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In response to oxidative damage, base excision repair (BER) enzymes perturb the structural equilibrium of the VEGF promoter between B-form and G4 DNA conformations, resulting in epigenetic-like modifications of gene expression. However, the mechanistic details remain enigmatic, including the activity and coordination of BER enzymes on the damaged G4 promoter. To address this, we investigated the ability of each BER factor to conduct its repair activity on VEGF promoter G4 DNA substrates by employing pre-steady-state kinetics assays and in vitro coupled BER assays. OGG1 was able to initiate BER on double-stranded VEGF promoter G4 DNA substrates. Moreover, pre-steady-state kinetics revealed that compared to B-form DNA, APE1 repair activity on the G4 was decreased ~two-fold and is the result of slower product release as opposed to inefficient strand cleavage. Interestingly, Pol ß performs multiple insertions on G4 substrates via strand displacement DNA synthesis in contrast to a single insertion on B-form DNA. The multiple insertions inhibit ligation of the Pol ß products, and hence BER is not completed on the VEGF G4 promoter substrates through canonical short-patch BER. Instead, repair requires the long-patch BER flap-endonuclease activity of FEN1 in response to the multiple insertions by Pol ß prior to ligation. Because the BER proteins and their repair activities are a key part of the VEGF transcriptional enhancement in response to oxidative DNA damage of the G4 VEGF promoter, the new insights reported here on BER activity in the context of this promoter are relevant toward understanding the mechanism of transcriptional regulation.

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Steric exclusion is a key element of enzyme substrate specificity, including in polymerases. Such substrate specificity restricts the enzymatic synthesis of 2'-modified nucleic acids, which are of interest in nucleic-acid-based drug development. Here we describe the discovery of a two-residue, nascent-strand, steric control 'gate' in an archaeal DNA polymerase. We show that engineering of the gate to reduce steric bulk in the context of a previously described RNA polymerase activity unlocks the synthesis of 2'-modified RNA oligomers, specifically the efficient synthesis of both defined and random-sequence 2'-O-methyl-RNA (2'OMe-RNA) and 2'-O-(2-methoxyethyl)-RNA (MOE-RNA) oligomers up to 750 nt. This enabled the discovery of RNA endonuclease catalysts entirely composed of 2'OMe-RNA (2'OMezymes) for the allele-specific cleavage of oncogenic KRAS (G12D) and ß-catenin CTNNB1 (S33Y) mRNAs, and the elaboration of mixed 2'OMe-/MOE-RNA aptamers with high affinity for vascular endothelial growth factor. Our results open up these 2'-modified RNAs-used in several approved nucleic acid therapeutics-for enzymatic synthesis and a wider exploration in directed evolution and nanotechnology.

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ADP-ribosylation (ADPRylation) is a reversible posttranslational modification resulting in the covalent attachment of ADP-ribose (ADPR) moieties on substrate proteins. Naturally occurring protein motifs and domains, including WWEs, PBZs (PAR binding zinc fingers), and macrodomains, act as "readers" for protein-linked ADPR. Although recombinant, antibody-like ADPR detection reagents containing these readers have facilitated the detection of ADPR, they are limited in their ability to capture the dynamic nature of ADPRylation. Herein, we describe the preparation and use of poly(ADP-ribose) (PAR) Trackers (PAR-Ts)-optimized dimerization-dependent or split-protein reassembly PAR sensors containing a naturally occurring PAR binding domain fused to both halves of dimerization-dependent GFP (ddGFP) or split nano luciferase (NanoLuc), respectively. We also describe how these tools can be used for the detection and quantification of PAR levels in biochemical assays with extracts and in living cells. These protocols will allow users to explore the broad utility of PAR-Ts for detecting PAR in various experimental and biological systems.

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In the midst of the COVID - 19 pandemic, a multidisciplinary team implemented evidence-based strategies to eliminate catheter associated urinary tract infections (CAUTI), as defined by the National Healthcare Safety Network (NHSN) surveillance definition for those units included in the NHSN standardized infection ratio. The team evaluated indwelling urinary catheters daily for indication, implemented a urinary catheter order set, established a urinary catheter insertion checklist, and promoted use of external urinary diversion devices. The facility NHSN standardized infection ratio for CAUTI was 0.37 in 2019, 0.23 in 2020, and 0.00 in 2021. A collaborative approach decreasing hospital acquired infections may be effective even in a climate of increased acuity, increased length of stay, and staffing challenges.

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CONTEXT: The COVID-19 pandemic increased the provision of contraception through telemedicine. This qualitative study describes provider perceptions of how telemedicine provision of contraception has impacted patient care. METHODS: We interviewed 40 obstetrics-gynecology and family medicine physicians, midwives, nurse practitioners, and support staff providing contraception via telemedicine in practices across Illinois, including Planned Parenthood of Illinois (PPIL) health centers. We analyzed interview content to identify themes around the perceived impact of telemedicine implementation on contraception access, contraceptive counseling, patient privacy, and provision of long-acting reversible contraception (LARC). RESULTS: Participants perceived that telemedicine implementation improved care by increasing contraception access, increasing focus on counseling while reducing bias, and allowing easier method switching. Participants thought disparities in telemedicine usage and limitations to the technological interface presented barriers to patient care. Participants' perceptions of how telemedicine implementation impacts patient privacy and LARC provision were mixed. Some participants found telemedicine implementation enhanced privacy, while others felt unable to ensure privacy in a virtual space. Participants found telemedicine modalities useful for counseling patients considering methods of LARC, but they sometimes presented an unnecessary extra step for those sure about receiving one at a practice offering same day insertion. CONCLUSION: Providers felt telemedicine provision of contraception positively impacted patient care. Improvements to counseling and easier access to method switching suggest that telemedicine implementation may help reduce contraceptive coercion. Our findings highlight the need to integrate LARC care with telemedicine workflows, improve patient privacy protections, and promote equitable access to all telemedicine modalities.

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Objective: To solicit Illinois staff and clinician perspectives on rapid implementation of telehealth for contraceptive counseling and recommendations to improve and sustain it in the long term. Study design: Researchers recruited and interviewed clinicians (n = 20) in primary care and obstetrics/gynecology clinics across 13 health care systems in Illinois, as well as clinicians (n = 11), leadership (n = 6) and staff (n = 7) from Planned Parenthood of Illinois clinics. Guided by the Consolidated Framework for Implementation Research, we coded and analyzed interview transcripts in Dedoose with a focus on themes regarding steps to improve quality and sustainability of telehealth. Results: Participants expressed generally positive attitudes towards telehealth, noting that it increased access to care and time for patient education. Still, many highlighted areas of implementation that needed improvement. Clinic operations were complicated by gaps in telehealth training and the logistical needs of balancing telehealth and in-person appointments. Clinics had difficulty ensuring patient awareness of telehealth as an option for care, in addition to deficiencies with the telehealth technology itself. Finally, innovative resources for telehealth patients, while existent, have not been evenly offered across clinics. This includes the use of self-injection birth control, as well as providing medical equipment such as blood pressure cuffs in community settings. Some themes reflect issues specific to contraceptive counseling while others reflect issues with telehealth implementation in general, including confusion about reimbursement. Conclusion: Illinois contraceptive care providers and staff wish to sustain telehealth for the long term, while also recommending specific improvements to patient communications, clinic operations, and access to supportive resources. Implications: Our study highlights considerations for clinics to optimize implementation of telehealth services for contraceptive care. Providers described the value of clear workflows to balance in-person and telehealth visits, streamlined communications platforms, targeted patient outreach, training on providing virtual contraceptive care, and creative approaches to ensuring patient access to resources.

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Reactive oxygen species attack the structure of DNA, thus altering its base-pairing properties. Consequently, oxidative stress-associated DNA lesions are a major source of the mutation load that gives rise to cancer and other diseases. Base excision repair (BER) is the pathway primarily tasked with repairing DNA base damage, with apurinic/apyrimidinic endonuclease (APE1) having both AP-endonuclease and 3' to 5' exonuclease (exo) DNA cleavage functions. The lesion 8-oxo-7,8-dihydroguanine (8-oxoG) can enter the genome as either a product of direct damage to the DNA, or through polymerase insertion at the 3'-end of a DNA strand during replication or repair. Importantly, 3'-8-oxoG impairs the ligation step of BER and therefore must be removed by the exo activity of a surrogate enzyme to prevent double stranded breaks and cell death. In the present study, we use X-ray crystallography to characterize the exo activity of APE1 on 3'-8-oxoG substrates. These structures support a unified APE1 exo mechanism that differs from its more canonical AP-endonuclease activity. In addition, through complementation of the structural data with enzyme kinetics and binding studies employing both wild-type and rationally designed APE1 mutants, we were able to identify and characterize unique protein: DNA contacts that specifically mediate 8-oxoG removal by APE1.

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OBJECTIVE: To determine the proportion of complete abortion without surgical intervention for patients who chose medication abortion with vaginal compared to buccal misoprostol following oral mifepristone through 70 days of gestation. METHODS: We performed a retrospective cohort study. We reviewed charts via electronic medical record data abstraction of patients receiving medication abortion with mifepristone and buccal or vaginal misoprostol between September 1, 2017 and August 1, 2019. Primary outcome was complete abortion without surgical intervention for any indication. Secondary outcomes were ongoing pregnancy and uterine aspiration for indications other than ongoing pregnancy. RESULTS: There were 14,504 encounters included in the data set. Of the 4814 patients who took vaginal misoprostol and the 4011 patients who took buccal misoprostol for whom follow up data is available, 4640 (96.4%) and 3917 (97.7%) had a complete abortion without surgical intervention, respectively (p = 0.002). At <64 days of gestation, complete abortion was 96.6% for vaginal administration compared to 98.0% for buccal (p = 0.001). At 64 to 70 days of gestation, complete abortion was 92.7% for vaginal administration compared to 93.2% for buccal (p = 0.08). Of the 1128 patients who took vaginal misoprostol at less than 6 hours after mifepristone, 95.3% experienced a complete abortion. CONCLUSION: Buccal administration of misoprostol is associated with a higher proportion of complete abortion before 64 days of gestation compared to vaginal misoprostol. Clinically, vaginal misoprostol is an effective route of administration through 70 days of gestation. IMPLICATIONS: Medication abortion with vaginal misoprostol is effective when administered through 70 days of gestation and with shorter intervals between mifepristone and misoprostol. Prospective research to better estimate effectiveness is warranted. Expanding medication abortion options promotes patient autonomy amid increasing restrictions and bans on abortion.

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ADP-ribosylation (ADPRylation) is a reversible post-translation modification resulting in the covalent attachment of ADP-ribose (ADPR) moieties on substrate proteins. Naturally occurring protein motifs and domains, including WWEs, PBZs, and macrodomains, act as 'readers' for protein-linked ADPR. Although recombinant, antibody-like ADPR detection reagents containing these readers have facilitated the detection of ADPR, they are limited in their ability to capture the dynamic nature of ADPRylation. Herein, we describe and characterize a set of poly(ADP-ribose) (PAR) Trackers (PAR-Ts)-optimized dimerization-dependent or split-protein reassembly PAR sensors in which a naturally occurring PAR binding domain, WWE, was fused to both halves of dimerization-dependent GFP (ddGFP) or split Nano Luciferase (NanoLuc), respectively. We demonstrate that these new tools allow the detection and quantification of PAR levels in extracts, living cells, and living tissues with greater sensitivity, as well as temporal and spatial precision. Importantly, these sensors detect changes in cellular ADPR levels in response to physiological cues (e.g., hormone-dependent induction of adipogenesis without DNA damage), as well as xenograft tumor tissues in living mice. Our results indicate that PAR Trackers have broad utility for detecting ADPR in many different experimental and biological systems.

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Single-molecule total internal reflection fluorescence (TIRF) microscopy allows for the real-time visualization of macromolecular dynamics and complex assembly. Prism-based TIRF microscopes (prismTIRF) are relatively simple to operate and can be easily modulated to fit the needs of a wide variety of experimental applications. While building a prismTIRF microscope without expert assistance can pose a significant challenge, the components needed to build a prismTIRF microscope are relatively affordable and, with some guidance, the assembly can be completed by a determined novice. Here, we provide an easy-to-follow guide for the design, assembly, and operation of a three-color prismTIRF microscope which can be utilized for the study of macromolecular complexes, including the multi-component protein-DNA complexes responsible for DNA repair, replication, and transcription. Our hope is that this article can assist laboratories that aspire to implement single-molecule TIRF techniques, and consequently expand the application of this technology.

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Although economies of scale are relatively well studied in the arts, economies of scope have received less attention. Yet recent trends toward freelancing and technological connectivity make scope economies especially timely in addressing structural challenges to artist-led incubators. This paper offers a conceptual framework for cooperative strategies that employ economies of scope both in the economic sense of joint production and in the financial sense of risk pooling. This framework distinguishes franchise, federation, and resource-sharing organizational structures as developed through case studies of two US-based organizations: ArtBuilt and REC (Resources for Every Creator), placed in a larger context of cooperative organizational strategy in the USA and Europe. The proposed strategies of cooperative networks (quasi-franchises, federations, or resource-sharing networks) also draw on a literature of spatial agglomeration in creative industries. The framework leads to more speculative ideas of "balance-sheet philanthropy" through credit backstopping by foundations, and of novel investment trusts that can be piloted across a range organizations including foundations, grant-makers, artist residency programs, and even for-profit companies engaged in reinsurance. The paper contributes managerial tools and strategies for the creative engagement of capacity building in arts organizations.

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DNA polymerase ß (Pol ß) is an essential mammalian enzyme involved in the repair of DNA damage during the base excision repair (BER) pathway. In hopes of faithfully restoring the coding potential to damaged DNA during BER, Pol ß first uses a lyase activity to remove the 5'-deoxyribose phosphate moiety from a nicked BER intermediate, followed by a DNA synthesis activity to insert a nucleotide triphosphate into the resultant 1-nucleotide gapped DNA substrate. This DNA synthesis activity of Pol ß has served as a model to characterize the molecular steps of the nucleotidyl transferase mechanism used by mammalian DNA polymerases during DNA synthesis. This is in part because Pol ß has been extremely amenable to X-ray crystallography, with the first crystal structure of apoenzyme rat Pol ß published in 1994 by Dr. Samuel Wilson and colleagues. Since this first structure, the Wilson lab and colleagues have published an astounding 267 structures of Pol ß that represent different liganded states, conformations, variants, and reaction intermediates. While many labs have made significant contributions to our understanding of Pol ß, the focus of this article is on the long history of the contributions from the Wilson lab. We have chosen to highlight select seminal Pol ß structures with emphasis on the overarching contributions each structure has made to the field.

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Base excision repair (BER) maintains genomic stability through the repair of DNA damage. Within BER, AP-endonuclease 1 (APE1) is a multifunctional enzyme that processes DNA intermediates through its backbone cleavage activity. To accomplish these repair activities, APE1 must recognize and accommodate several diverse DNA substrates. This is hypothesized to occur through a DNA sculpting mechanism where structural adjustments of the DNA substrate are imposed by the protein; however, how APE1 uniquely sculpts each substrate within a single rigid active site remains unclear. Here, we utilize structural and biochemical approaches to probe the DNA sculpting mechanism of APE1, specifically by characterizing a protein loop that intercalates the minor groove of the DNA (termed the intercalating loop). Pre-steady-state kinetics reveal a tyrosine residue within the intercalating loop (Y269) that is critical for AP-endonuclease activity. Using X-ray crystallography and molecular dynamics simulations, we determined the Y269 residue acts to anchor the intercalating loop on abasic DNA. Atomic force microscopy reveals the Y269 residue is required for proper DNA bending by APE1, providing evidence for the importance of this mechanism. We conclude that this previously unappreciated tyrosine residue is key to anchoring the intercalating loop and stabilizing the DNA in the APE1 active site.

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Under conditions of oxidative stress, reactive oxygen species (ROS) continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. When the nucleobase structure is altered, its base-pairing properties may also be altered, promoting mutations. Consequently, oxidative DNA damage is a major source of the mutation load that gives rise to numerous human maladies, including cancer. Base excision repair (BER) is the primary pathway tasked with removing and replacing mutagenic DNA base damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme with AP-endonuclease and 3' to 5' exonuclease functions during BER, and therefore is key to maintenance of genome stability. Polymorphisms, or SNPs, in the gene encoding APE1 (APEX1) have been identified among specific human populations and result in variants of APE1 with modified function. These defects in APE1 potentially result in impaired DNA repair capabilities and consequently an increased risk of disease for individuals within these populations. In the present study, we determined the X-ray crystal structures of three prevalent disease-associated APE1 SNPs (D148E, L104R, and R237C). Each APE1 SNP results in unique localized changes in protein structure, including protein dynamics and DNA binding contacts. Combined with comprehensive biochemical characterization, including pre-steady-state kinetic and DNA binding analyses, variant APE1:DNA complex structures with both AP-endonuclease and exonuclease substrates were analyzed to elucidate how these SNPs might perturb the two major repair functions employed by APE1 during BER.

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INTRODUCTION: Although pre-exposure prophylaxis (PrEP) is recommended by the Centers for Disease Control and Prevention, there is a practice gap in treatment at Planned Parenthood of Illinois. This project evaluated a clinical practice alert and evidence-based patient education script to determine if the intervention increased the number of appointments to discuss or initiate PrEP in patients at risk for acquiring HIV. METHOD: From October to December 2018, a clinical practice alert and evidence-based patient education script were implemented at one Planned Parenthood of Illinois health center. Aggregate data collected included the number of times the clinical alert was generated, the number of times staff read the script, the number of scheduled appointments to discuss PrEP, and the number of times PrEP was prescribed. Qualitative data were collected from clinic staff to further evaluate the intervention. RESULTS: Eleven patients triggered the alert and staff read the education script nine times during the 8-week implementation period. One patient scheduled an appointment to discuss PrEP; no new prescriptions were initiated. One identified patient scheduled an appointment with a provider to initiate PrEP on a date after the implementation period ended. Staff found the alert and script helpful to initiate conversations with patients. CONCLUSIONS: This intervention established a system for clinic staff to identify patients at risk for acquiring HIV in order to discuss accurate, evidence-based PrEP information. Findings are limited to this particular setting due to a small sample size, which eliminated the possibility for statistical analysis.

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DNA is susceptible to a range of chemical modifications, with one of the most frequent lesions being apurinic/apyrimidinic (AP) sites. AP sites arise due to damage-induced (e.g. alkylation) or spontaneous hydrolysis of the N-glycosidic bond that links the base to the sugar moiety of the phosphodiester backbone, or through the enzymatic activity of DNA glycosylases, which release inappropriate bases as part of the base excision repair (BER) response. Unrepaired AP sites, which lack instructional information, have the potential to cause mutagenesis or to arrest progressing DNA or RNA polymerases, potentially causing outcomes such as cellular transformation, senescence or death. The predominant enzyme in humans responsible for repairing AP lesions is AP endonuclease 1 (APE1). Besides being a powerful AP endonuclease, APE1 possesses additional DNA repair activities, such as 3'-5' exonuclease, 3'-phophodiesterase and nucleotide incision repair. In addition, APE1 has been shown to stimulate the DNA-binding activity of a number of transcription factors through its 'REF1' function, thereby regulating gene expression. In this article, we review the structural and biochemical features of this multifunctional protein, while reporting on new structures of the APE1 variants Cys65Ala and Lys98Ala. Using a functional complementation approach, we also describe the importance of the repair and REF1 activities in promoting cell survival, including the proposed passing-the-baton coordination in BER. Finally, results are presented indicating a critical role for APE1 nuclease activities in resistance to the genotoxins methyl methanesulphonate and bleomycin, supporting biologically important functions as an AP endonuclease and 3'-phosphodiesterase, respectively.

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DNA polymerases are vital for the synthesis of new DNA strands. Since the discovery of DNA polymerase I in Escherichia coli, a diverse library of mammalian DNA polymerases involved in DNA replication, DNA repair, antibody generation, and cell checkpoint signaling has emerged. While the unique functions of these DNA polymerases are differentiated by their association with accessory factors and/or the presence of distinctive catalytic domains, atomic resolution structures of DNA polymerases in complex with their DNA substrates have revealed mechanistic subtleties that contribute to their specialization. In this review, the structure and function of all 15 mammalian DNA polymerases from families B, Y, X, and A will be reviewed and discussed with special emphasis on the insights gleaned from recently published atomic resolution structures.

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Phosphofructokinase from Bacillus stearothermophilus (BsPFK) is a 136 kDa homotetromeric enzyme. Binding of the substrate, fructose 6-phosphate (Fru-6-P), is allosterically regulated by the K-type inhibitor phosphoenolpyruvate (PEP). The allosteric coupling between the substrate and inhibitor is quantified by a standard coupling free energy that defines an equilibrium with the Fru-6-P-bound and PEP-bound complexes on one side and the apo form and ternary complex on the other. Methyl-transverse relaxation-optimized spectroscopy (Me-TROSY) nuclear magnetic resonance was employed to gain structural information about BsPFK in all four states of ligation relevant to the allosteric coupling. BsPFK was uniformly labeled with 15N and 2H and specifically labeled with δ-[13CH3]-isoleucine utilizing an isotopically labeled α-keto acid isoleucine precursor. Me-TROSY experiments were conducted on all four ligation states, and all 30 isoleucines, which are well dispersed throughout each subunit of the enzyme, are well-resolved in chemical shift correlation maps of 13C and 1H. Assignments for 17 isoleucines were determined through three-dimensional HMQC-NOESY experiments with [U-15N,2H];Ileδ1-[13CH3]-BsPFK and complementary HNCA and HNCOCA experiments with [U-2H,15N,13C]-BsPFK. The assignments allowed for the mapping of resonances representing isoleucine residues to a previously determined X-ray crystallography structure. This analysis, performed for all four states of ligation, has allowed specific regions of the enzyme influenced by the binding of allosteric ligands and those involved in the propagation of the allosteric effect to be identified and distinguished from one another.

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OBJECTIVES: We explored how negative stories about long-acting reversible contraception (LARC) - defined as a firsthand negative experience with LARC shared directly with the study participant - were involved in participants' decisions about whether to use LARC following abortion, and how counseling affected the influence of negative LARC stories on contraceptive choices. STUDY DESIGN: We performed a multi-methods study, embedded within a trial examining the impact of a theory-based counseling intervention on LARC uptake post-abortion. Participants completed a baseline survey to determine the influence of negative LARC stories. We subsequently invited respondents who reported having heard negative LARC stories to participate in a semi-structured qualitative interview. We analyzed quantitative data with univariate statistics. We analyzed qualitative data using thematic content analysis. RESULTS: Among the 60 participants, 16 (27%) reported having heard negative LARC stories. Two of the 16 (13%) planned to initiate LARC prior to counseling, compared to 18 of 44 women (41%) who had not heard negative LARC stories (p=0.06). Prior to counseling, 69% of participants with negative LARC stories reported that these stories made them less likely to use LARC. In qualitative interviews with 9 women, we identified several key themes: (1) negative LARC stories deterred LARC use; (2) friends and family were valued informants; (3) potential side effects were important to LARC decision-making; and (4) positive and negative features of the counseling encounter influenced the effect of negative LARC stories. CONCLUSIONS: Negative LARC stories are common among women presenting for abortion at our institution and may influence patient uptake of these methods. Implications This study uses a multi-methods approach to examine the influence of negative stories about long-acting reversible contraception (LARC) on decision-making about LARC. These findings can help providers elicit patients' needs in contraception counseling and generate hypotheses for future counseling research.

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Young African American and Latina women aged 15 to 24 are more likely to adopt short-acting forms of contraception over long-acting reversible contraception. Mobile applications and other forms of digital media may be useful for providing adolescents with information about sexual and reproductive health both inside and outside of the health care setting. The miPlan app was designed in accordance with principles of user experience design, and its content was informed by the theory of planned behavior and the transtheoretical model of behavior change. A university-based design team engaged young African American and Latina women to inform app development and provide input on app design, conducting multiple rounds of usability testing. Researchers then evaluated the acceptability of the miPlan app in family planning clinics among African American and Latina women aged 15 to 24. Participants rated the app highly acceptable, finding it both easy to use and highly informative. We demonstrate that mobile applications designed in conjunction with user populations may be effective at providing health information due to users' ability to identify with them and their accessibility.

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