County-level associations between food retailer availability and violent crime rate.

BACKGROUND: Violent crime (i.e., homicide, armed robbery, aggravated assault, and rape) continues to be a major public health concern in America. Several studies have linked the availability and density of specific features of the retail food environment, such as convenience stores and liquor stores, to violent crime rates due to the criminal activity that often occurs in and near these retailers. Nevertheless, there continues to be limited understanding of how other features (e.g., grocery stores, supercenters, restaurants, etc.) are associated with violent crime occurrence. This study aimed to fill this gap in knowledge by examining U.S. county-level associations between food retailer availability and violent crime rate. METHODS: We analyzed 2014 data on 3108 counties from the U.S. Department of Agriculture's Food Environment Atlas and Department of Justice's Unified Crime Reporting Program. Per capita food retailer measures represented the number of stores per 10,000 county residents. Violent crime rate represented the number of police reported violent crimes per 10,000 county residents. We used spatial lag regression models to assess associations between per capita retailer availability and violent crime rate after adjusting for potential confounders (e.g., % under 18, % Black, % Hispanic, % poverty, population density, etc.). In addition, we examined stratified OLS regression models to evaluate associations by metropolitan county status. RESULTS: Adjusted spatial regression models revealed that greater supercenter availability [ß: 2.42; 95% CI: 0.91-3.93; p-value: 0.001] and greater fast food restaurant availability [ß: 0.30; 95% CI: 0.18-0.42; p-value: < 0.001] were associated with higher violent crime rate. Greater availability of farmers' markets [ß: -0.42; 95% CI: -0.77 - - 0.07); p-value: 0.02] was associated with lower violent crime rate. Associations varied between metropolitan and non-metropolitan counties. Stratified OLS models revealed that greater grocery store availability was associated with lower violent crime rate among metropolitan counties only. Greater fast food restaurant availability was associated with lower violent crime rate among non-metropolitan counties only. CONCLUSIONS: Certain features of the retail food environment appear to be associated with county-level violent crime rates in America. These findings highlight the need for additional research on the influence of food retail and food landscape on violent crime occurrence at the community level.

Cyanthiwigin Natural Product Core as a Complex Molecular Scaffold for Comparative Late-Stage C-H Functionalization Studies.

The desire for maximally efficient transformations in complex molecule synthesis has contributed to a surge of interest in C-H functionalization methods development in recent years. In contrast to the steady stream of methodological reports, however, there are noticeably fewer studies comparing the efficacies of different C-H functionalization protocols on a single structurally intricate substrate. Recognizing the importance of heteroatom incorporation in complex molecule synthesis, this report discloses a comparative examination of diverse strategies for C-O, C-N, and C-X bond formation through late-stage C-H oxidation of the tricyclic cyanthiwigin natural product core. Methods for allylic C-H acetoxylation, tertiary C-H hydroxylation, tertiary C-H amination, tertiary C-H azidation, and secondary C-H halogenation are explored. These efforts highlight the robustness and selectivities of many well-established protocols for C-H oxidation when applied to a complex molecular framework, and the findings are relevant to chemists aiming to employ such strategies in the context of chemical synthesis.

Quantitative Measurement of Rate of Targeted Protein Degradation.

Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This is accomplished by using mono- or bifunctional small molecules designed to induce the proximity of target proteins and E3 ubiquitin ligases, leading to ubiquitination and subsequent proteasome-dependent degradation of the target. One of the most significant attributes of the TPD approach is its proposed catalytic mechanism of action, which permits substoichiometric exposure to achieve the desired pharmacological effects. However, apart from one in vitro study, studies supporting the catalytic mechanism of degraders are largely inferred based on potency. A more comprehensive understanding of the degrader catalytic mechanism of action can help aspects of compound development. To address this knowledge gap, we developed a workflow for the quantitative measurement of the catalytic rate of degraders in cells. Comparing a selective and promiscuous BTK degrader, we demonstrate that both compounds function as efficient catalysts of BTK degradation, with the promiscuous degrader exhibiting faster rates due to its ability to induce more favorable ternary complexes. By leveraging computational modeling, we show that the catalytic rate is highly dynamic as the target is depleted from cells. Further investigation of the promiscuous kinase degrader revealed that the catalytic rate is a better predictor of optimal degrader activity toward a specific target compared to degradation magnitude alone. In summary, we present a versatile method for mapping the catalytic activity of any degrader for TPD in cells.

Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety.

In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N-linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to facilitate infection. As such, STT3A/B, the catalytic domain of the OST complex, became an intriguing drug target with broad-spectrum antiviral potential. However, due to the critical role N-linked glycosylation plays in a number of fundamental human processes, the toxicological ramifications of STT3A/B inhibition required attention commensurate to that given to antiviral efficacy. Herein, we describe how known STT3A/B inhibitor NGI-1 inspired the discovery of superior tool compounds which were evaluated in in vitro efficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating N-linked glycosylation as well as the broader scientific community.

A silica sol-gel design strategy for nanostructured metallic materials.

Batteries, fuel cells and solar cells, among many other high-current-density devices, could benefit from the precise meso- to macroscopic structure control afforded by the silica sol-gel process. The porous materials made by silica sol-gel chemistry are typically insulators, however, which has restricted their application. Here we present a simple, yet highly versatile silica sol-gel process built around a multifunctional sol-gel precursor that is derived from the following: amino acids, hydroxy acids or peptides; a silicon alkoxide; and a metal acetate. This approach allows a wide range of biological functionalities and metals--including noble metals--to be combined into a library of sol-gel materials with a high degree of control over composition and structure. We demonstrate that the sol-gel process based on these precursors is compatible with block-copolymer self-assembly, colloidal crystal templating and the Stöber process. As a result of the exceptionally high metal content, these materials can be thermally processed to make porous nanocomposites with metallic percolation networks that have an electrical conductivity of over 1,000 S cm(-1). This improves the electrical conductivity of porous silica sol-gel nanocomposites by three orders of magnitude over existing approaches, opening applications to high-current-density devices.

An Innovation 10 Years in the Making: The Stories in the Pages of ACS Medicinal Chemistry Letters.

Innovation in medicinal chemistry has been at the heart of ACS Medicinal Chemistry Letters since the journal's founding 10 years ago. In his inaugural editorial, Editor-in-Chief Dennis Liotta laid out a vision for the journal to become the "premier international journal for rapid communication of cutting-edge studies," and, after 10 years, it has become exactly that. The great hope of drug discovery scientists is that their innovations will lead to new therapeutics to treat unmet medical needs. In the spirit of innovation and in celebration of the recent 10th anniversary of ACS Med. Chem. Lett., we highlight five therapeutics that were first reported or first comprehensively characterized within ACS Med. Chem. Lett.. This overview also serves to introduce the expansion of the scope of the Innovations article type to include Topical Innovations. With this extension, the journal hopes to provide a forum to showcase concise (rather than comprehensive) reviews of topics that are both timely and of great interest to the medicinal chemistry community. Moreover, these articles will emphasize the next steps to move the field toward new areas of interest in medicinal chemistry. Appropriate topics might include case studies of clinical candidates or approved drugs, new assay technologies in drug discovery, novel target classes, and innovative new approaches towards modulation of human physiology. Since its founding 10 years ago, ACS Med. Chem. Lett. has established itself as a venue for the rapid communication of studies in medicinal chemistry and drug discovery. There have been several drugs and clinical candidates that were first reported or first comprehensively characterized in ACS Med. Chem. Lett. In celebration of the 10th anniversary of ACS Med. Chem. Lett. this Topical Innovations article highlights five of these compounds: Ivosidenib, Siponimod, Glasdegib, Parsaclisib, and Dabrafenib.

Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery. By examining chemical shift perturbations in 2D [1H, 13C-HSQC] spectra of isotopically labeled IL17A, we discovered fragments binding the cytokine at a previously undescribed site near the IL17A C-terminal region, albeit with weak affinity (> 250 µM). Importantly this binding location was distinct from previously known chemical matter modulating cytokine responses. Subsequently through analog screening, we identified related compounds that bound symmetrically in this novel site with two copies. From this observation we employed a linking strategy via structure-based drug design and obtained compounds with increased binding affinity (< 50 nM) and showed functional inhibition of IL17A-induced cellular signaling (IC50~1 µM). We also describe a fluorescence-based probe molecule suitable to discern/screen for additional molecules binding in this C-terminal site.

Society of Behavioral Medicine (SBM) position statement: provide funding for incentive programs to expand healthy food offerings in SNAP-authorized small food stores.

Individuals and families with limited access to healthy foods often experience increased risk for poor diet and chronic disease. Low-income communities are more likely to have a large number of small food stores (e.g., corner stores and dollar stores) compared to higher-income communities. Since many of these small food stores participate in the Supplemental Nutrition Assistance Program (SNAP), increasing healthy food offerings in these stores may expand healthy food retail in low-income communities. We recommend the provision of funding for incentive programs that encourage SNAP-authorized small food stores in low-income communities to expand their healthy food offerings. This programming should (a) provide seed grants to store owners to develop or reconfigure store infrastructure, (b) offer store owners technical assistance and educational materials on marketing strategies for promoting healthy food items to customers, and (c) give a tax break to SNAP-authorized small food stores in low-income communities that maintain a predetermined minimum stock of U.S. Department of Agriculture-recognized staple foods.

Association of the addition of a transversus abdominis plane block to an enhanced recovery program with opioid consumption, postoperative antiemetic use, and discharge time in patients undergoing laparoscopic bariatric surgery: a retrospective study.

BACKGROUND: Increasing numbers of laparoscopic bariatric surgeries are being performed and enhanced recovery from anesthesia and surgery (ERAS) protocols have been implemented to optimize care for these patients. We evaluated the effects of an anesthesiologist placed preoperative transversus abdominis plane block (TAP) as part of a bariatric surgery ERAS protocol. We hypothesized that an anesthesiologist placed preoperative TAP added to an ERAS protocol following laparoscopic bariatric surgery would reduce total opioid consumption. METHODS: A retrospective cohort of consecutive patients between January 1, 2017 and December 31, 2018 at a single large tertiary care center studied. TAP blocks were added to the ERAS protocol beginning in the second quarter of 2017. The primary outcome was total opioid analgesia use in mg oral morphine equivalents. Secondary outcomes were antiemetics administered and length of hospitalization. Data were analyzed using a generalized linear mixed model adjusted for sociodemographic, surgical, and preoperative risk factors that have been associated with opioid and antiemetic use and length of hospitalization. RESULTS: Five hundred and nine cases were analyzed; TAP blocks were performed in 94/144 (65%) laparoscopic Roux-en-Y gastric bypass (LRYGB) and in 172/365 (47%) laparoscopic sleeve gastrectomy (LSG) patients. Mean (95% CI) adjusted total opioid administered was lower by 11% (1% to 19%, p=0.02), antiemetic drug administration was lower by 15% (-2% to 25%, p=0.06) and discharge time lower by 39% (26% to 48%, p<0.01) following LRYGB in the TAP group. Mean (95% CI) adjusted total opioid administered was lower by 9% (2% to 16%, p<0.01), antiemetic drug administration was lower by 11% (3% to 18%, p<0.01) and discharge time lower by 11% (2% to 18%, p=0.02) following LSG in the TAP group. CONCLUSIONS: TAP blocks added to a laparoscopic bariatric surgery ERAS protocol were associated with decreased total opioid use, number of antiemetic treatments, and length of stay; however, these changes were not likely clinically important. Our findings do not support widespread clinical benefit of TAP use in ERAS protocols for laparoscopic bariatric surgery.

Studies on the chemistry and reactivity of alpha-substituted ketones in isonitrile-based multicomponent reactions.

Using the Passerini and Ugi reactions as representative tests, the utility of several alpha-substituted ketones R-CO-CH(2)-X (X = sulfonyloxy, acyloxy, azido, halo, hydroxy, and sulfonyl) in isonitrile-based multicomponent reactions was explored. In a relative rate study (R = PhCH(2)CH(2)), each of the alpha-substituted ketones underwent Passerini condensation more rapidly than the parent ketone. Short, highly convergent routes to oxazoline, beta-lactam, di-O-acylglyceramides, and other molecular frameworks were developed.

Moved by Reading in a Spanish-Speaking, Dual Language Learner Population.

Purpose: The aim of this study was to evaluate the effectiveness of an English-only version and a Spanish-support version of an embodied reading comprehension intervention (Moved by Reading) consisting of 3 stages (physical manipulation, imagined manipulation, and transfer) for Spanish-English dual language learners. Method: Sixty-one dual language learners in Arizona were randomly assigned to 4 groups (Spanish-support control, Spanish-support intervention, English-only control, and English-only intervention). Analyses of variance were used to compare control and intervention groups and to compare groups according to the language of the intervention. Results: Children in the Spanish-support intervention group significantly outperformed both control groups during the physical manipulation stage, whereas children in the English-only intervention group outperformed both control groups in the imagined manipulation stage, but there was little transfer to a new, unrelated text. Conclusions: The Moved by Reading intervention, in both its English-only and Spanish-support versions, improved performance on comprehension questions, but in different stages of the intervention. The Spanish-support version of the intervention was most effective in the physical manipulation stage, whereas the English-only version was more effective in the imagined manipulation stage. Neither version was effective in producing significant transfer effects.

How Language Is Embodied in Bilinguals and Children with Specific Language Impairment.

This manuscript explores the role of embodied views of language comprehension and production in bilingualism and specific language impairment. Reconceptualizing popular models of bilingual language processing, the embodied theory is first extended to this area. Issues such as semantic grounding in a second language and potential differences between early and late acquisition of a second language are discussed. Predictions are made about how this theory informs novel ways of thinking about teaching a second language. Secondly, the comorbidity of speech, language, and motor impairments and how embodiment theory informs the discussion of the etiology of these impairments is examined. A hypothesis is presented suggesting that what is often referred to as specific language impairment may not be so specific due to widespread subclinical motor deficits in this population. Predictions are made about how weaknesses and instabilities in speech motor control, even at a subclinical level, may disrupt the neural network that connects acoustic input, articulatory motor plans, and semantics. Finally, I make predictions about how this information informs clinical practice for professionals such as speech language pathologists and occupational and physical therapists. These new hypotheses are placed within the larger framework of the body of work pertaining to semantic grounding, action-based language acquisition, and action-perception links that underlie language learning and conceptual grounding.

Comparative Study of the Limitations and Challenges in Atom-Transfer C-H Oxidations.

A comparative study is disclosed that seeks to highlight the current limitations and challenges that exist in the field of atom-transfer C-H oxidations. State-of-the-art methods are benchmarked in order to showcase clear differences and similarities. A novel Mn-mediated method for C-H oxidation is disclosed that serves as a rapid and simple method for aliphatic C-H hydroxylation. Finally, two methods that allow for C-H oxidation in the presence of pyridine-containing substrates are studied, something that is rare in the field but of great interest to the chemical community.

Learning and processing of nonverbal symbolic information in bilinguals and monolinguals.

Bilinguals have been shown to outperform monolinguals on word learning and on inhibition tasks that require competition resolution. Yet the scope of such bilingual advantages remains underspecified. We compared bilinguals and monolinguals on nonverbal symbolic learning and on competition resolution while processing newly-learned material. Participants were trained on 12 tone-to-symbol mappings, combining timbre, pitch, and duration of tones. During subsequent processing, participants viewed a display with four symbols, and were instructed to identify the symbol that matched a simultaneously-presented tone. On competition trials, two symbols matched the tone in timbre and pitch, but only one matched the tone on timbre, pitch, and duration. No learning differences emerged between 27 Spanish-English bilinguals and 27 English monolinguals, and more successful learners performed better on the Peabody Picture Vocabulary task. During the processing task, competition trials yielded responses with lower accuracies and longer latencies than control trials. Further, in both groups, more successful learning of tone-to-symbol mappings was associated with more successful retrieval during processing. In monolinguals, English receptive vocabulary scores also influenced retrieval efficiency during processing, with English/Spanish vocabulary less related to the novel processing task in bilinguals. Finally, to examine inhibition of competing stimuli, priming probes were presented after each tone-symbol processing trial. These probes suggested that bilinguals, and to a lesser extent monolinguals, showed residual inhibition of competitors at 200 ms post-target identification. Together, findings suggest that learning of novel symbolic information may depend in part on previous linguistic knowledge (not bilingualism per se), and that, during processing of newly-learned material, subtle differences in retrieval and competition resolution may emerge between bilinguals and monolinguals.