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In biology, an immense diversity of protein structural and functional motifs originates from only 20 common proteinogenic native amino acids arranged in various sequences. Is it possible to attain the same diversity in electronic materials based on organic macromolecules composed of non-native residues with different characteristics? This publication describes the design, preparation and characterization of non-native aromatic β-amino acid residues, i.e. derivatives of anthranilic acid, for polyamides that can efficiently mediate hole transfer. Chemical derivatization with three types of substituents at two positions of the aromatic ring allows for adjusting the energy levels of the frontier orbitals of the anthranilamide residues over a range of about one electronvolt. Most importantly, the anthranilamide residues possess permanent electric dipoles, adding to the electronic properties of the bioinspired conjugates they compose, making them molecular electrets.

Planewave-corrected methods have proven effective for accurately modeling nuclear magnetic resonance (NMR) parameters in crystalline systems. Recent work extended the application of planewave-corrected calculations beyond the second row, predicting EFG tensor parameters for 35 Cl using a simple molecular correction to projector augmented-wave (PAW) density functional theory (DFT). Here we extend this work using fragment and cluster-based calculations coupled with polarizable continuum (PCM) methods to improve further the accuracy of planewave-corrected 35 Cl EFG tensor calculations. Benchmark data from a test set comprised of 105 individual 35 Cl EFG tensor principal components for chlorine-containing molecular crystals and crystalline chloride salts shows fragment-corrected planewave calculations using the PBE0 hybrid density functional improve the accuracy of predicted EFG tensor components by 30 % relative to traditional planewave calculations. We compare the influence of different geometry optimization methods and density functionals on the accuracy of predicted 35 Cl EFG tensor parameters. Four cases of spectral assignment are presented to demonstrate the utility of improving the accuracy of predicted 35 Cl EFG tensor parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. At the systemic as well as sub-cellular level, human aging has also been associated with diverse lipid alterations, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, we performed comprehensive multi-omics analyses and uncovered a role for a key PUFA biosynthesis gene, ELOVL2 , in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global down-regulation in lymphoid cell markers and expression of genes involved specifically in B cell development. Flow cytometric analyses of immune cell markers confirmed an aging-associated loss of B cell markers that was exacerbated in the bone marrow of Elovl2 mutant mice and unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker of accelerated immune aging. Complementary lipidomic studies extended these findings to reveal select alterations in lipid species in aged and Elovl2 mutant mouse bone marrow samples, suggesting significant changes in the biophysical properties of cellular membranes. Furthermore, single cell RNA-seq analysis of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (<7%) of CD34 + HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B -expressing lymphoid-committed cells, were almost completely absent in CD34 + cells isolated from elderly (>60 years old) bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in down-regulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.

Solid-state nuclear magnetic resonance (NMR) spectroscopy and quantum chemical density functional theory (DFT) calculations are widely used to characterize vanadium centers in biological and pharmaceutically relevant compounds. Several techniques have been recently developed to improve the accuracy of predicted NMR parameters obtained from DFT. Fragment-based and planewave-corrected methods employing hybrid density functionals are particularly effective tools for solid-state applications. A recent benchmark study involving molecular crystal compounds found that fragment-based NMR calculations using hybrid density functionals improve the accuracy of predicted 51 V chemical shieldings by 20% relative to traditional planewave methods. This work extends the previous study, including a careful analysis of 51 V chemical shift anisotropy, electric field gradient calculations, and a more extensive test set. The accuracy of planewave-corrected techniques and recently developed fragment-based methods using electrostatic embedding based on the polarized continuum model (PCM) are found to be highly competitive with previous methods. Planewave-corrected methods achieve a 34% improvement in the errors of predicted 51 V chemical shieldings relative to planewave. Additionally, planewave-corrected and fragment-based calculations were performed using PCM embedding, improving the accuracy of predicted 51 V chemical shielding (CS) tensor principal values by 30% and C q values by 15% relative to traditional planewave methods. The performance of these methods is further examined using a redox-active oxovandium complex and a common 51 V NMR reference compound., (© 2023 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

Water-soluble deep cavitands with cationic functions at the lower rim can selectively bind iodide anions in purely aqueous solution. By pairing this lower rim recognition with an indicator dye that is bound in the host cavity, optical sensing of anions is possible. The selectivity for iodide is high enough that micromolar concentrations of iodide can be detected in the presence of molar chloride. Iodide binding at the "remote" lower rim causes a conformational change in the host, displacing the bound dye from the cavity and effecting a fluorescence response. The sensing is sensitive, selective, and works in complex environments, so will be important for optical anion detection in biorelevant media.

Nuclear quadrupole resonances for 14 N and 17 O nuclei are exquisitely sensitive to interactions with surrounding atoms. As a result, nitrogen and oxygen solid-state nuclear magnetic resonance (ssNMR) provides a powerful tool for investigating structure and dynamics in complex systems. First-principles calculations are increasingly used to facilitate spectral assignment and to evaluate and adjust crystal structures. Recent work combining the strengths of planewave density functional theory (DFT) calculations with a single molecule correction obtained using a higher level of theory has proven successful in improving the accuracy of predicted chemical shielding (CS) tensors and 17 O quadrupolar coupling constants ( C q ). Here we extend this work by examining the accuracy of predicted 14 N and 17 O electric field gradient (EFG) tensor components obtained using alternative planewave-corrections involving cluster and two-body fragment-based calculations. We benchmark the accuracy of CS and EFG tensor predictions for both nitrogen and oxygen using planewave, two-body fragment, and enhanced planewave-corrected techniques. Combining planewave and two-body fragment calculations reduces the error in predicted 17 O C q values by 35% relative to traditional planewave calculations. These enhanced planewave-correction methods improve the accuracy of 17 O and 14 N EFG tensor components by 15% relative to planewave DFT but yield minimal improvement relative to a simple molecular correction. However, in structural environments involving either high symmetry or strong intermolecular interactions, enhanced planewave-corrected methods provide a distinct advantage., (© 2022 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

Ab initio predictions of chemical shifts and electric field gradient (EFG) tensor components are frequently used to help interpret solid-state nuclear magnetic resonance (NMR) experiments. Typically, these predictions employ density functional theory (DFT) with generalized gradient approximation (GGA) functionals, though hybrid functionals have been shown to improve accuracy relative to experiment. Here, the performance of a dozen models beyond the GGA approximation are examined for the prediction of solid-state NMR observables, including meta-GGA, hybrid, and double-hybrid density functionals and second-order Møller-Plesset perturbation theory (MP2). These models are tested on organic molecular crystal data sets containing 169 experimental 13 C and 15 N chemical shifts and 114 17 O and 14 N EFG tensor components. To make these calculations affordable, gauge-including projector augmented wave (GIPAW) Perdew-Burke-Ernzerhof (PBE) calculations with periodic boundary conditions are combined with a local intramolecular correction computed at the higher level of theory. Within the context of typical NMR property calculations performed on a static, DFT-optimized crystal structure, the benchmarking finds that the double-hybrid DFT functionals produce errors versus experiment that are no smaller than those of hybrid functionals in the best cases, and they can be larger. MP2 errors versus experiment are even bigger. Overall, no practical advantages are found for using any of the tested double-hybrid functionals or MP2 to predict experimental solid-state NMR chemical shifts and EFG tensor components for routine organic crystals, especially given the higher computational cost of those methods. This finding likely reflects error cancellation benefiting the hybrid functionals. Improving the accuracy of the predicted chemical shifts and EFG tensors relative to experiment would probably require more robust treatments of the crystal structures, their dynamics, and other factors.

Ab initio methods for predicting NMR parameters in the solid state are an essential tool for assigning experimental spectra and play an increasingly important role in structural characterizations. Recently, a molecular correction (MC) technique has been developed which combines the strengths of plane-wave methods (GIPAW) with single molecule calculations employing Gaussian basis sets. The GIPAW + MC method relies on a periodic calculation performed at a lower level of theory to model the crystalline environment. The GIPAW result is then corrected using a single molecule calculation performed at a higher level of theory. The success of the GIPAW + MC method in predicting a range of NMR parameters is a result of the highly local character of the tensors underlying the NMR observable. However, in applications involving strong intermolecular interactions we find that expanding the region treated at the higher level of theory more accurately captures local many-body contributions to the N15 NMR chemical shielding (CS) tensor. We propose alternative corrections to GIPAW which capture interactions between adjacent molecules at a higher level of theory using either fragment or cluster-based calculations. Benchmark calculations performed on N15 and C13 data sets show that these advanced GIPAW-corrected calculations improve the accuracy of chemical shielding tensor predictions relative to existing methods. Specifically, cluster-based N15 corrections show a 24% and 17% reduction in RMS error relative to GIPAW and GIPAW + MC calculations, respectively. Comparing the benchmark data sets using multiple computational models demonstrates that N15 CS tensor calculations are significantly more sensitive to intermolecular interactions relative to C13. However, fragment and cluster-based corrections that include direct hydrogen bond partners are sufficient for optimizing the accuracy of GIPAW-corrected methods. Finally, GIPAW-corrected methods are applied to the particularly challenging NMR spectral assignment of guanosine dihydrate which contains two guanosine molecules in the asymmetric unit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Military veterans are a high-risk group for health risk behaviors, including alcohol and cannabis use. However, research on veteran vs. non-veteran rates of alcohol/cannabis use are inconsistent across studies. Further, no research has investigated veteran vs. non-veteran rates of alcohol and cannabis co-use, and few studies have tested whether demographic variables, particularly race/ethnicity, moderate group differences. Therefore, the current study tested whether 1) veteran vs. non-veterans differed in rates of alcohol use, cannabis use, and alcohol and cannabis co-use, and 2) whether demographic covariates (age, sex, race/ethnicity) moderated associations., Methods: Data on adults (N = 706,897; 53.4% female) were derived from the 2002-2019 National Study on Drug Use and Health. Participant demographics, alcohol use frequency, drinking quantity, and cannabis use frequency were self-reported., Results: Non-veterans reported higher drinking quantity, cannabis frequency, and co-use. However, being a veteran was a risk factor for heavier drinking for women, ethnic/racial minoritized participants, and adults under the age of 50. Additionally, veteran status was a risk factor for cannabis use frequency in racial/ethnic minoritized participants and women. Similarly, being a veteran was a risk factor for alcohol and cannabis co-use for racial/ethnic minoritized participants, and the buffering effect of being a Veteran on co-use was reduced for older participants and women., Conclusions: Results suggest that, at the population level, non-veterans may be heavier alcohol/cannabis users. However, moderating analyses suggested that being a veteran is a risk factor for women, racial/ethnic minoritized individuals, and younger individuals. Findings are discussed in terms of public health implications., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Stated preference research currently lacks a form of evidence that is well suited for small samples. A preference path is a sequence of two or more choices showing the evolution of an object following an adaptive process., Objectives: The aims were to introduce preference paths and their kaizen tasks and to demonstrate how to analyze their evidence using a small sample., Methods: Twenty respondents were assigned the same 16 profiles generated from an orthogonal array based on the five attributes of the EQ-5D-5L descriptive system. Each kaizen task began with an opt-out paired comparison (i.e., choosing between the initial 10-year profile and the opt-out "dying immediately"), followed by choosing three changes, and ended with a second paired comparison (final profile versus opt-out) if the respondent chose opt-out initially. By maximum likelihood with respondent clusters, we estimated the 20 main effects using conditional logit and Zermelo-Bradley-Terry (ZBT) specifications., Results: Apart from demonstrating heterogeneity and profile effects, all main effect estimates were non-negative, and most were significant (15 for logit and all 20 for ZBT; p value < 0.05). Under the logit and ZBT specifications, the value of the worst EQ-5D-5L profile (55555) is - 0.920 quality-adjusted life years (QALYs) or - 1.478 QALYs, respectively. Furthermore, the findings illustrate a log-linear relationship between the logit and ZBT main effects., Conclusion: This paper demonstrates the feasibility of a stated-preference study that estimates 20 main effects using path evidence from 20 respondents (16 kaizen tasks, 15-min interviews). This approach shows promise for future application in stated-preference research, particularly in small samples., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Modern approaches for calculating electric field gradient (EFF) tensors in molecular solids rely upon plane-wave calculations employing periodic boundary conditions (PBC). In practice, models employing PBCs are limited to generalized gradient approximation (GGA) density functionals. Hybrid density functionals applied in the context of gauge-including atomic orbital (GIAO) calculations have been shown to substantially improve the accuracy of predicted NMR parameters. Here we propose an efficient method that effectively combines the benefits of both periodic calculations and single-molecule techniques for predicting electric field gradient tensors in molecular solids. Periodic calculations using plane-wave basis sets were used to model the crystalline environment. We then introduce a molecular correction to the periodic result obtained from a single-molecule calculation performed with a hybrid density functional. Single-molecule calculations performed using hybrid density functionals were found to significantly improve the agreement of predicted 17 O quadrupolar coupling constants ( C q ) with experiment. We demonstrate a 31% reduction in the RMS error for the predicted 17 O C q values relative to standard plane-wave methods using a carefully constructed test set comprised of 22 oxygen-containing molecular crystals. We show comparable improvements in accuracy using five different hybrid density functionals and find predicted C q values to be relatively insensitive to the choice of basis set used in the single molecule calculation. Finally, the utility of high-accuracy 17 O C q predictions is demonstrated by examining the disordered 4-Nitrobenzaldehyde crystal structure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hartman, Mathews and Harper.)

Nuclear magnetic resonance (NMR) spectroscopy plays a crucial role in determining molecular structure for complex biological and pharmaceutical compounds. NMR investigations are increasingly reliant on computation for mapping spectral features to chemical structures. Here we benchmark the accuracy of fragment-based 51 V chemical shielding tensor calculations using a training set comprised of 10 biologically and pharmaceutically relevant oxovanadium complexes. Using our self-consistent reproduction of the Madelung potential (SCRMP) electrostatic embedding model, we demonstrate comparable performance between fragment methods and computationally demanding cluster-based techniques. Specifically, fragment methods employing hybrid density functionals are capable of reproducing the experimental 51 V isotropic chemical shifts with a training set rms error of ~9 ​ppm, representing a 20% improvement over traditional plane wave techniques. We provide training set-derived linear regression models for mapping the absolute shieldings obtained from computation to the experimentally determined chemical shifts using four common density functionals; PBE0, B3LYP, PBE, and BLYP. Finally, we establish the utility of fragment methods and the reported regression parameters examining four oxovanadium structures excluded from the training set including the tetracoordinate oxovanadium silicate [Formula: see text] , VO 15 NGlySalbz which contains redox-active ligands, and the solid-state form of the common 51 V NMR reference compound VOCl 3 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The ability to theoretically predict accurate NMR chemical shifts in solids is increasingly important due to the role such shifts play in selecting among proposed model structures. Herein, two theoretical methods are evaluated for their ability to assign 15 N shifts from guanosine dihydrate to one of the two independent molecules present in the lattice. The NMR data consist of 15 N shift tensors from 10 resonances. Analysis using periodic boundary or fragment methods consider a benchmark dataset to estimate errors and predict uncertainties of 5.6 and 6.2 ppm, respectively. Despite this high accuracy, only one of the five sites were confidently assigned to a specific molecule of the asymmetric unit. This limitation is not due to negligible differences in experimental data, as most sites exhibit differences of >6.0 ppm between pairs of resonances representing a given position. Instead, the theoretical methods are insufficiently accurate to make assignments at most positions., (© 2021 Wiley-VCH GmbH.)

Prior research demonstrates contextual influences on drug responses in both animals and humans, although studies in humans typically focus on only one aspect of context (e.g., social) and examine a limited range of subjective experiences. The current study sought to address these limitations by examining the impact of both social and physical context on the full range of subjective alcohol effects. The sample included 448 young adult social drinkers (57% male, 66.5% White) randomly assigned to consume alcohol (target blood alcohol concentration of .08 g%) or placebo in 1 of 4 contexts (solitary lab, group lab, solitary bar, group bar). Results indicated that high arousal positive (HAP) effects of alcohol (e.g., talkative, lively) were stronger in nonbar relative to bar contexts and that low arousal positive (LAP) effects (e.g., relaxed, calm) were only present in the group lab context. There were also main effects of social context such that high arousal effects (both positive and negative) were stronger in group contexts, regardless of beverage condition. These findings highlight the importance of considering context when examining alcohol effects. Studies designed to isolate pharmacological HAP effects may benefit from a nonbar setting, and studies of LAP effects might be most effective in a simulated living room or home environment, although future studies are needed to directly address this possibility. Further, studies with an explicit focus on expectancies or that need strong control for expectancies might benefit from a group context, particularly when studying high arousal effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Crystals composed of photoreactive molecules represent a new class of photomechanical materials with the potential to generate large forces on fast timescales. An example is the photodimerization of 9- tert -butyl-anthracene ester ( 9TBAE ) in molecular crystal nanorods that leads to an average elongation of 8%. Previous work showed that this expansion results from the formation of a metastable crystalline product. In this article, it is shown how a novel combination of ensemble oriented-crystal solid-state NMR, X-ray diffraction, and first principles computational modeling can be used to establish the absolute unit cell orientations relative to the shape change, revealing the atomic-resolution mechanism for the photomechanical response and enabling the construction of a model that predicts an elongation of 7.4%, in good agreement with the experimental value. According to this model, the nanorod expansion does not result from an overall change in the volume of the unit cell, but rather from an anisotropic rearrangement of the molecular contents. The ability to understand quantitatively how molecular-level photochemistry generates mechanical displacements allows us to predict that the expansion could be tuned from +9% to -9.5% by controlling the initial orientation of the unit cell with respect to the nanorod axis. This application of NMR-assisted crystallography provides a new tool capable of tying the atomic-level structural rearrangement of the reacting molecular species to the mechanical response of a nanostructured sample., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: The beginning of college is a period in which increased alcohol use often coincides with greater involvement in romantic relationships. Existing literature yields inconsistent findings regarding the influence of relationship types on drinking behavior, perhaps because these studies have not accounted for recent changes in the way college students engage in dating/sexual relationships., Methods: The present study sought to address this issue using a longitudinal study design by examining the effects of both relationship type and sexual activity on heavy episodic drinking (HED) among 1,847 college students over the course of the first 3 semesters of college., Results: Results indicated that the effects of relationship type depended on whether an individual was sexually active. Nondating but sexually active students reported rates of HED comparable to students who defined themselves as casual daters. Conversely, nondating students who were not sexually active reported drinking behavior similar to those involved in exclusive relationships. Further, transitions between low- and high-risk relationship/sexual activity types were associated with corresponding changes in HED. Transitioning into a high-risk relationship was associated with significant increases in levels of HED, whereas transitioning into a low-risk relationship was associated with significant decreases in HED., Conclusions: Together, results indicate that engaging in nonexclusive dating or casual sexual relationships may play an important role in the development of problematic patterns of alcohol use during the early college years. These findings have potentially important implications both for future research and for prevention and intervention efforts targeting high-risk college drinkers., (© 2020 by the Research Society on Alcoholism.)

Background and Objective: Recent evidence has shown that online surveys can reliably collect preference data, which markedly decrease the cost of health preference studies and expand their representativeness. As the use of mobile technology continues to grow, we wanted to examine its potential impact on health preferences., Methods: Two recently completed discrete choice experiments using members of the US general population (n = 15,292) included information on respondent device (cell phone, tablet, Mac, PC) and internet connection (business, cellular, college, government, residential). In this analysis, we tested for differences in respondent characteristics, participation, response quality, and utility values for the 5-level EQ-5D (EQ-5D-5L) by device and connection., Results: Compared to Mac and PC users, respondents using a cell phone or tablet had longer completion times and were significantly more likely to drop out during the surveys (p < 0.001). Tablet users also demonstrated more logical inconsistencies (p = 0.05). Likewise, respondents using a cellular internet connection exhibit significantly less consistency in their health preferences. However, matched samples for tablets and cell phones produced similar EQ-5D-5L utility values (mean differences < 0.06 on a quality-adjusted life-year [QALY] scale for all potential health states)., Conclusion: Allowing respondents to complete online surveys using a cell phone or tablet or over a cellular connection substantially increases the diversity of respondents and the likelihood of obtaining a representative sample, as many individuals have cell phones but not a computer. While the results showed systematic variability in participation and response quality by device and connection type, this study did not show any meaningful changes in utility values.

Background: Adolescent and young adult alcohol use is a major public health concern; alcohol is the most widely used substance by teenagers. It is imperative to better understand alcohol use during adolescence and early adulthood given the important changes that occur. Although numerous measures aim to capture alcohol use during this time, no existing measure gathers comprehensive information on alcohol use across these developmental stages. We developed the Comprehensive Early Drinking History Form (CEDHF), which retrospectively gathers drinking information for each year since onset of first regular use, including quantity/frequency of both regular use and periods of heaviest drinking. The CEDHF also collects information on aggregate drinking experiences between age of onset and age of first regular use., Methods: Using a sample of young adults (ages 21 to 27) from an ongoing longitudinal study, we examined whether the CEDHF predicted both concurrent (N = 303) and future (N = 75) alcohol-related problems over and above other commonly used alcohol use measures (e.g., age of onset, age of first intoxication, Timeline Follow-Back) and current alcohol problems., Results: Controlling for gender, age, and current problems, the CEDHF predicted both concurrent and future alcohol-related problems over and above these other widely used measures of alcohol exposure., Conclusions: The CEDHF may be a valuable tool when longitudinal studies are not feasible as it provides more comprehensive information than other widely used measures of early alcohol exposure. Further, this measure can provide detailed information regarding who is at highest risk for future consequences., (© 2018 by the Research Society on Alcoholism.)

Standard nuclear magnetic resonance (NMR) spectroscopy experiments measure isotropic chemical shifts, but measuring the chemical shielding anisotropy (CSA) tensor can provide additional insights into solid state chemical structures. Interpreting the principal components of these tensors is facilitated by first-principles chemical shielding tensor predictions. Here, the ability to predict molecular crystal CSA tensor components for 13 C and 15 N nuclei with fragment-based electronic structure techniques is explored. Similar to what has been found previously for isotropic chemical shifts, the benchmarking demonstrates that fragment-based techniques can accurately reproduce CSA tensor components. The use of hybrid density functionals like PBE0 or B3LYP provide higher accuracy than generalized gradient approximation functionals like PBE. Unlike for planewave density functional techniques, hybrid density functionals can be employed routinely with modest computational cost in fragment approaches. Finally, good consistency between the regression parameters used to map either isotropic shieldings or CSA tensor components is demonstrated, providing further evidence for the quality of the models and highlighting that models trained for isotropic shifts can also be applied to CSA tensor components., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives Examining the association between maternal smoking and losses in childhood health-related quality of life due to behavior problems provides parents and policymakers another tool for the valuation of smoking cessation during pregnancy. Methods Using the National Longitudinal Survey of Youth 1979 Child and Young Adult data, this study retrospectively examined a cohort of 4114 women and 8668 children. In addition to questions focusing on maternal smoking and general demographics, each survey included the Behavior Problems Index (BPI), a 28-item questionnaire with six subscales measuring childhood behavior problems (antisocial behavior, anxiousness/depression, headstrongness, hyperactivity, immature dependency, and peer conflict/social withdrawal). Responses to the BPI, completed by mothers with children ages 4-14, were summarized on a QALY scale using published preference weights. Results Children whose mothers smoked during pregnancy experience additional QALY losses of 0.181, on average, per year due to increased behavior problems. Boys suffered larger QALY losses associated with maternal smoking (0.242) compared to girls (0.119; p value = .021), regardless of age. Moreover, heavier smoking during pregnancy (i.e., 1 or more packs/day) was associated with larger QALY losses (0.282; p-value < .001). Conclusions for Practice These findings illustrate the burden of maternal smoking during pregnancy on child health, namely behavioral problems. The losses in QALYs may be incorporated into economic evaluations for smoking cessation interventions during pregnancy. Future research will investigate how maternal smoking following childbirth is associated with child QALYs.

Stars with hot Jupiters tend to be rotating faster than other stars of the same age and mass. This trend has been attributed to tidal interactions between the star and planet. A constraint on the dissipation parameter Q ⋆ ' follows from the assumption that tides have managed to spin up the star to the observed rate within the age of the system. This technique was applied previously to HATS-18 and WASP-19. Here we analyze the sample of all 188 known hot Jupiters with an orbital period < 3.5 days and a "cool" host star ( T eff < 6100K). We find evidence that the tidal dissipation parameter ( Q ⋆ ' ) increases sharply with forcing frequency, from 10 5 at 0.5 day -1 to 10 7 at 2 day -1 . This helps to resolve a number of apparent discrepancies between studies of tidal dissipation in binary stars, hot Jupiters, and warm Jupiters. It may also allow for a hot Jupiter to damp the obliquity of its host star prior to being destroyed by tidal decay.

Purpose: Summarizing patient-reported outcomes (PROs) on a quality-adjusted life year (QALY) scale is an essential component to any economic evaluation comparing alternative medical treatments. While multiple studies have compared PRO items and instruments based on their psychometric properties, no study has compared the preference-based summary of the EQ-5D-3L and Patient Reported Outcomes Measurement Information System (PROMIS-29) instruments. As part of this comparison, a major aim of this manuscript is to transform PROMIS-29 utility values to an EQ-5D-3L scale., Methods: A nationally representative survey of 2623 US adults completed the 29-item PROMIS health profile instrument (PROMIS-29) and the 3-level version of the EQ-5D instrument (EQ-5D-3L). Their responses were summarized on a health utility scale using published estimates. Using regression analysis, PROMIS-29 and EQ-5D-3L utility weights were compared with each other as well as with self-reported general health., Results: PROMIS-29 utility weights were much lower than the EQ-5D-3L weights. However, a correlation coefficient of 0.769 between the utility values of the two instruments suggests that the main discordance is simply a difference in scale between the measures. It is also possible to map PROMIS-29 utility weights onto an EQ-5D-3L scale. EQ-5D-3L losses equal .1784 × (PROMIS-29 Losses) .7286 ., Conclusions: The published estimates of the PROMIS-29 produce lower utility values than many other health instruments. Mapping the PROMIS-29 estimates to an EQ-5D-3L scale alleviates this issue and allows for a more straightforward comparison between the PROMIS-29 and other common health instruments.

Objective: To identify which specifications and approaches to model selection better predict health preferences, the International Academy of Health Preference Research (IAHPR) hosted a predictive modeling competition including 18 teams from around the world., Methods: In April 2016, an exploratory survey was fielded: 4074 US respondents completed 20 out of 1560 paired comparisons by choosing between two health descriptions (e.g., longer life span vs. better health). The exploratory data were distributed to all teams. By July, eight teams had submitted their predictions for 1600 additional pairs and described their analytical approach. After these predictions had been posted online, a confirmatory survey was fielded (4148 additional respondents)., Results: The victorious team, "Discreetly Charming Econometricians," led by Michał Jakubczyk, achieved the smallest χ 2 , 4391.54 (a predefined criterion). Its primary scientific findings were that different models performed better with different pairs, that the value of life span is not constant proportional, and that logit models have poor predictive validity in health valuation., Conclusions: The results demonstrated the diversity and potential of new analytical approaches in health preference research and highlighted the importance of predictive validity in health valuation., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Fragment-based methods predict nuclear magnetic resonance (NMR) chemical shielding tensors in molecular crystals with high accuracy and computational efficiency. Such methods typically employ electrostatic embedding to mimic the crystalline environment, and the quality of the results can be sensitive to the embedding treatment. To improve the quality of this embedding environment for fragment-based molecular crystal property calculations, we borrow ideas from the embedded ion method to incorporate self-consistently polarized Madelung field effects. The self-consistent reproduction of the Madelung potential (SCRMP) model developed here constructs an array of point charges that incorporates self-consistent lattice polarization and which reproduces the Madelung potential at all atomic sites involved in the quantum mechanical region of the system. The performance of fragment- and cluster-based 1 H, 13 C, 14 N, and 17 O chemical shift predictions using SCRMP and density functionals like PBE and PBE0 are assessed. The improved embedding model results in substantial improvements in the predicted 17 O chemical shifts and modest improvements in the 15 N ones. Finally, the performance of the model is demonstrated by examining the assignment of the two oxygen chemical shifts in the challenging γ-polymorph of glycine. Overall, the SCRMP-embedded NMR chemical shift predictions are on par with or more accurate than those obtained with the widely used gauge-including projector augmented wave (GIPAW) model.

Molecular crystals occur widely in pharmaceuticals, foods, explosives, organic semiconductors, and many other applications. Thanks to substantial progress in electronic structure modeling of molecular crystals, attention is now shifting from basic crystal structure prediction and lattice energy modeling toward the accurate prediction of experimentally observable properties at finite temperatures and pressures. This Account discusses how fragment-based electronic structure methods can be used to model a variety of experimentally relevant molecular crystal properties. First, it describes the coupling of fragment electronic structure models with quasi-harmonic techniques for modeling the thermal expansion of molecular crystals, and what effects this expansion has on thermochemical and mechanical properties. Excellent agreement with experiment is demonstrated for the molar volume, sublimation enthalpy, entropy, and free energy, and the bulk modulus of phase I carbon dioxide when large basis second-order Møller-Plesset perturbation theory (MP2) or coupled cluster theories (CCSD(T)) are used. In addition, physical insight is offered into how neglect of thermal expansion affects these properties. Zero-point vibrational motion leads to an appreciable expansion in the molar volume; in carbon dioxide, it accounts for around 30% of the overall volume expansion between the electronic structure energy minimum and the molar volume at the sublimation point. In addition, because thermal expansion typically weakens the intermolecular interactions, neglecting thermal expansion artificially stabilizes the solid and causes the sublimation enthalpy to be too large at higher temperatures. Thermal expansion also frequently weakens the lower-frequency lattice phonon modes; neglecting thermal expansion causes the entropy of sublimation to be overestimated. Interestingly, the sublimation free energy is less significantly affected by neglecting thermal expansion because the systematic errors in the enthalpy and entropy cancel somewhat. Second, because solid state nuclear magnetic resonance (NMR) plays an increasingly important role in molecular crystal studies, this Account discusses how fragment methods can be used to achieve higher-accuracy chemical shifts in molecular crystals. Whereas widely used plane wave density functional theory models are largely restricted to generalized gradient approximation (GGA) functionals like PBE in practice, fragment methods allow the routine use of hybrid density functionals with only modest increases in computational cost. In extensive molecular crystal benchmarks, hybrid functionals like PBE0 predict chemical shifts with 20-30% higher accuracy than GGAs, particularly for 1 H, 13 C, and 15 N nuclei. Due to their higher sensitivity to polarization effects, 17 O chemical shifts prove slightly harder to predict with fragment methods. Nevertheless, the fragment model results are still competitive with those from GIPAW. The improved accuracy achievable with fragment approaches and hybrid density functionals increases discrimination between different potential assignments of individual shifts or crystal structures, which is critical in NMR crystallography applications. This higher accuracy and greater discrimination are highlighted in application to the solid state NMR of different acetaminophen and testosterone crystal forms.

Chemical shift prediction plays an important role in the determination or validation of crystal structures with solid-state nuclear magnetic resonance (NMR) spectroscopy. One of the fundamental theoretical challenges lies in discriminating variations in chemical shifts resulting from different crystallographic environments. Fragment-based electronic structure methods provide an alternative to the widely used plane wave gauge-including projector augmented wave (GIPAW) density functional technique for chemical shift prediction. Fragment methods allow hybrid density functionals to be employed routinely in chemical shift prediction, and we have recently demonstrated appreciable improvements in the accuracy of the predicted shifts when using the hybrid PBE0 functional instead of generalized gradient approximation (GGA) functionals like PBE. Here, we investigate the solid-state 13 C and 15 N NMR spectra for multiple crystal forms of acetaminophen, phenobarbital, and testosterone. We demonstrate that the use of the hybrid density functional instead of a GGA provides both higher accuracy in the chemical shifts and increased discrimination among the different crystallographic environments. Finally, these results also provide compelling evidence for the transferability of the linear regression parameters mapping predicted chemical shieldings to chemical shifts that were derived in an earlier study.

The performance of fragment-based ab initio(1)H, (13)C, (15)N and (17)O chemical shift predictions is assessed against experimental NMR chemical shift data in four benchmark sets of molecular crystals. Employing a variety of commonly used density functionals (PBE0, B3LYP, TPSSh, OPBE, PBE, TPSS), we explore the relative performance of cluster, two-body fragment, and combined cluster/fragment models. The hybrid density functionals (PBE0, B3LYP and TPSSh) generally out-perform their generalized gradient approximation (GGA)-based counterparts. (1)H, (13)C, (15)N, and (17)O isotropic chemical shifts can be predicted with root-mean-square errors of 0.3, 1.5, 4.2, and 9.8 ppm, respectively, using a computationally inexpensive electrostatically embedded two-body PBE0 fragment model. Oxygen chemical shieldings prove particularly sensitive to local many-body effects, and using a combined cluster/fragment model instead of the simple two-body fragment model decreases the root-mean-square errors to 7.6 ppm. These fragment-based model errors compare favorably with GIPAW PBE ones of 0.4, 2.2, 5.4, and 7.2 ppm for the same (1)H, (13)C, (15)N, and (17)O test sets. Using these benchmark calculations, a set of recommended linear regression parameters for mapping between calculated chemical shieldings and observed chemical shifts are provided and their robustness assessed using statistical cross-validation. We demonstrate the utility of these approaches and the reported scaling parameters on applications to 9-tert-butyl anthracene, several histidine co-crystals, benzoic acid and the C-nitrosoarene SnCl2(CH3)2(NODMA)2.

Objectives: To estimate the prevalence and losses in quality-adjusted life years (QALYs) associated with 20 child health conditions., Methods: Using data from the 2009-2010 National Survey of Children with Special Health Care Needs, preference weights were applied to 14 functional difficulties to summarize the quality of life burden of 20 health conditions., Results: Among the 14 functional difficulties, "a little trouble with breathing" had the highest prevalence (37.1 %), but amounted to a loss of just 0.16 QALYs from the perspective of US adults. Though less prevalent, "a lot of behavioral problems" and "chronic pain" were associated with the greatest losses (1.86 and 3.43 QALYs). Among the 20 conditions, allergies and asthma were the most prevalent but were associated with the least burden. Muscular dystrophy and cerebral palsy were among the least prevalent and most burdensome. Furthermore, a scatterplot shows the association between condition prevalence and burden., Conclusions: In child health, condition prevalence is negatively associated with quality of life burden from the perspective of US adults. Both should be considered carefully when evaluating the appropriate role for public health prevention and interventions.

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

We assess the quality of fragment-based ab initio isotropic (13)C chemical shift predictions for a collection of 25 molecular crystals with eight different density functionals. We explore the relative performance of cluster, two-body fragment, combined cluster/fragment, and the planewave gauge-including projector augmented wave (GIPAW) models relative to experiment. When electrostatic embedding is employed to capture many-body polarization effects, the simple and computationally inexpensive two-body fragment model predicts both isotropic (13)C chemical shifts and the chemical shielding tensors as well as both cluster models and the GIPAW approach. Unlike the GIPAW approach, hybrid density functionals can be used readily in a fragment model, and all four hybrid functionals tested here (PBE0, B3LYP, B3PW91, and B97-2) predict chemical shifts in noticeably better agreement with experiment than the four generalized gradient approximation (GGA) functionals considered (PBE, OPBE, BLYP, and BP86). A set of recommended linear regression parameters for mapping between calculated chemical shieldings and observed chemical shifts are provided based on these benchmark calculations. Statistical cross-validation procedures are used to demonstrate the robustness of these fits.