Structure Formation in Supraparticles Composed of Spherical and Elongated Particles.

We studied the evaporation-induced formation of supraparticles from dispersions of elongated colloidal particles using experiments and computer simulations. Aqueous droplets containing a dispersion of ellipsoidal and spherical polystyrene particles were dried on superamphiphobic surfaces at different humidity values that led to varying evaporation rates. Supraparticles made from only ellipsoidal particles showed short-range lateral ordering at the supraparticle surface and random orientations in the interior regardless of the evaporation rate. Particle-based simulations corroborated the experimental observations in the evaporation-limited regime and showed an increase in the local nematic ordering as the diffusion-limited regime was reached. A thin shell of ellipsoids was observed at the surface when supraparticles were made from binary mixtures of ellipsoids and spheres. Image analysis revealed that the supraparticle porosity increased with an increasing aspect ratio of the ellipsoids.

Mesoscale simulations of diffusion and sedimentation in shape-anisotropic nanoparticle suspensions.

We determine the long-time self-diffusion coefficient and sedimentation coefficient for suspensions of nanoparticles with anisotropic shapes (octahedra, cubes, tetrahedra, and spherocylinders) as a function of nanoparticle concentration using mesoscale simulations. We use a discrete particle model for the nanoparticles, and we account for solvent-mediated hydrodynamic interactions between nanoparticles using the multiparticle collision dynamics method. Our simulations are compared to theoretical predictions and experimental data from existing literature, demonstrating good agreement in the majority of cases. Further, we find that the self-diffusion coefficient of the regular polyhedral shapes can be estimated from that of a sphere whose diameter is the average of their inscribed and circumscribed sphere diameters.

A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence.

Post-transcriptional modifications can impact the stability and functionality of many different classes of RNA molecules and are an especially important aspect of tRNA regulation. It is hypothesized that cells can orchestrate rapid responses to changing environmental conditions by adjusting the specific types and levels of tRNA modifications. We uncovered strong evidence in support of this tRNA global regulation hypothesis by examining effects of the well-conserved tRNA modifying enzyme MiaA in extraintestinal pathogenic Escherichia coli (ExPEC), a major cause of urinary tract and bloodstream infections. MiaA mediates the prenylation of adenosine-37 within tRNAs that decode UNN codons, and we found it to be crucial to the fitness and virulence of ExPEC. MiaA levels shifted in response to stress via a post-transcriptional mechanism, resulting in marked changes in the amounts of fully modified MiaA substrates. Both ablation and forced overproduction of MiaA stimulated translational frameshifting and profoundly altered the ExPEC proteome, with variable effects attributable to UNN content, changes in the catalytic activity of MiaA, or availability of metabolic precursors. Cumulatively, these data indicate that balanced input from MiaA is critical for optimizing cellular responses, with MiaA acting much like a rheostat that can be used to realign global protein expression patterns.

Multiscale modeling of solute diffusion in triblock copolymer membranes.

We develop a multiscale simulation model for diffusion of solutes through porous triblock copolymer membranes. The approach combines two techniques: self-consistent field theory (SCFT) to predict the structure of the self-assembled, solvated membrane and on-lattice kinetic Monte Carlo (kMC) simulations to model diffusion of solutes. Solvation is simulated in SCFT by constraining the glassy membrane matrix while relaxing the brush-like membrane pore coating against the solvent. The kMC simulations capture the resulting solute spatial distribution and concentration-dependent local diffusivity in the polymer-coated pores; we parameterize the latter using particle-based simulations. We apply our approach to simulate solute diffusion through nonequilibrium morphologies of a model triblock copolymer, and we correlate diffusivity with structural descriptors of the morphologies. We also compare the model's predictions to alternative approaches based on simple lattice random walks and find our multiscale model to be more robust and systematic to parameterize. Our multiscale modeling approach is general and can be readily extended in the future to other chemistries, morphologies, and models for the local solute diffusivity and interactions with the membrane.

Operating in an Opioid Crisis: A Temporal Analysis of Pain Medication Prescribing Practices in Plastic Surgery.

BACKGROUND: In response to the opioid epidemic, the United States declared a public health emergency in 2017. We evaluated pain medication prescribing practices among plastic and reconstructive surgeons, assessing pain medication prescription rates and opioid-related mortality both nationally and regionally within the United States. METHODS: A retrospective analysis of Medicare Part D prescriber data among plastic surgeons from 2013 through 2017 was conducted. Pain medications were categorized as opioid and nonopioid medications. Trends in surgeon prescribing habits were evaluated using the Cochrane-Armitage trend test. RESULTS: A total of 708,817 pain medication claims were identified: 612,123 claims (86%) were for opioid pain medications and 96,694 claims (14%) were for nonopioid pain medications. Total pain medication claims decreased from 44% of all medications in 2013 to 37% in 2017 (P < 0.001). Opioid medications decreased from 37% of total medication claims to 32% (P < 0.001). The overall opioid prescription rate fell from 1.53 claims per beneficiary in 2013 to 1.32 in 2017 (P < 0.001). Nonopioid pain medications decreased from 7% in 2013 to 6% in 2017 (P < 0.001); nonsteroidal anti-inflammatory drug claims increased by 44%. The prescription rate of nonopioid medications decreased from 2.40 claims per beneficiary in 2013 to 2.32 in 2017 (P < 0.001). An overall increase in opioid-related mortality was observed. Trends in pain medication prescriptions varied significantly among US regions and divisions. CONCLUSIONS: Plastic surgeons are prescribing less opioids and relying more on nonopioid pain medications. Increased adoption of multimodal pain treatment approaches among surgeons is a likely explanation for this trend in face of the current opioid crisis.

Trends in Medicare Reimbursement for the Top 20 Surgical Procedures in Craniofacial Trauma.

BACKGROUND: Research regarding financial trends in craniofacial trauma surgery is limited. Understanding these trends is important to the evolvement of suitable reimbursement models in craniofacial plastic surgery. The purpose of this study was to evaluate the trends in Medicare reimbursement rates for the top 20 most utilized surgical procedures for facial trauma. METHODS: The 20 most commonly utilized Current Procedural Terminology (CPT) codes for facial trauma repairs in 2018 were queried from The National Summary Data File from the Centers for Medicare & Medicaid Services (CMS). Reimbursement data for each procedure was then extracted from The Physician Fee Schedule Lookup Tool. Changes to the United States consumer price index (CPI) were used to adjust all gathered data for inflation to 2021 US dollars (USD). The average annual and the total percent change in reimbursement were calculated for the included procedures based on the adjusted trends from the years 2000 to 2021. RESULTS: From 2000 to 2021, the average reimbursement for all procedures decreased by 16.6% after adjusting for inflation. Closed treatment of temporomandibular joint dislocation and closed treatment of nasal bone fractures without manipulation demonstrated the greatest decrease in mean adjusted reimbursement at -48.7% and -48.3%, respectively, while closed treatment of nasal bone fractures without stabilization demonstrated the smallest mean decrease at -1.4% during the study period. Open treatment of nasal septal fractures with or without stabilization demonstrated the greatest increase in mean adjusted reimbursement at 18.9%, while closed treatment of nasal septal fractures with or without stabilization demonstrated the smallest increase at 1.2%. The average reimbursement for all closed procedures in the top 20 decreased by 19.3%, while that for all open procedures decreased by 15.5%. The adjusted reimbursement rate for all top 20 procedures decreased by an average of 0.8% each year. CONCLUSIONS: To the best of our knowledge, this is the first study to comprehensively evaluate trends in Medicare reimbursement for facial trauma surgical repairs. Adjusting for inflation, Medicare reimbursement for the top 20 most commonly utilized procedures has largely decreased from 2000 to 2021. Consideration of these trends by surgeons, hospital systems, and policymakers will be important to assure continued access to meaningful surgical facial trauma care in the United States.

Ethics Education in U.S. Allopathic Medical Schools: A National Survey of Medical School Deans and Ethics Course Directors.

AbstractPurpose: to characterize ethics course content, structure, resources, pedagogic methods, and opinions among academic administrators and course directors at U.S. medical schools. METHOD: An online questionnaire addressed to academic deans and ethics course directors identified by medical school websites was emailed to 157 Association of American Medical Colleges member medical schools in two successive waves in early 2022. Descriptive statistics were utilized to summarize responses. RESULTS: Representatives from 61 (39%) schools responded. Thirty-two (52%) respondents were course directors; 26 (43%) were deans of academic affairs, medical education, or curriculum; and 3 with other roles also completed the survey (5%). All 61 schools reported some form of formal ethics education during the first year of medical school, with most (n = 54, 89%) reporting a formal mandatory introductory course during preclinical education. Schools primarily utilized lecture and small-group teaching methods. Knowledge-based examinations, attendance, and participation were most commonly used for assessment. A large majority regarded ethics as equally or more important than other foundational courses, but fewer (n = 37, 60%) provided faculty training for teaching ethics. CONCLUSIONS: Despite a response rate of 39 percent, the authors conclude that medical schools include ethics in their curricula in small-group and lecture formats with heterogeneity regarding content taught. Preclinical curricular redesigns must innovate and implement best practices for ensuring sound delivery of ethics content in future curricula. Additional large-scale research is necessary to determine said best practices.

Novel gas exposure system for the controlled exposure of plants to gaseous hydrogen fluoride.

Plants can serve as sensitive bioindicators of the presence of contaminant vapors in the atmosphere. This work describes a novel laboratory-based gas exposure system capable of calibrating plants as bioindicators for the detection and delineation of the atmospheric contaminant hydrogen fluoride (HF) as a preparatory step for monitoring release emissions. To evaluate changes in plant phenotype and stress-induced physiological effects attributed to HF alone, the gas exposure chamber must have additional controls to simulate otherwise optimal plant growth conditions including variables such as light intensity, photoperiod, temperature, and irrigation. The exposure system was designed to maintain constant growth conditions during a series of independent experiments that varied between optimal (control) and stressful (HF exposure) conditions. The system was also designed to ensure the safe handling and application of HF. An initial system calibration introduced HF gas into the exposure chamber and monitored HF concentrations by cavity ring-down spectroscopy for a 48-h period. Stable concentrations inside the exposure chamber were observed after approximately 15 h, and losses of HF to the system ranged from 88 to 91%. A model plant species (Festuca arundinacea) was then exposed to HF for 48 h. Visual phenotype stress-induced responses aligned with symptoms reported in the literature for fluoride exposure (tip dieback and discoloration along the dieback transition margin). Fluoride concentrations in exposed tissues compared to control tissues confirmed enhanced fluoride uptake due to HF exposure. The system described herein can be applied to other reactive atmospheric pollutants of interest in support of bioindicator research.

Colloidal Nanocrystal Gels from Thermodynamic Principles.

Gels assembled from solvent-dispersed nanocrystals are of interest for functional materials because they promise the opportunity to retain distinctive properties of individual nanocrystals combined with tunable, structure-dependent collective behavior. By incorporating stimuli-responsive components, these materials could also be dynamically reconfigured between structurally distinct states. However, nanocrystal gels have so far been formed mostly through irreversible aggregation, which has limited the realization of these possibilities. Meanwhile, gelation strategies for larger colloidal microparticles have been developed using reversible physical or chemical interactions. These approaches have enabled the experimental navigation of theoretically predicted phase diagrams, helping to establish an understanding of how thermodynamic behavior can guide gel formation in these materials. However, the translation of these principles to the nanoscale poses both practical and fundamental challenges. The molecules guiding assembly can no longer be safely assumed to be vanishingly small compared to the particles nor large compared to the solvent.In this Account, we discuss recent progress toward the assembly of tunable nanocrystal gels using two strategies guided by equilibrium considerations: (1) reversible chemical bonding between functionalized nanocrystals and difunctional linker molecules and (2) nonspecific, polymer-induced depletion attractions. The effective nanocrystal attractions, mediated in both approaches by a secondary molecule, compete against stabilizing repulsions to promote reversible assembly. The structure and properties of the nanocrystal gels are controlled microscopically by the design of the secondary molecule and macroscopically by its concentration. This mode of control is compelling because it largely decouples nanocrystal synthesis and functionalization from the design of interactions that drive assembly. Statistical thermodynamic theory and computer simulation have been applied to simple models that describe the bonding motifs in these assembling systems, furnish predictions for conditions under which gelation is likely to occur, and suggest strategies for tuning and disassembling the gel networks. Insights from these models have guided experimental realizations of reversible gels with optical properties in the infrared range that are sensitive to the gel structure. This process avoids time-consuming and costly trial-and-error experimental investigations to accelerate the development of nanocrystal gel assemblies.These advances highlight the need to better understand interactions between nanocrystals, how interactions give rise to gel structure, and properties that emerge. Such an understanding could suggest new approaches for creating stimuli-responsive and dissipative assembled materials whose properties are tunable on demand through directed reconfiguration of the underlying gel microstructure. It may also make nanocrystal gels amenable to computationally guided design using inverse methods to rapidly optimize experimental parameters for targeted functionalities.

Fatty Acid Composition of Proximal Femur Bone Marrow Adipose Tissue in Subjects With Systemic Lupus Erythematous Using 3 T Magnetic Resonance Spectroscopy.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied. PURPOSE: To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients. STUDY TYPE: Prospective. SUBJECTS: A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls. FIELD STRENGTH/SEQUENCE: Stimulated echo acquisition mode (STEAM) sequence at 3 T. ASSESSMENT: MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed. STATISTICAL TESTS: Intergroup comparisons were carried out using ANOVA. A P value < 0.05 was considered statistically significant. RESULTS: SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05). DATA CONCLUSION: SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Extrusion of pilosebaceous units into blisters of patients affected by a new variant of endemic pemphigus in El Bagre, Colombia, South America.

BACKGROUND: A new variant of endemic pemphigus foliaceus is present in El Bagre, Colombia, and surrounding municipalities (El Bagre-EPF) that affects the skin and in some presentations affects other organs with autoantibodies directed against cell junctions. METHODS: We studied 200 El Bagre-EPF patient perilesional skin biopsies, as well as 200 skin biopsies from normal controls in the endemic area. RESULTS: We observed blister extrusions of sebaceous glands or entire pilosebaceous units via the isthmus in 23% of the patients and not in the controls. CONCLUSIONS: The extrusion of hair follicular unit contents is consistent with our previous pathologic findings of autoreactivity to these units, and their observed clinical decrease in patients affected by El Bagre-EPF.

Dynamic density functional theory for drying colloidal suspensions: Comparison of hard-sphere free-energy functionals.

Dynamic density functional theory (DDFT) is a promising approach for predicting the structural evolution of a drying suspension containing one or more types of colloidal particles. The assumed free-energy functional is a key component of DDFT that dictates the thermodynamics of the model and, in turn, the density flux due to a concentration gradient. In this work, we compare several commonly used free-energy functionals for drying hard-sphere suspensions, including local-density approximations based on the ideal-gas, virial, and Boublík-Mansoori-Carnahan-Starling-Leland (BMCSL) equations of state as well as a weighted-density approximation based on fundamental measure theory (FMT). To determine the accuracy of each functional, we model one- and two-component hard-sphere suspensions in a drying film with varied initial heights and compositions, and we compare the DDFT-predicted volume fraction profiles to particle-based Brownian dynamics (BD) simulations. FMT accurately predicts the structure of the one-component suspensions even at high concentrations and when significant density gradients develop, but the virial and BMCSL equations of state provide reasonable approximations for smaller concentrations at a reduced computational cost. In the two-component suspensions, FMT and BMCSL are similar to each other but modestly overpredict the extent of stratification by size compared to BD simulations. This work provides helpful guidance for selecting thermodynamic models for soft materials in nonequilibrium processes, such as solvent drying, solvent freezing, and sedimentation.

Diffusion and sedimentation in colloidal suspensions using multiparticle collision dynamics with a discrete particle model.

We study self-diffusion and sedimentation in colloidal suspensions of nearly hard spheres using the multiparticle collision dynamics simulation method for the solvent with a discrete mesh model for the colloidal particles (MD+MPCD). We cover colloid volume fractions from 0.01 to 0.40 and compare the MD+MPCD simulations to experimental data and Brownian dynamics simulations with free-draining hydrodynamics (BD) as well as pairwise far-field hydrodynamics described using the Rotne-Prager-Yamakawa mobility tensor (BD+RPY). The dynamics in MD+MPCD suggest that the colloidal particles are only partially coupled to the solvent at short times. However, the long-time self-diffusion coefficient in MD+MPCD is comparable to that in experiments, and the sedimentation coefficient in MD+MPCD is in good agreement with that in experiments and BD+RPY, suggesting that MD+MPCD gives a reasonable description of hydrodynamic interactions in colloidal suspensions. The discrete-particle MD+MPCD approach is convenient and readily extended to more complex shapes, and we determine the long-time self-diffusion coefficient in suspensions of nearly hard cubes to demonstrate its generality.

Lysines in the lyase active site of DNA polymerase ß destabilize nonspecific DNA binding, facilitating searching and DNA gap recognition.

DNA polymerase (pol) ß catalyzes two reactions at DNA gaps generated during base excision repair, gap-filling DNA synthesis and lyase-dependent 5´-end deoxyribose phosphate removal. The lyase domain of pol ß has been proposed to function in DNA gap recognition and to facilitate DNA scanning during substrate search. However, the mechanisms and molecular interactions used by pol ß for substrate search and recognition are not clear. To provide insight into this process, a comparison was made of the DNA binding affinities of WT pol ß, pol λ, and pol µ, and several variants of pol ß, for 1-nt-gap-containing and undamaged DNA. Surprisingly, this analysis revealed that mutation of three lysine residues in the lyase active site of pol ß, 35, 68, and 72, to alanine (pol ß KΔ3A) increased the binding affinity for nonspecific DNA ∼11-fold compared with that of the WT. WT pol µ, lacking homologous lysines, displayed nonspecific DNA binding behavior similar to that of pol ß KΔ3A, in line with previous data demonstrating both enzymes were deficient in processive searching. In fluorescent microscopy experiments using mouse fibroblasts deficient in PARP-1, the ability of pol ß KΔ3A to localize to sites of laser-induced DNA damage was strongly decreased compared with that of WT pol ß. These data suggest that the three lysines in the lyase active site destabilize pol ß when bound to DNA nonspecifically, promoting DNA scanning and providing binding specificity for gapped DNA.

DNA polymerase ß nucleotide-stabilized template misalignment fidelity depends on local sequence context.

DNA polymerase ß has two DNA-binding domains that interact with the opposite sides of short DNA gaps. These domains contribute two activities that modify the 5' and 3' margins of gapped DNA during base excision repair. DNA gaps greater than 1 nucleotide (nt) pose an architectural and logistical problem for the two domains to interact with their respective DNA termini. Here, crystallographic and kinetic analyses of 2-nt gap-filling DNA synthesis revealed that the fidelity of DNA synthesis depends on local sequence context. This was due to template dynamics that altered which of the two template nucleotides in the gap served as the coding nucleotide. We observed that, when a purine nucleotide was in the first coding position, DNA synthesis fidelity was similar to that observed with a 1-nt gap. However, when the initial templating nucleotide was a pyrimidine, fidelity was decreased. If the first templating nucleotide was a cytidine, there was a significantly higher probability that the downstream template nucleotide coded for the incoming nucleotide. This dNTP-stabilized misalignment reduced base substitution and frameshift deletion fidelities. A crystal structure of a binary DNA product complex revealed that the cytidine in the first templating site was in an extrahelical position, permitting the downstream template nucleotide to occupy the coding position. These results indicate that DNA polymerase ß can induce a strain in the DNA that modulates the position of the coding nucleotide and thereby impacts the identity of the incoming nucleotide. Our findings demonstrate that "correct" DNA synthesis can result in errors when template dynamics induce coding ambiguity.

Wertheim's thermodynamic perturbation theory with double-bond association and its application to colloid-linker mixtures.

We extend Wertheim's thermodynamic perturbation theory to derive the association free energy of a multicomponent mixture for which double bonds can form between any two pairs of the molecules' arbitrary number of bonding sites. This generalization reduces in limiting cases to prior theories that restrict double bonding to at most one pair of sites per molecule. We apply the new theory to an associating mixture of colloidal particles ("colloids") and flexible chain molecules ("linkers"). The linkers have two functional end groups, each of which may bond to one of several sites on the colloids. Due to their flexibility, a significant fraction of linkers can "loop" with both ends bonding to sites on the same colloid instead of bridging sites on different colloids. We use the theory to show that the fraction of linkers in loops depends sensitively on the linker end-to-end distance relative to the colloid bonding-site distance, which suggests strategies for mitigating the loop formation that may otherwise hinder linker-mediated colloidal assembly.

Effects of linker flexibility on phase behavior and structure of linked colloidal gels.

Colloidal nanocrystal gels can be assembled using a difunctional "linker" molecule to mediate bonding between nanocrystals. The conditions for gelation and the structure of the gel are controlled macroscopically by the linker concentration and microscopically by the linker's molecular characteristics. Here, we demonstrate using a toy model for a colloid-linker mixture that linker flexibility plays a key role in determining both phase behavior and the structure of the mixture. We fix the linker length and systematically vary its bending stiffness to span the flexible, semiflexible, and rigid regimes. At fixed linker concentration, flexible-linker and rigid-linker mixtures phase separate at low colloid volume fractions, in agreement with predictions of first-order thermodynamic perturbation theory, but the semiflexible-linker mixtures do not. We correlate and attribute this qualitatively different behavior to undesirable "loop" linking motifs that are predicted to be more prevalent for linkers with end-to-end distances commensurate with the locations of chemical bonding sites on the colloids. Linker flexibility also influences the spacing between linked colloids, suggesting strategies to design gels with desired phase behavior, structure, and, by extension, structure-dependent properties.

Universal Gelation of Metal Oxide Nanocrystals via Depletion Attractions.

Nanocrystal gelation provides a powerful framework to translate nanoscale properties into bulk materials and to engineer emergent properties through the assembled microstructure. However, many established gelation strategies rely on chemical reactions and specific interactions, e.g., stabilizing ligands or ions on the nanocrystals' surfaces, and are therefore not easily transferable. Here, we report a general gelation strategy via nonspecific and purely entropic depletion attractions applied to three types of metal oxide nanocrystals. The gelation thresholds of two compositionally distinct spherical nanocrystals agree quantitatively, demonstrating the adaptability of the approach for different chemistries. Consistent with theoretical phase behavior predictions, nanocrystal cubes form gels at a lower polymer concentration than nanocrystal spheres, allowing shape to serve as a handle to control gelation. These results suggest that the fundamental underpinnings of depletion-driven assembly, traditionally associated with larger colloidal particles, are also applicable at the nanoscale.

Ribosome Fate during Decoding of UGA-Sec Codons.

Decoding of genetic information into polypeptides occurs during translation, generally following the codon assignment rules of the organism's genetic code. However, recoding signals in certain mRNAs can overwrite the normal rules of translation. An exquisite example of this occurs during translation of selenoprotein mRNAs, wherein UGA codons are reassigned to encode for the 21st proteogenic amino acid, selenocysteine. In this review, we will examine what is known about the mechanisms of UGA recoding and discuss the fate of ribosomes that fail to incorporate selenocysteine.

Molecular basis for the faithful replication of 5-methylcytosine and its oxidized forms by DNA polymerase ß.

DNA methylation is an epigenetic mark that regulates gene expression in mammals. One method of methylation removal is through ten-eleven translocation-catalyzed oxidation and the base excision repair pathway. The iterative oxidation of 5-methylcytosine catalyzed by ten-eleven translocation enzymes produces three oxidized forms of cytosine: 5-hydroxmethylcytosine, 5-formylcytosine, and 5-carboxycytosine. The effect these modifications have on the efficiency and fidelity of the base excision repair pathway during the repair of opposing base damage, and in particular DNA polymerization, remains to be elucidated. Using kinetic assays, we show that the catalytic efficiency for the incorporation of dGTP catalyzed by human DNA polymerase ß is not affected when 5-methylcytosine, 5-hydroxmethylcytosine, and 5-formylcytosine are in the DNA template. In contrast, the catalytic efficiency of dGTP insertion decreases ∼20-fold when 5-carboxycytosine is in the templating position, as compared with unmodified cytosine. However, DNA polymerase fidelity is unaltered when these modifications are in the templating position. Structural analysis reveals that the methyl, hydroxymethyl, and formyl modifications are easily accommodated within the polymerase active site. However, to accommodate the carboxyl modification, the phosphate backbone on the templating nucleotide shifts ∼2.5 Å to avoid a potential steric/repulsive clash. This altered conformation is stabilized by lysine 280, which makes a direct interaction with the carboxyl modification and the phosphate backbone of the templating strand. This work provides the molecular basis for the accommodation of epigenetic base modifications in a polymerase active site and suggests that these modifications are not mutagenically copied during base excision repair.