLF and shown to be essential for XRCC4 function in DSB repair and V(D)J recombination. On the other hand, the role of the remaining C-terminal region of XRCC4 is not well understood. In the present study, we noticed that a stretch of ∼20 amino acids located at the extreme C-terminus of XRCC4 is highly conserved among vertebrate species. To explore its possible importance, series of mutants in this region were constructed and assessed for the functionality in terms of ability to rescue radiosensitivity of M10 cells lacking XRCC4. Among 13 mutants, M10 transfectant with N326L mutant (M10-XRCC4{sup N326L}) showed elevated radiosensitivity. N326L protein showed defective nuclear localization. N326L sequence matched the consensus sequence of nuclear export signal. Leptomycin B treatment accumulated XRCC4{sup N326L} in the nucleus but only partially rescued radiosensitivity of M10-XRCC4{sup N326L}. These results collectively indicated that the functional defects of XRCC4{sup N326L} might be partially, but not solely, due to its exclusion from nucleus by synthetic nuclear export signal. Further mutation of XRCC4 Asn326 to other amino acids, i.e., alanine, aspartic acid or glutamine did not affect the nuclear localization but still exhibited radiosensitivity. The present results indicated the importance of the extremely C-terminal region of XRCC4 and, especially, Asn326 therein. - Highlights: • Extremely C-terminal region of XRCC4 is highly conserved among vertebrate species. • XRCC4 C-terminal point mutants, R325F and N326L, are functionally deficient in terms of survival after irradiation. • N326L localizes to the cytoplasm because of synthetic nuclear export signal. • Leptomycin B restores the nuclear localization of N326L but only partially reverses radiosensitivity. • Other N326 mutants (N326A, N326D and N326Q) are functionally deficient in terms of survival after irradiation.

60 APPLIED LIFE SCIENCES↗

Novel and rapid osteoporosis model established in zebrafish using high iron stress

Highlights: • Establish a rapid and robust zebrafish model of osteoporosis using high iron stress. • High iron-overloaded results in severe defects in skeletal development. • High iron stress leads significant downregulation of osteoblast-specific mRNAs. • This osteoporosis phenotype is effectively repaired by a known drug Alendronate (AL). • AL could rescue osteoporosis larval fish through facilitating osteoblast differentiation. Osteoporosis is a global public health concern and, it can result from numerous pathogenic mechanisms, many of which are closely related with age, nutritional disorders, endocrine imbalance, or adverse drug side effects presented by glucocorticoids, heparin, and anti-epileptics. Given its wide range etiologies, it is crucial to establish an animal model of osteoporosis for use in screening potential drugs quickly and effectively. Previous research has reported that an accumulation of elevated iron in the body is an independent risk factor for osteoporosis. As such, we sought to use both zebrafish larvae and adults to model an osteoporosis phenotype using high iron stress (FAC, ferric ammonium citrate). Skeletal staining results suggested that iron-overload caused a significant decrease in bone calcification as well as severe developmental cartilage defects. In addition, osteoblast and cartilage-specific mRNA expression levels were downregulated after exposure to a high-iron environment. Most importantly, we demonstrated in both larval and adult fish that high iron-induced osteogenic defects were significantly rescued using alendronate (AL), a drug known to be effective against to human osteoporosis. Even more, the repair effect of AL was achieved by facilitating osteoblast differentiation and targeting Bmp signaling. Taken together, our findings propose an rapid and effective osteoporosis model, which could be used widely for future osteoporosis drug screening.

60 APPLIED LIFE SCIENCES↗

Engineered U7 snRNA mediates sustained splicing correction in erythroid cells from β-thalassemia/HbE patients

Highlights: • Defect of β{sup E}-globin pre-mRNA splicing was repaired by engineered splice-switching U7 snRNA. • Splice-switching oligonucleotide sequence was identified by a two-step tiling approach. • The engineered U7 snRNA improve pathology of erythroid cells from thalassemia patients. Repair of a splicing defect of β-globin pre-mRNA harboring hemoglobin E (HbE) mutation was successfully accomplished in erythroid cells from patients with β-thalassemia/HbE disorder by a synthetic splice-switching oligonucleotide (SSO). However, its application is limited by short-term effectiveness and requirement of lifelong periodic administration of SSO, especially for chronic diseases like thalassemias. Here, we engineered lentiviral vectors that stably express U7 small nuclear RNA (U7 snRNA) carrying the splice-switching sequence of the SSO that restores correct splicing of β{sup E}-globin pre-mRNA and achieves a long-term therapeutic effect. Using a two-step tiling approach, we systematically screened U7 snRNAs carrying splice-switching SSO sequences targeted to the cryptic 5′ splice site created by HbE mutation. We tested this approach and identified the most responsive element for mediating splicing correction in engineered U7 snRNAs in HeLa-β{sup E} cell model cell line. Remarkably, the U7 snRNA lentiviral vector (U7 βE4+1) targeted to this region effectively restored the correctly-spliced β{sup E}-globin mRNA for at least 5 months. Moreover, the effects of the U7 βE4+1 snRNA lentiviral vector were also evident as upregulation of the correctly-spliced β{sup E}-globin mRNA in erythroid progenitor cells from β-thalassemia/HbE patients treated with the vector, which led to improvements of pathologies in erythroid progenitor cells from thalassemia patients. These results suggest that the splicing correction of β{sup E}-globin pre-mRNA by the engineered U7 snRNA lentiviral vector provides a promising, long-term treatment for β-thalassemia/HbE.

60 APPLIED LIFE SCIENCES↗

MicroRNA-185 inhibits the growth and proliferation of osteoblasts in fracture healing by targeting PTH gene through down-regulating Wnt/β -catenin axis: In an animal experiment

Fracture healing is a repair process of a mechanical discontinuity loss of force transmission, and pathological mobility of bone. Increasing evidence suggests that microRNA (miRNA) could regulate chondrocyte, osteoblast, and osteoclast differentiation and function, indicating miRNA as key regulators of bone formation, resorption, remodeling, and repair. Hence, during this study, we established a right femur fracture mouse model to explore the effect microRNA-185 (miR-185) has on osteoblasts in mice during fracture healing and its underlying mechanism. After successfully model establishment, osteoblasts were extracted and treated with a series of mimics or inhibitors of miR-185, or siRNA against PTH. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis were performed to determine the levels of miR-185, PTH, β-catenin and Wnt5b. Cell viability, cycle distribution and apoptosis were detected by means of MTT and flow cytometry assays. Dual luciferase reporter gene assay verified that PTH is a target gene of miR-185. Osteoblasts transfected with miR-185 mimics or siRNA against PTH presented with decreased levels of PTH, β-catenin and Wnt5b which indicated that miR-185 blocks the Wnt/β -catenin axis by inhibiting PTH. Moreover, miR-185 inhibitors promoted the osteoblast viability and reduced apoptosis with more cells arrested at the G1 stage. MiR-185 mimics were observed to have inhibitory effects on osteoblasts as opposed to those induced by miR-185 inhibitors. Above key results indicated that suppression of miR-185 targeting PTH could promote osteoblast growth and proliferation in mice during fracture healing through activating Wnt/β -catenin axis.

60 APPLIED LIFE SCIENCES↗

In vivo gene correction with targeted sequence substitution through microhomology-mediated end joining

Highlights: • A novel microhomology mediated end joining (MMEJ) gene correction method was tested. • MMEJ resulted in precise targeted sequence substitution (TSS) in vitro and in vivo. • MMEJ-TSS showed superior efficiency than homology-directed repair (HDR) in vitro. • MMEJ-TSS resulted in the survival of mice model of hereditary tyrosinemia in vivo. • MMEJ-TSS could overcome the limitations of HDR for gene therapy. Genome editing technology using programmable nucleases has rapidly evolved in recent years. The primary mechanism to achieve precise integration of a transgene is mainly based on homology-directed repair (HDR). However, an HDR-based genome-editing approach is less efficient than non-homologous end-joining (NHEJ). Recently, a microhomology-mediated end-joining (MMEJ)-based transgene integration approach was developed, showing feasibility both in vitro and in vivo. We expanded this method to achieve targeted sequence substitution (TSS) of mutated sequences with normal sequences using double-guide RNAs (gRNAs), and a donor template flanking the microhomologies and target sequence of the gRNAs in vitro and in vivo. Our method could realize more efficient sequence substitution than the HDR-based method in vitro using a reporter cell line, and led to the survival of a hereditary tyrosinemia mouse model in vivo. The proposed MMEJ-based TSS approach could provide a novel therapeutic strategy, in addition to HDR, to achieve gene correction from a mutated sequence to a normal sequence.

60 APPLIED LIFE SCIENCES↗

Influence of 8-Oxoguanosine on the Fine Structure of DNA Studied with Biasing-Potential Replica Exchange Simulations

Chemical modification or radiation can cause DNA damage, which plays a crucial role for mutagenesis of DNA, carcinogenesis, and aging. DNA damage can also alter the fine structure of DNA that may serve as a recognition signal for DNA repair enzymes. A new, advanced sampling replica-exchange method has been developed to specifically enhance the sampling of conformational substates in duplex DNA during molecular dynamics (MD) simulations. The approach employs specific biasing potentials acting on pairs of pseudodihedral angles of the nucleic acid backbone that are added in the replica simulations to promote transitions of the most common substates of the DNA backbone. The sampled states can exchange with a reference simulation under the control of the original force field. The application to 7,8-dihydro-8oxo-guanosine, one of the most common oxidative damage in DNA indicated better convergence of sampled states during 10 ns simulations compared to 20 times longer standard MD simulations. It is well suited to study systematically the fine structure and dynamics of large nucleic acids under realistic conditions, including explicit solvent and ions. The biasing potential-replica exchange MD simulations indicated significant differences in the population of nucleic acid backbone substates in the case of 7,8-dihydro-8oxo-guanosine compared to a regular guanosine in the same sequence context. This concerns both the ratio of the B-DNA substates BI and BII associated with the backbone dihedral angles ε and z but also coupled changes in the backbone dihedral angles a and g. Such differences may play a crucial role in the initial recognition of damaged DNA by repair enzymes.

Environmental Molecular Sciences Laboratory↗

Room temperature slot-die coated perovskite layer modified with sulfonyl-γ-AApeptide for high performance perovskite solar devices

Perovskite solar cells (PSCs) exhibited remarkable progress for small aperture area cells, however, the performance of its counterpart, large aperture area cells, lags due to non-uniform and defective perovskite layers. Here, we fabricate reproducible large area homogeneous perovskite films at room temperature and without controlling humidity (up to 40 % RH) with a slot die coater on a c-TiO 2 layer deposited using a large area chemical bath. A new artificial peptide – sulfonyl-γ-AApeptide (F-GLU-S) was employed to modify the slot-die coated perovskite surface, grain boundaries and electronic defects. The multi-functional F-GLU-S with carbonyl, carboxyl, sulfonyl, benzene, and chloro groups was capable of strongly interacting with the perovskite layer and repairing the uncoordinated Pb 2+ ions and halide vacancies. As a result, both the electron and hole densities of defects were significantly suppressed; consequently, the non-radiative recombination was effectively suppressed for the modified device which can be explicitly seen in the device performance where both V oc and FF of the modified device improved considerably. Therefore, F-GLU-S modified slot-die coated MAPbI 3 – based devices demonstrated outstanding performance of 21.44 % PCE with a V oc of 1.13 V, J sc of 24.64 cm –2 , and FF 76.99 %. Furthermore, F-GLU-S passivation impeded the infiltration of moisture and oxygen due to its hydrophobic nature and defect repair potential. As a result, the modified device retained above 92 % of its original PCE after 720 h in air (room temperature and 40–60 % RH).

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

The S. cerevisiae Pif1 helicase functions with DNA polymerase (Pol) δ in DNA synthesis during break-induced replication (BIR), a conserved pathway responsible for replication fork repair and telomere recombination. Pif1 interacts with the DNA polymerase processivity clamp PCNA, but the functional significance of the Pif1-PCNA complex remains to be elucidated. Here, we solve the crystal structure of PCNA in complex with a non-canonical PCNA-interacting motif in Pif1. The structure guides the construction of a Pif1 mutant that is deficient in PCNA interaction. This mutation impairs the ability of Pif1 to enhance DNA strand displacement synthesis by Pol δ in vitro and also the efficiency of BIR in cells. These results provide insights into the role of the Pif1-PCNA-Pol δ ensemble during DNA break repair by homologous recombination.

59 BASIC BIOLOGICAL SCIENCES↗