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Background Nicotine products are believed to be associated with a higher incidence of incisional hernia (IH) recurrence and postoperative complications after IH repair.Methods A retrospective analysis of the Abdominal Core Health Quality Collaborative (ACHQC) database was performed. Outcomes included risk of IH recurrence, 30-day surgical site infection (SSI), and 30-day surgical site occurrence (SSO).Results We included 14,663 patients. Nicotine users who quit within 1 year of surgery had a 26% higher risk of IH recurrence compared to patients who quit more than a year before surgery or never users. Patients who quit using nicotine within 1 year of surgery had a 54% higher odds of SSI compared to former nicotine users who quit more than a year before surgery.Conclusion Former nicotine users with less than 1 year of nicotine use cessation before surgery exhibited worse outcomes than those with more than a year of cessation or no prior use.

Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN’s helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC50= 22 nM, KD= 40 nM, KI= 32 nM), and the most potent compound identified, H3B-968, has inhibitory activity IC50∼ 10 nM. These kinetic properties trend toward other known covalent druglike molecules. Our work provides a new avenue for screening WRN for inhibitors that may be adaptable to different therapeutic modalities such as targeted protein degradation, as well as a proof of concept for the inhibition of WRN helicase activity by covalent molecules.

Background: Well-designed foot and ankle clinical outcomes research requires region-specific subjective outcome measures. Many foot and ankle–specific instruments are now available. Determining which instruments to choose is daunting. We present a patient survey to determine the most relevant questions pertaining to them.Methods: Sixteen foot and ankle–specific outcome instruments were chosen based on popularity, emphasizing valid, reliable, responsive scores. Subjective portions were consolidated and given to 109 patients with osteochondral lesion of the talus (OLT) (39), ankle instability (35), and ankle arthritis (35). Outcome instruments were measured according to 4 criteria: number of questions endorsed by 51%, number with high mean importance, number with low mean importance, and number with the highest-ranking frequency importance product. Instruments were then ranked based on relative score, with the highest scores indicating the instrument was the most useful for that sample.Results: The Foot and Ankle Outcome Score (FAOS) achieved the highest score in all 4 categories for OLT, followed by Foot and Ankle Ability Measure (FAAM) and American Academy of Orthopaedic Surgeons (AAOS) Foot and Ankle Score. The FAOS achieved the highest score in all 4 categories for ankle instability, followed by FAAM and AAOS. For osteoarthritis, the FAOS achieved the highest relative score followed by FAAM and AAOS. The AOF, Ankle Osteoarthritis Score, and AAS are instruments commonly used that had lower relative scores.Conclusion: The FAOS, FAAM, and AAOS Foot and Ankle Score contain several items important to patients with osteochondral lesions of the talus, ankle instability, and ankle osteoarthritis.Level of Evidence: Level II, prospective comparative study.

In this study, Finci et. al. present the cryo-EM structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5), part of the U2 snRNP, bound to E7107 at 3.95 A. The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action.

We present a new open‐source tool for magnetospheric computations, that is modeling of cosmic ray (CR) propagation in the geomagnetosphere, named “Oulu—Open‐source geomagneToSphere prOpagation tool” (OTSO), available on GitHub (https://github.com/NLarsen15/OTSO) and Zenodo (https://doi.org/10.5281/zenodo.7516233). A tool of this nature is required in order to interpret experiments and study phenomena within the CR research field. Within this work, OTSO is applied to the investigation of several ground‐level enhancement events. Here, we demonstrated several applications of OTSO, namely the computation of asymptotic directions of selected CR stations, effective rigidity cut‐off across the globe at various conditions within the design, and general properties, including the magnetospheric models employed. Comparison and validation of OTSO with older widely used tools such as MAGNETOCOSMICS was performed, and good agreement was achieved. An application of OTSO for providing the necessary background for the analysis of two notable ground‐level enhancements is demonstrated and their spectral and angular characteristics are presented. Cosmic rays (CRs) are hazardous to humans and are constantly bombarding the Earth. Some impacts of these CRs are increased radiation doses for aviation crew and their passengers and damaging spacecraft. Luckily the Earth’s magnetic field deflects most of these harmful particles away, mitigating most of the potential damage. The interaction between the Earth’s magnetic field and incoming CRs is complex but needs to be properly understood and accurately modeled for the study of specific phenomena relevant to the CR research field. This work presents a new open‐source tool for magnetospheric computations named the “Oulu—Open‐source geomagneToSphere prOpagation tool” (OTSO). This tool can compute the trajectory of CRs within the Earth’s magnetic field under various magnetospheric conditions. Within this work, comparison and validation of OTSO with an older widely used tool (MAGNETOCOSMICS) was performed with a good agreement observed. OTSO was also used to successfully aid in the analysis of two ground‐level enhancement events. OTSO demonstrates its usefulness as a tool to aid in the study of CRs in the magnetosphere, and its open‐source nature allows for further development by the research community. We present a new open‐source tool for geomagnetospheric computations, named “Oulu—Open‐source geomagneToSphere prOpagation tool” (OTSO)The new tool shows a good agreement with other tools that preform a similar function (e.g., MAGNETOCOSMICS)Ground level enhancement (GLE) 66 and 71 were both successfully analyzed using the tool proving that it can preform comprehensive GLE analyses for future studies We present a new open‐source tool for geomagnetospheric computations, named “Oulu—Open‐source geomagneToSphere prOpagation tool” (OTSO) The new tool shows a good agreement with other tools that preform a similar function (e.g., MAGNETOCOSMICS) Ground level enhancement (GLE) 66 and 71 were both successfully analyzed using the tool proving that it can preform comprehensive GLE analyses for future studies

Transforming growth factor-β activated kinase-1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family that regulates several signaling pathways including NF-κB signal transduction and p38 activation. TAK1 deregulation has been implicated in human diseases including cancer and inflammation. Here, we show that, in addition to its kinase activity, TAK1 has intrinsic ATPase activity, that (5Z)-7-Oxozeaenol irreversibly inhibits TAK1, and that sensitivity to (5Z)-7-Oxozeaenol inhibition in hematological cancer cell lines is NRAS mutation status and TAK1 pathway dependent. X-ray crystallographic and mass spectrometric studies showed that (5Z)-7-Oxozeaenol forms a covalent complex with TAK1. Detailed biochemical characterization revealed that (5Z)-7-Oxozeaenol inhibited both the kinase and the ATPase activity of TAK1 following a bi-phase kinetics, consistent with the irreversible inhibition mechanism. In DoHH2 cells, (5Z)-7-Oxozeaenol potently inhibited the p38 phosphorylation driven by TAK1, and the inhibition lasted over 6 h after withdrawal of (5Z)-7-Oxozeaenol. Profiling (5Z)-7-Oxozeaenol in a panel of hematological cancer cells showed that sensitive cell lines tended to carry NRAS mutations and that genes in TAK1 regulated pathways were enriched in sensitive cell lines. Taken together, we have elucidated the molecular mechanism of a TAK1 irreversible inhibitor and laid the foundation for designing next generation TAK1 irreversible inhibitors. The NRAS-TAK1-Wnt signaling network discerned in our study may prove to be useful in patient selection for TAK1 targeted agents in hematological cancers.

There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and confirmed in vivo by assessing its ability to prevent cocaine-induced convulsions and lethality in the rat. The therapeutic efficiency of the enzyme was demonstrated by the increasing dose of cocaine (100-1000 mg/kg, i.p.) required to produce toxic effects after a single intravenous injection of CocE. The enzyme demonstrated rapid kinetics for cocaine degradation in rat and human serum. Two catalytically inactive mutants of CocE (S117A or Y44F) failed to protect rats from the toxic effects of cocaine, confirming the protective effects are due to hydrolytic activity. However, butyrylcholinesterase, an endogenous cocaine-hydrolyzing enzyme, was inactive (1.3-13 mg, i.v.) in this rat toxicity procedure. Furthermore, CocE did not block the lethality of WIN-35065-2 (560 mg/kg, i.p.), a cocaine analog that lacks the benzoyl ester moiety targeted by CocE. This characterization of CocE provides preliminary evidence that the enzyme could serve as a suitable antidote to cocaine toxicity in humans.

There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and confirmed in vivo by assessing its ability to prevent cocaine-induced convulsions and lethality in the rat. The therapeutic efficiency of the enzyme was demonstrated by the increasing dose of cocaine (100-1000 mg/kg, i.p.) required to produce toxic effects after a single intravenous injection of CocE. The enzyme demonstrated rapid kinetics for cocaine degradation in rat and human serum. Two catalytically inactive mutants of CocE (S117A or Y44F) failed to protect rats from the toxic effects of cocaine, confirming the protective effects are due to hydrolytic activity. However, butyrylcholinesterase, an endogenous cocaine-hydrolyzing enzyme, was inactive (1.3-13 mg, i.v.) in this rat toxicity procedure. Furthermore, CocE did not block the lethality of WIN-35065-2 (560 mg/kg, i.p.), a cocaine analog that lacks the benzoyl ester moiety targeted by CocE. This characterization of CocE provides preliminary evidence that the enzyme could serve as a suitable antidote to cocaine toxicity in humans.

Here we report the first structure of a cocaine-degrading enzyme. The bacterial esterase, cocE, hydrolyzes pharmacologically active (−)-cocaine to a nonpsychoactive metabolite with a rate faster than any other reported cocaine esterase (kcat = 7.8 s−1 and KM = 640 nM). Because of the high catalytic proficiency of cocE, it is an attractive candidate for novel protein-based therapies for cocaine overdose. The crystal structure of cocE, solved by multiple anomalous dispersion (MAD) methods, reveals that cocE is a serine esterase composed of three domains: (i) a canonical α/β hydrolase fold (ii) an α-helical domain that caps the active site and (iii) a jelly-roll-like β-domain that interacts extensively with the other two domains. The active site was identified within the interface of all three domains by analysis of the crystal structures of transition state analog adduct and product complexes, which were refined at 1.58 Å and 1.63 Å resolution, respectively. These structural studies suggest that substrate recognition arises partly from interactions between the benzoyl moiety of cocaine and a highly evolved specificity pocket.

Murine antibody 1D4 selectively catalyzes a highly disfavored β-elimination reaction. Crystal structures of unliganded 1D4 and 1D4 in complex with a transition-state analog (TSA) have elucidated a possible general base mode of catalysis. The structures of the unliganded and liganded Fabs were determined to 1.80 and 1.85 A˚ resolution, respectively. The structure of the complex reveals a binding pocket with high shape complementarity to the TSA, which is recruited to coerce the substrate into the sterically demanding, eclipsed conformation that is required for catalysis. A histidine residue and two water molecules are likely involved in the catalysis. The structure supports either a concerted E2 or stepwise E1cB-like mechanism for elimination. Finally, the liganded 1D4 structure shows minor conformational rearrangements in CDR H2, indicative of induced-fit binding of the hapten. 1D4 has pushed the boundaries of antibody-mediated catalysis into the realm of disfavored reactions and, hence, represents an important milestone in the development of this technology.

Murine monoclonal antibody GNC92H2 was elicited by active immunization with a cocaine immunoconjugate and binds free cocaine with excellent specificity and moderate affinity. Improvement of affinity, as well as humanization of GNC92H2, would be advantageous in immunopharmacotherapy for cocaine addiction, and for emergency cases of drug overdose. Toward this end, the crystal structure of an engineered murine-human chimeric Fab of GNC92H2 complexed with cocaine was determined at 2.3 A˚ resolution. Structural analysis reveals a binding pocket with high shape and charge complementarity to the cocaine framework, which explains the specificity for cocaine, as opposed to the pharmacologically inactive cocaine metabolites. Importantly, the structure provides a foundation for mutagenesis to enhance the binding affinity for cocaine and potent cocaine derivatives, such as cocaethylene, and for additional humanization of the antibody.

We use a series of 230-nm wavelength images acquired with the Hubble Space Telescope Wide Field and Planetary Camera 2 to trace the spreading of debris introduced into Jupiter's stratosphere by the impact of Comet Shoemaker–Levy 9. Impact debris was transported rapidly equatorward by stratospheric winds from the impact latitude at −45° to at least −20° during the 3.2-year period covered by the observations. We use the observations to test the formulation of mixing and transport in two-dimensional (latitude–height) models for the jovian stratosphere. Two different models for the transport are considered. In the first model, advection by the residual circulation of Westet al.(1992,Icarus100, 245–259) is taken to be the sole transport mechanism. We find that this circulation advects the debris slowly poleward, in disagreement with the observations. In the second model, horizontal diffusive transport by large-scale quasi-geostrophic eddies is also included. The horizontal eddy diffusion coefficients (Kyy) are derived from a map of annual-average Eliassen–Palm flux divergence produced by Westet al.(1992). Introduction of the derived Kyyinto the dynamical model causes a rapid spreading of the debris in both the equatorward and the poleward directions. We find that the predicted rate of equatorward spreading of the impact debris optical depth is in good agreement with that derived from the observations. We conclude that our derived eddy Kyyprovides a useful first-order description of zonal mean eddy transport at mid-latitudes in the southern hemisphere of Jupiter's stratosphere.

The medial ulnar collateral ligament (MUCL) is the primary stabilizer against valgus stress on the elbow. The anatomy of the 3 bundles of the MUCL has been well studied in adults, but our review of the English literature found no study evaluating the origin of the MUCL in a large group of asymptomatic, skeletally immature elbows as it relates to the medial epicondylar physis.