Moon-forming impactor as a source of Earth's basal mantle anomalies.

Seismic images of Earth's interior have revealed two continent-sized anomalies with low seismic velocities, known as the large low-velocity provinces (LLVPs), in the lowermost mantle1. The LLVPs are often interpreted as intrinsically dense heterogeneities that are compositionally distinct from the surrounding mantle2. Here we show that LLVPs may represent buried relics of Theia mantle material (TMM) that was preserved in proto-Earth's mantle after the Moon-forming giant impact3. Our canonical giant-impact simulations show that a fraction of Theia's mantle could have been delivered to proto-Earth's solid lower mantle. We find that TMM is intrinsically 2.0-3.5% denser than proto-Earth's mantle based on models of Theia's mantle and the observed higher FeO content of the Moon. Our mantle convection models show that dense TMM blobs with a size of tens of kilometres after the impact can later sink and accumulate into LLVP-like thermochemical piles atop Earth's core and survive to the present day. The LLVPs may, thus, be a natural consequence of the Moon-forming giant impact. Because giant impacts are common at the end stages of planet accretion, similar mantle heterogeneities caused by impacts may also exist in the interiors of other planetary bodies.

Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss.

von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.

Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence.

The function of the Vibrio 7(th) pandemic island-1 (VSP-1) in cholera pathogenesis has remained obscure. Utilizing chromatin immunoprecipitation sequencing and RNA sequencing to map the regulon of the master virulence regulator ToxT, we identify a TCP island-encoded small RNA that reduces the expression of a previously unrecognized VSP-1-encoded transcription factor termed VspR. VspR modulates the expression of several VSP-1 genes including one that encodes a novel class of di-nucleotide cyclase (DncV), which preferentially synthesizes a previously undescribed hybrid cyclic AMP-GMP molecule. We show that DncV is required for efficient intestinal colonization and downregulates V. cholerae chemotaxis, a phenotype previously associated with hyperinfectivity. This pathway couples the actions of previously disparate genomic islands, defines VSP-1 as a pathogenicity island in V. cholerae, and implicates its occurrence in 7(th) pandemic strains as a benefit for host adaptation through the production of a regulatory cyclic di-nucleotide.

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. SIGNIFICANCE STATEMENT: Nuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets.

Quantum supremacy using a programmable superconducting processor.

The promise of quantum computers is that certain computational tasks might be executed exponentially faster on a quantum processor than on a classical processor1. A fundamental challenge is to build a high-fidelity processor capable of running quantum algorithms in an exponentially large computational space. Here we report the use of a processor with programmable superconducting qubits2-7 to create quantum states on 53 qubits, corresponding to a computational state-space of dimension 253 (about 1016). Measurements from repeated experiments sample the resulting probability distribution, which we verify using classical simulations. Our Sycamore processor takes about 200 seconds to sample one instance of a quantum circuit a million times-our benchmarks currently indicate that the equivalent task for a state-of-the-art classical supercomputer would take approximately 10,000 years. This dramatic increase in speed compared to all known classical algorithms is an experimental realization of quantum supremacy8-14 for this specific computational task, heralding a much-anticipated computing paradigm.

A structural mechanism of nuclear receptor biased agonism.

Efforts to decrease the adverse effects of nuclear receptor (NR) drugs have yielded experimental agonists that produce better outcomes in mice. Some of these agonists have been shown to cause different, not just less intense, on-target transcriptomic effects; however, a structural explanation for such agonist-specific effects remains unknown. Here, we show that partial agonists of the NR peroxisome proliferator-associated receptor γ (PPARγ), which induce better outcomes in mice compared to clinically utilized type II diabetes PPARγ-binding drugs thiazolidinediones (TZDs), also favor a different group of coactivator peptides than the TZDs. We find that PPARγ full agonists can also be biased relative to each other in terms of coactivator peptide binding. We find differences in coactivator-PPARγ bonding between the coactivator subgroups which allow agonists to favor one group of coactivator peptides over another, including differential bonding to a C-terminal residue of helix 4. Analysis of all available NR-coactivator structures indicates that such differential helix 4 bonding persists across other NR-coactivator complexes, providing a general structural mechanism of biased agonism for many NRs. Further work will be necessary to determine if such bias translates into altered coactivator occupancy and physiology in cells.

SPCS: a spatial and pattern combined smoothing method for spatial transcriptomic expression.

High-dimensional, localized ribonucleic acid (RNA) sequencing is now possible owing to recent developments in spatial transcriptomics (ST). ST is based on highly multiplexed sequence analysis and uses barcodes to match the sequenced reads to their respective tissue locations. ST expression data suffer from high noise and dropout events; however, smoothing techniques have the promise to improve the data interpretability prior to performing downstream analyses. Single-cell RNA sequencing (scRNA-seq) data similarly suffer from these limitations, and smoothing methods developed for scRNA-seq can only utilize associations in transcriptome space (also known as one-factor smoothing methods). Since they do not account for spatial relationships, these one-factor smoothing methods cannot take full advantage of ST data. In this study, we present a novel two-factor smoothing technique, spatial and pattern combined smoothing (SPCS), that employs the k-nearest neighbor (kNN) technique to utilize information from transcriptome and spatial relationships. By performing SPCS on multiple ST slides from pancreatic ductal adenocarcinoma (PDAC), dorsolateral prefrontal cortex (DLPFC) and simulated high-grade serous ovarian cancer (HGSOC) datasets, smoothed ST slides have better separability, partition accuracy and biological interpretability than the ones smoothed by preexisting one-factor methods. Source code of SPCS is provided in Github (https://github.com/Usos/SPCS).

Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.

Multiscale Modeling of Plutonium Radiation Chemistry in Nitric Acid Solutions. 1. Cobalt-60 Gamma Irradiation of Pu(IV).

Careful manipulation of the plutonium oxidation states is essential in the study and utilization of its rich redox chemistry. To achieve this level of control, a comprehensive mechanistic understanding of radiation-induced plutonium redox chemistry is critical due to the unavoidable exposure of plutonium to ionizing radiation fields, both inherent and from in-process applications. To this end, we have developed an experimentally evaluated multiscale computer model for the prediction of gamma radiation-induced Pu(IV) redox chemistry in concentrated nitric acid solutions (1.0, 3.0, and 6.0 M). Under these acidic, aqueous solution conditions, cobalt-60 gamma irradiation afforded marginal net conversion of Pu(IV) to Pu(VI), the extent of which was dependent on the concentration of HNO3 and absorbed gamma dose. Multiscale calculations, which are in excellent agreement with experimental data, indicate that this observation is due to a combination of inherent plutonium disproportionation reactions and several radiation-induced processes, including redox cycling between Pu(IV) and Pu(III), as achieved by the reduction of Pu(IV) by nitrous acid and hydrogen peroxide, the oxidation of Pu(III) by nitrate and hydroxyl radicals, and the sequential oxidation of Pu(IV) to Pu(V) and Pu(VI) by the remaining available yield of nitrate radicals.

Primate conservation: A public issue?

Nonhuman primates (primates) are one of the most endangered mammalian taxa in the world. In the Global North, primates are considered exotic species and, as such, humans' impact on primate conservation and responsibility to protect primates is often ignored. This view differs from the spectrum of relations and attitudes of humans that live in connection to primates, which can include viewing these animals as culturally/religiously significant, cohabitors of forests, nuisances, or sources of protein. While conservationists argue that primates deserve our protection, the conservation crisis facing primates is rarely framed as a public issue, in contrast to other global crises, such as climate change. However, over half of the world's human population lives within 100 km of primate habitat. Thus, humans and primates share the same environments. We suggest leveraging a holistic approach, such as One Health, that considers the interconnectedness of primates, humans, and their shared environments, through the lens of public anthropology. By approaching primate conservation as an intersectional issue that affects and is affected by humans, researchers and conservationists can identify strategies that simultaneously protect primates and address global inequities that frequently affect people in primate range countries. Reflexive research practices further allow academics to consider the broader impact of their ecological research through means such as publicly accessible dissemination of results, equitable capacity-building of high-quality personnel in primate range countries, and social activism. The use of inter-, multi-, and transdisciplinary concepts and methodology can address the intersectional challenges associated with implementing ethical and sustainable primate conservation measures.

Wear of Third-Generation Cross-Linked Polyethylene in Primary Total Hip Arthroplasty: A 10-Year Analysis.

BACKGROUND: Sequential modifications to the manufacturing process of highly cross-linked polyethylene (HXLPE) have improved the wear resistance and implant survival of these liners in total hip arthroplasty (THA). However, no study has examined the long-term (mean 10 year) wear rates and clinical outcomes of third-generation HXLPE in THA. The aim of our study was to report the longest-to-date analysis of wear rates and clinical outcomes of a third-generation HXLPE liner. METHODS: A series of 133 THAs using a specific HXLPE acetabular liner were retrospectively evaluated. Linear and volumetric wear rates were determined using a validated radiographic technique and clinical outcomes were analyzed. Multivariate analyses were performed to determine risk factors for accelerated wear. RESULTS: At a mean follow-up of 10.4 years (range, 8 to 13.4), the mean linear wear rate was 0.0172 mm/year and the mean volumetric wear rate was 16.99 mm3/year. There were no instances of osteolysis or mechanical failures at any time point and there was a 100% acetabular component survival rate. Younger age and use of offset liners were independent risk factors for increased wear (P < .01 for both). CONCLUSIONS: Our series of a third-generation HXLPE demonstrated very low wear rates and excellent implant survival at a mean of 10.4 years following primary THA. Future comparative studies at the 15- and 20-year follow-up timepoints are necessary to determine if such findings translate to true improvements in the tribological properties and longevity of these liners when compared to previous generations of HXLPE liners.

-A machine learning model to predict surgical site infection after surgery of lower extremity fractures.

PURPOSE: This study aimed to develop machine learning algorithms for identifying predictive factors associated with the risk of postoperative surgical site infection in patients with lower extremity fractures. METHODS: A machine learning analysis was conducted on a dataset comprising 1,579 patients who underwent surgical fixation for lower extremity fractures to create a predictive model for risk stratification of postoperative surgical site infection. We evaluated different clinical and demographic variables to train four machine learning models (neural networks, boosted generalised linear model, naïve bayes, and penalised discriminant analysis). Performance was measured by the area under the curve score, Youdon's index and Brier score. A multivariate adaptive regression splines (MARS) was used to optimise predictor selection. RESULTS: The final model consisted of five predictors. (1) Operating room time, (2) ankle region, (3) open injury, (4) body mass index, and (5) age. The best-performing machine learning algorithm demonstrated a promising predictive performance, with an area under the ROC curve, Youdon's index, and Brier score of 77.8%, 62.5%, and 5.1%-5.6%, respectively. CONCLUSION: The proposed predictive model not only assists surgeons in determining high-risk factors for surgical site infections but also empowers patients to closely monitor these factors and take proactive measures to prevent complications. Furthermore, by considering the identified predictors, this model can serve as a reference for implementing preventive measures and reducing postoperative complications, ultimately enhancing patient outcomes. However, further investigations involving larger datasets and external validations are required to confirm the reliability and applicability of our model.

The Training and Tapering Practices of Highland Games Heavy Event Athletes.

ABSTRACT: Winwood, PW, Keogh, JW, Travis, SK, Grieve, I, and Pritchard, HJ. The training and tapering practices of Highland Games heavy event athletes. J Strength Cond Res 38(3): e116-e124, 2024-This study provides the first empirical evidence of how Highland Games heavy event athletes train and taper for Highland Games competitions. Athletes (n = 169) (mean ± SD: age 40.8 ± 10.7 years, height 181.2 ± 9.5 cm, weight 107.2 ± 23.0 kg, 18.8 ± 10.3 years of general resistance training, and 8.1 ± 6.9 years of competitive Highland Games experience) completed a self-reported 4-page online survey on training and tapering practices. Analysis by sex (male and female) and competitive standard (local or regional, national, and international) was conducted. Seventy-eight percent (n = 132) of athletes reported that they used a taper. Athletes stated that their taper length was 5.2 ± 3.5 days, with the step (36%) and linear tapers (33%) being the most performed. Athletes reported that their highest training volume and intensity were 5.5 and 3.8 weeks out (respectively) from competition, and all training ceased 2.4 ± 1.4 days before competition. Training volume decreased during the taper by 34%. Athletes typically stated that, tapering was performed to achieve recovery, peak performance, and injury prevention; training intensity, frequency, and duration stayed the same or decreased; game-specific training increased with reductions in traditional exercises; the caber toss, weight for height, and heavy weight throw were performed further out from competition than other events; muscular power and strength were the most common types of training performed; static stretching, foam rolling, and massage were strategies used in the taper; and poor tapering occurred because of life/work circumstances, lack of sleep/rest, or training too heavy/hard. These results may aid Highland Games athletes to optimize training and tapering variables leading to improved performances.

TSAFinder: exhaustive tumor-specific antigen detection with RNAseq.

MOTIVATION: Tumor-specific antigen (TSA) identification in human cancer predicts response to immunotherapy and provides targets for cancer vaccine and adoptive T-cell therapies with curative potential, and TSAs that are highly expressed at the RNA level are more likely to be presented on major histocompatibility complex (MHC)-I. Direct measurements of the RNA expression of peptides would allow for generalized prediction of TSAs. Human leukocyte antigen (HLA)-I genotypes were predicted with seq2HLA. RNA sequencing (RNAseq) fastq files were translated into all possible peptides of length 8-11, and peptides with high and low expressions in the tumor and control samples, respectively, were tested for their MHC-I binding potential with netMHCpan-4.0. RESULTS: A novel pipeline for TSA prediction from RNAseq was used to predict all possible unique peptides size 8-11 on previously published murine and human lung and lymphoma tumors and validated on matched tumor and control lung adenocarcinoma (LUAD) samples. We show that neoantigens predicted by exomeSeq are typically poorly expressed at the RNA level, and a fraction is expressed in matched normal samples. TSAs presented in the proteomics data have higher RNA abundance and lower MHC-I binding percentile, and these attributes are used to discover high confidence TSAs within the validation cohort. Finally, a subset of these high confidence TSAs is expressed in a majority of LUAD tumors and represents attractive vaccine targets. AVAILABILITY AND IMPLEMENTATION: The datasets were derived from sources in the public domain as follows: TSAFinder is open-source software written in python and R. It is licensed under CC-BY-NC-SA and can be downloaded at https://github.com/RNAseqTSA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Tailoring the Wettability and Substrate Adherence of Thin Polymer Films with Surface-Segregating Bottlebrush Copolymer Additives.

We developed "reactive" bottlebrush polymers based on styrene (S) and t-butyl acrylate (tBA) as additives for polystyrene (PS) coatings. The bottlebrush polymers spontaneously bloom to both the air and substrate interfaces during solution casting. While neat PS films are hydrophobic and poorly adhere to the native oxide on clean silicon wafers, the hydrophilicity and substrate adherence of bottlebrush-incorporating PS films can be tailored through the thermally activated deprotection of tBA to produce acrylic acid (AA) and acrylic anhydride (AH). A critical design parameter is the manner by which tBA is incorporated into the bottlebrush: When the bottlebrush side chains are copolymers of S and tBA, the extent of deprotection is extremely low, even after prolonged thermal annealing at elevated temperature. However, when the bottlebrush contains a mixture of poly(t-butyl acrylate) (PtBA) and PS side chains, nearly all tBA is converted to AA and AH. Consequently, using the "mixed-chain" bottlebrush design with thermal processing and appropriate conditioning, the water contact angle is reduced from over 90° on unmodified PS down to 75° on bottlebrush-incorporating PS films, and the substrate adherence is improved in proportion to the extent of tBA deprotection.

Growth of Coal Mining Operations in the Elk River Valley (Canada) Linked to Increasing Solute Transport of Se, NO3-, and SO42- into the Transboundary Koocanusa Reservoir (USA-Canada).

Koocanusa Reservoir (KOC) is a waterbody that spans the United States (U.S.) and Canadian border. Increasing concentrations of total selenium (Se), nitrate + nitrite (NO3-, nitrite is insignificant or not present), and sulfate (SO42-) in KOC and downstream in the Kootenai River (Kootenay River in Canada) are tied to expanding coal mining operations in the Elk River Watershed, Canada. Using a paired watershed approach, trends in flow-normalized concentrations and loads were evaluated for Se, NO3-, and SO42- for the two largest tributaries, the Kootenay and Elk Rivers, Canada. Increases in concentration (SO42- 120%, Se 581%, NO3- 784%) and load (SO42- 129%, Se 443%, NO3- 697%) in the Elk River (1979-2022 for NO3-, 1984-2022 for Se and SO42-) are among the largest documented increases in the primary literature, while only a small magnitude increase in SO42- (7.7% concentration) and decreases in Se (-10%) and NO3- (-8.5%) were observed in the Kootenay River. Between 2009 and 2019, the Elk River contributed, on average, 29% of the combined flow, 95% of the Se, 76% of the NO3-, and 38% of the SO42- entering the reservoir from these two major tributaries. The largest increase in solute concentrations occurred during baseflows, indicating a change in solute transport and delivery dynamics in the Elk River Watershed, which may be attributable to altered landscapes from coal mining operations including altered groundwater flow paths and increased chemical weathering in waste rock dumps. More recently there is evidence of surface water treatment operations providing some reduction in concentrations during low flow times of year; however, these appear to have a limited effect on annual loads entering KOC. These findings imply that current mine water treatment, which is focused on surface waters, may not sufficiently reduce the influence of mine-waste-derived solutes in the Elk River to allow constituent concentrations in KOC to meet U.S. water-quality standards.

CT Approach to Lung Injury.

Diffuse alveolar damage (DAD), which represents the pathologic changes seen after acute lung injury, is caused by damage to all three layers of the alveolar wall and can ultimately result in alveolar collapse with loss of the normal pulmonary architecture. DAD has an acute phase that predominantly manifests as airspace disease at CT owing to filling of the alveoli with cells, plasma fluids, and hyaline membranes. DAD then evolves into a heterogeneous organizing phase, with mixed airspace and interstitial disease characterized by volume loss, architectural distortion, fibrosis, and parenchymal loss. Patients with DAD have a severe clinical course and typically require prolonged mechanical ventilation, which may result in ventilator-induced lung injury. In those patients who survive DAD, the lungs will remodel over time, but most will have residual findings at chest CT. Organizing pneumonia (OP) is a descriptive term for a histologic pattern characterized by intra-alveolar fibroblast plugs. The significance and pathogenesis of OP are controversial. Some authors regard it as part of a spectrum of acute lung injury, while others consider it a marker of acute or subacute lung injury. At CT, OP manifests with various forms of airspace disease that are most commonly bilateral and relatively homogeneous in appearance at individual time points. Patients with OP most often have a mild clinical course, although some may have residual findings at CT. In patients with DAD and OP, imaging findings can be combined with clinical information to suggest the diagnosis in many cases, with biopsy reserved for difficult cases with atypical findings or clinical manifestations. To best participate in the multidisciplinary approach to patients with lung injury, radiologists must not only recognize these entities but also describe them with consistent and meaningful terminology, examples of which are emphasized in the article. © RSNA, 2023 See the invited commentary by Kligerman et al in this issue. Quiz questions for this article are available in the supplemental material.

Simulations of frustrated Ising Hamiltonians using quantum approximate optimization.

Novel magnetic materials are important for future technological advances. Theoretical and numerical calculations of ground-state properties are essential in understanding these materials, however, computational complexity limits conventional methods for studying these states. Here we investigate an alternative approach to preparing materials ground states using the quantum approximate optimization algorithm (QAOA) on near-term quantum computers. We study classical Ising spin models on unit cells of square, Shastry-Sutherland and triangular lattices, with varying field amplitudes and couplings in the material Hamiltonian. We find relationships between the theoretical QAOA success probability and the structure of the ground state, indicating that only a modest number of measurements ([Formula: see text]) are needed to find the ground state of our nine-spin Hamiltonians, even for parameters leading to frustrated magnetism. We further demonstrate the approach in calculations on a trapped-ion quantum computer and succeed in recovering each ground state of the Shastry-Sutherland unit cell with probabilities close to ideal theoretical values. The results demonstrate the viability of QAOA for materials ground state preparation in the frustrated Ising limit, giving important first steps towards larger sizes and more complex Hamiltonians where quantum computational advantage may prove essential in developing a systematic understanding of novel materials. This article is part of the theme issue 'Quantum annealing and computation: challenges and perspectives'.

Impact of lanthanide ion complexation and temperature on the chemical reactivity of N,N,N',N'-tetraoctyl diglycolamide (TODGA) with the dodecane radical cation.

The impact of trivalent lanthanide ion complexation and temperature on the chemical reactivity of N,N,N',N'-tetraoctyl diglycolamide (TODGA) with the n-dodecane radical cation (RH˙+) has been measured by electron pulse radiolysis and evaluated by quantum mechanical calculations. Additionally, Arrhenius parameters were determined for the reaction of the non-complexed TODGA ligand with the RH˙+ from 10-40 °C, giving the activation energy (Ea = 17.43 ± 1.64 kJ mol-1) and pre-exponential factor (A = (2.36 ± 0.05) × 1013 M-1 s-1). The complexation of Nd(III), Gd(III), and Yb(III) ions by TODGA yielded [LnIII(TODGA)3(NO3)3] complexes that exhibited significantly increased reactivity (up to 9.3× faster) with the RH˙+, relative to the non-complexed ligand: k([LnIII(TODGA)3(NO3)3] + RH˙+) = (8.99 ± 0.93) × 1010, (2.88 ± 0.40) × 1010, and (1.53 ± 0.34) × 1010 M-1 s-1, for Nd(III), Gd(III), and Yb(III) ions, respectively. The rate coefficient enhancement measured for these complexes exhibited a dependence on atomic number, decreasing as the lanthanide series was traversed. Preliminary reaction free energy calculations-based on a model [LnIII(TOGDA)]3+ complex system-indicate that both electron/hole and proton transfer reactions are energetically unfavorable for complexed TODGA. Furthermore, complementary average local ionization energy calculations showed that the most reactive region of model N,N,N',N'-tetraethyl diglycolamide (TEDGA) complexes, [LnIII(TEGDA)3(NO3)3], toward electrophilic attack is for the coordinated nitrate (NO3-) counter anions. Therefore, it is possible that radical reactions with the complexed NO3- counter anions dominate the differences in rates seen for the [LnIII(TODGA)3(NO3)3] complexes, and are likely responsible for the reported radioprotection in the presence of TODGA complexes.

Competition between bridged dinucleotides and activated mononucleotides determines the error frequency of nonenzymatic RNA primer extension.

Nonenzymatic copying of RNA templates with activated nucleotides is a useful model for studying the emergence of heredity at the origin of life. Previous experiments with defined-sequence templates have pointed to the poor fidelity of primer extension as a major problem. Here we examine the origin of mismatches during primer extension on random templates in the simultaneous presence of all four 2-aminoimidazole-activated nucleotides. Using a deep sequencing approach that reports on millions of individual template-product pairs, we are able to examine correct and incorrect polymerization as a function of sequence context. We have previously shown that the predominant pathway for primer extension involves reaction with imidazolium-bridged dinucleotides, which form spontaneously by the reaction of two mononucleotides with each other. We now show that the sequences of correctly paired products reveal patterns that are expected from the bridged dinucleotide mechanism, whereas those associated with mismatches are consistent with direct reaction of the primer with activated mononucleotides. Increasing the ratio of bridged dinucleotides to activated mononucleotides, either by using purified components or by using isocyanide-based activation chemistry, reduces the error frequency. Our results point to testable strategies for the accurate nonenzymatic copying of arbitrary RNA sequences.