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Efficient Synthesis of Functionalized Aryl Spiro[2.2]pentanes and Vinylcyclopropanes Using Sulfones as Carbene Equivalents with Mechanistic Investigations
Get PDF Spiro[2.2]pentanes have been studied for over a century, captivating synthetic and physical chemists due to their high strain and unique topology. Recently the aryl spiro[2.2]pentane scaffold has shown promise in small molecule drug leads and bioisosteres. However, synthetic strategies to access highly functionalized aryl spiropentanes are limited using state-of-the-art methods. Building on previous work in the group, we have developed a method for the synthesis of functionalized, aryl spiro[2.2]pentanes using dialkyl sulfone reagents, which behave as nucleophilic carbene equivalents. Using this strategy, we have synthesized 16 spiropentanes from 9 different arylmethylenecyclopropanes and 7 different sulfones in up to 81% yield. Attempts to synthesize spiropentanes using cyclopropyl sulfones instead afforded vinylcyclopropanes, via an elimination mechanism. We have 14 examples of vinylcyclopropanes derived from styrene starting materials synthesized in up to 65% yield.
Understanding the mechanism by which these sulfones interreact with olefines to make strained rings may lead us to developing altered reaction conditions such as using more mild bases, stereoselective parameters, or working on a wider range of starting materials. We wish to explore the exact mechanism of the ring closure and elimination of the sulfinate to build cyclopropanes from styrenes via stereochemical probes. In doing so we can determine whether the mechanism proceeds via a back-side attack as in an SN2 reaction or from a front-side attack in accordance with computational data we have for a concerted SN1 pathway. We are in the process of building a chiral nonracemic starting product to subject to ring closure conditions and observe whether stereochemistry is retained (concerted SN1) or inverted (SN2). To date we are still working on building this starting material to test this hypothesis.Bachelor of Scienc
Breaking the reproducibility barrier with standardized protocols for plant-microbiome research.
Get PDFInter-laboratory replicability is crucial yet challenging in microbiome research. Leveraging microbiomes to promote soil health and plant growth requires understanding underlying molecular mechanisms using reproducible experimental systems. In a global collaborative effort involving five laboratories, we aimed to help advance reproducibility in microbiome studies by testing our ability to replicate synthetic community assembly experiments. Our study compared fabricated ecosystems constructed using two different synthetic bacterial communities, the model grass Brachypodium distachyon, and sterile EcoFAB 2.0 devices. All participating laboratories observed consistent inoculum-dependent changes in plant phenotype, root exudate composition, and final bacterial community structure, where Paraburkholderia sp. OAS925 could dramatically shift microbiome composition. Comparative genomics and exudate utilization linked the pH-dependent colonization ability of Paraburkholderia, which was further confirmed with motility assays. The study provides detailed protocols, benchmarking datasets, and best practices to help advance replicable science and inform future multi-laboratory reproducibility studies
Adsorption Characteristics of Bacterial Cellulose Membranes Toward Methylene Blue Dye in Aqueous Environment
Get PDFWater pollution has escalated to critical levels in recent years as evident by the multiplicity of contaminants found in potable water sources. A point-source major contributor is the textile industry, which discharges substantial amounts of dye into rivers and lakes. Bacterial cellulose (BC), a renewable and low-cost nanocellulose material, has emerged as a potential solution addressing dye removal from these contaminated waters. Methylene Blue (MB) was selected as a representative dye for our adsorption studies. As a baseline for evaluating efficacy, BC was dried using three different methods: freeze-drying, oven-drying, and room-temperature drying. The adsorptive behavior of these dried BC samples toward MB in an aqueous environment was evaluated. Furthermore, to elucidate the structure–property relationship of dried BC, several characterization techniques were employed. Our studies revealed that freeze-dried BC exhibited the highest initial adsorption rate, while oven-dried BC demonstrated the overall highest adsorption capacity. Moreover, the adsorption data corresponded well with pseudo-second-order and Freundlich isotherm models. This investigation provides a comprehensive understanding of how BC, dried through different methods, performs in the adsorption of MB by establishing a baseline for future research
Sexual and reproductive health service delivery innovations and adaptations during COVID-19: A systematic review and crowdsourcing open call
Get PDFThis paper sought to identify and describe the innovations and adaptations implemented to ensure delivery of Sexual and Reproductive Health services during the COVID-19 pandemic and the potential for enhancing SRH services in other settings or in future emergencies. We searched five databases including PubMed, EMBASE, Scopus, Cochrane Library, and CINAHL. The review was registered on Prospero (CRD42022329411). The open call was launched and promoted widely; each submission was screened by five independent reviewers. The GRADE-CERQual methodology was used to assess confidence in each study finding. A thematic synthesis approach was employed for textual data and for studies with similar outcomes, a fixed effects model was employed. We identified 10,891 citations and 78 studies were included. We received 80 submissions to the open call, and 18 submissions contributed to the study findings. Submissions came from 42 countries, most of which were LMICs (37/42). Telemedicine was one main mode of continuing SRH services during the pandemic (moderate certainty). Teleabortion, or the provision of medication abortion remotely via telemedicine, was found to be a safe and effective way to maintain abortion service (97·9% of cases with 95% CI = 95·6 to 99·4%). However, increased reliance on telemedicine exacerbates inequities for low-income and rural populations. Self-care and self-testing enabled individuals to receive care for STIs (moderate certainty). This work identified strategies used to deliver SRH services during COVID-19 and the data suggest that many strategies relied on telemedicine to sustain SRH services. Self-care interventions were also used to sustain delivery of SRH services. There is need for further research to understand the long-term impact of these interventions and how they can be sustained over time
COVID-19 Pandemic Exposure and Toddler Behavioral Health in the ECHO Program
Get PDFKey Points Question Are toddlers who experienced the COVID-19 pandemic at increased risk for internalizing and externalizing problems? Findings This cohort study of 3438 toddlers across the United States and Puerto Rico found that those born before the pandemic but assessed during it as well as those born and assessed during the pandemic exhibited fewer parent-reported internalizing and externalizing problems compared with toddlers born and assessed before the pandemic. Meaning These findings suggest that pandemic exposure was not associated with increased behavioral difficulties in toddlers and underscore the need to identify protective factors. This cohort study evaluates whether the COVID-19 pandemic was associated with parent-reported internalizing and externalizing problems among US toddlers who participated in the Environmental Influences on Child Health Outcomes (ECHO) program. Importance Studies suggest developmental concerns for infants born during the COVID-19 pandemic, but evidence on its impact on toddler behavioral and emotional well-being remains limited. Objective To assess whether birth timing relative to the COVID-19 pandemic is associated with toddler internalizing and externalizing problems. Design, Setting, and Participants This retrospective cohort study utilized Environmental Influences on Child Health Outcomes (ECHO) cohort data collected between September 27, 2009, and July 21, 2023. Children were divided into 3 groups: the prepandemic group, who were born and assessed before March 13, 2020; the pandemic-assessed group, who were born before March 13, 2020, but assessed after that date; and the pandemic-born group, who were born and assessed on or after March 13, 2020. Data were collected from 9 ECHO cohort sites across the United States and Puerto Rico. Exposure The COVID-19 pandemic, designated as starting on March 13, 2020. Main Outcome and Measure Parent-reported internalizing and externalizing symptoms on the Preschool Child Behavior Checklist (CBCL 1½-5) at age 18 to 39 months. Results The 3438 children (mean [SD] age, 2.33 years [5.38 months]; 1770 [51.5%] male; 537 [16.2%] Black, 1722 [50.1%] Hispanic; and 1538 [44.7%] White) were divided into 3 groups: 1323 in the prepandemic group (mean [SD] age, 2.41 years [5.66 months]); 1690 in the pandemic-assessed group (mean [SD] age, 2.32 years [5.16 months]); and 425 in the pandemic-born group (mean [SD] age, 2.14 years [4.47 months]). Both the pandemic-assessed group (unadjusted β = −1.51; 95% CI, −2.27 to −0.75; adjusted β = −1.73; 95% CI, −2.48 to −0.99) and the pandemic-born group (unadjusted β = −2.03; 95% CI, −3.13 to −0.93; adjusted β = −1.90; 95% CI, −2.99 to −0.80) had lower levels of internalizing problems compared with the prepandemic (ie, historical) group. Similarly, both the pandemic-assessed (unadjusted β = −1.74; 95% CI, −2.46 to −1.02; adjusted β = −1.81; 95% CI, −2.53 to −1.09) and the pandemic-born group (unadjusted β = −3.16; 95% CI, −4.20 to −2.12; adjusted β = −3.17; 95% CI, −4.22 to −2.12) each had lower levels of externalizing problems compared with the prepandemic group. Conclusions and Relevance In this study, toddlers with prenatal and postnatal as well as those with only postnatal COVID-19 pandemic exposure showed fewer internalizing and externalizing problems than those born and assessed prior to the onset of the pandemic. These findings underscore the need for further research to identify protective factors that may buffer the impact of the pandemic on child behavior
A large reverse-genetic screen identifies numerous regulators of testis nascent myotube collective cell migration and collective organ sculpting.
Get PDFCollective cell migration is critical for morphogenesis, homeostasis, and wound healing. Migrating mesenchymal cells form tissues that shape the body's organs. We developed a powerful model, exploring how Drosophila nascent myotubes migrate onto the testis during pupal development, forming the muscles ensheathing it and creating its characteristic spiral shape. To define genes regulating this, we used RNAseq to identify genes expressed in myotubes during migration. Using this dataset, we curated a list of 131 ligands, receptors, and cytoskeletal regulators, including all Rho/Ras/Rap1 regulators, as candidates. We then expressed 279 shRNAs targeting these genes and examined adult testes. We identified 29 genes with diverse roles in morphogenesis. Some have phenotypes consistent with defective migration, while others alter testis shape in different ways, revealing the underlying logic of testis morphogenesis. We followed up the Rho-family GEF dPix in detail. dPix knockdown drastically reduced migration and thus muscle coverage. Our data suggest different isoforms of dPix play distinct roles in this process and reveal a role for its partner Git. We also explored whether dPix regulates Cdc42 activity or cell adhesion. Our RNAseq dataset and genetic analysis provide an important resource for the community to explore cell migration and organ morphogenesis
Toward the clinical translation of safe intravenous long circulating ILNEs contrast agent for CT imaging
Get PDFRationale: X-ray computed tomography (CT) is crucial in precision medicine for diagnostic and therapeutic guidance. However, current small molecule CT contrast agents pose risks such as nephrotoxicity, short blood circulation time, limited scan durations, potential thyroid impact, and immune responses. These challenges necessitate the development of kidney-safe nanoparticle (NP)-based contrast agents (CAs).
Methods: We developed safe intravenous blood pool NP-based CT CAs at a clinical-equivalent dose of 300 mgI/kg, suitable for vascular and hepatic imaging. Our iodinated lipid nanoemulsions (ILNEs) were optimized for shelf-life stability, osmolarity, and viscosity for excellent injectability. The ILNEs were designed to offer high contrast and were tested for minimal protein interaction, prolonged blood circulation, and hepatic clearance. In vitro studies, along with tests in mice and porcine models, were conducted to confirm safety, cytocompatibility, and absence of tissue damage.
Results: The ILNEs demonstrated high x-ray attenuation, improved contrast enhancement, extended stability, and batch-to-batch consistency. They exhibited minimal protein interaction, prolonged blood residency of about 4 h, and hepatic clearance within three days, avoiding nephrotoxicity. Blood and thyroid-stimulating hormone (TSH) analyses, along with kidney and liver function tests, confirmed the safety of ILNEs.
Conclusion: Our ILNEs offer a promising alternative to current CT contrast agents, with improved safety and efficacy profiles. The results support further toxicity evaluations for clinical translation, highlighting the potential of ILNEs in vascular and hepatic imaging without the associated risks of nephrotoxicity
Racism, Sociopolitical Context, and Emotional Well-Being in Immigrant Latina Mothers and Their Preschool-Aged Children: A Mixed Methods Study
Get PDFOBJECTIVE: The cumulative consequences of maternally experienced racism stress may be transmitted intergenerationally from mother to child during sensitive developmental periods. Guided by segmented assimilation theory and the multidimensional conceptualization of racism-related stress, we examined how sociopolitical context (sanctuary vs. nonsanctuary county status) may play a critical role in maternal and child emotional well-being. METHOD: We employed a concurrent nested mixed methods design, QUAN(+qual). Immigrant Latina mothers (N = 92) completed structured questionnaires assessing racism stress, depressive symptoms, and their preschool-aged children's emotional-behavioral difficulties. We conducted bivariate and moderation analyses to examine associations. In addition, a subsample of participants (n = 22) described experiences of racism and/or community support during survey administration; these elaborations were analyzed using conventional content analysis. RESULTS: Mothers residing in nonsanctuary counties reported higher levels of depressive symptoms (z = 2.88, p = .004) and racism stress (z = 2.04, p = .041). Sanctuary county designation moderated the relationship between mothers' experiences of racism stress and children's internalizing and externalizing behaviors, with significantly stronger associations observed in nonsanctuary counties across both adjusted and unadjusted models. Qualitative findings revealed that racism permeated place-based life domains-reinforcing exclusion, posing a pervasive emotional threat, and limiting social mobility. Mothers primarily described intergroup community support in sanctuary counties. CONCLUSIONS: Community-based support programs should expand into areas where families face high levels of racism stress and scarce community support. During the vulnerable postmigration period, mutually opposing forces of community support and racism may have far-reaching impacts across immigrant generations and broader society
Incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in North Carolina from December 2020 – February 2022
Get PDFBACKGROUND: Surveillance estimates of SARS-CoV-2 infections over time have relied on mandatory clinician and laboratory reporting. These estimates increasingly underestimated true viral incidence due to asymptomatic infections, variable access to testing, and self-administered diagnostics. To overcome these limitations, the North Carolina Department of Health and Human Services partnered with academic researchers to conduct three concurrent population-based longitudinal cohort studies in three distinct North Carolina counties to offer more accurate estimates of the incidence, prevalence, and vaccination rates for SARS-CoV-2. METHODS: We enrolled and followed adult residents of three North Carolina counties from August 2020-February 2022. Demographic and health information was collected in biweekly surveys. Nasal swabs were collected biweekly and tested for SARS-CoV-2 using PCR testing. Blood samples were collected monthly and tested for antibodies to the SARS-CoV-2 nucleocapsid and spike proteins. We calculated monthly seroprevalence, sero-incidence, PCR test positivity, and vaccination uptake. RESULTS: We enrolled 646 participants. Routine blood samples and nasal swab samples were contributed by 639 and 642 participants, respectively. By February 2022, 98% (95% CI: 97.4-98.2) had antibodies to the SARS-CoV-2 spike protein, and 13% (95% CI: 12.4-14.2) had antibodies to the nucleocapsid protein, indicating viral exposure. PCR testing detected infection among 14% (95% CI: 13.1-15.0) of participants, but cumulative PCR test positivity was only 1.3% (95% CI: 1.2-1.4). Over half of PCR-detected infections were asymptomatic. By February 2022, 97% of participants had completed the primary vaccine series, and 52% had received a booster dose. CONCLUSIONS: Nearly all participants had anti-SARS-CoV-2 antibodies by the end of follow-up, primarily through vaccination. The incidence of PCR-detected infections was similar to antibody testing, but PCR test positivity substantially underestimated incident infections. These findings emphasize the importance of prospective infection monitoring via antibody testing in a comprehensive approach to tracking viral infections in the community setting
Estimating Daily Suspended Sediment Flux From Multiple Data Sources Using Deep Learning
Get PDFSuspended sediment concentration, flux, and river discharge are essential indicators of river ecosystem health and reflect watershed‐scale processes. Monitoring these variables is labor‐intensive, leading to sparse and geographically biased observations and the development of models to fill in the observational gaps. These models generally use either climatological data or satellite images to estimate one of these variables. In this work, we present a novel deep learning model that can leverage multiple data sources with different temporal characteristics to produce continuous daily estimates of suspended sediment concentration (SSC), suspended sediment flux (SSF), and discharge. The model first encodes daily hydrological data from the ERA5‐Land reanalysis using a Long Short‐Term Memory network and water color data from Landsat satellites using a Multi‐Layer Perceptron network, then merge these encoded data sources using a cross‐attention decoder. We train and test the model on a large data set of in situ observations from 630 river sites over 43 years in the contiguous United States, covering a wide range of watersheds and conditions. We produce SSC, SSF, and discharge predictions with respective relative errors of 49%, 57%, and 44%, and relative bias of −2.5%, 2.6%, and 3.7%. We use our model to create a data set of continuous daily SSC, SSF, and discharge for all large rivers in the contiguous United States. This new model architecture provides a valuable tool for monitoring river systems, addressing limitations of single‐source models and offering a framework applicable to other Earth systems monitoring problems where integrating diverse data streams may be useful. Suspended sediment concentration, flux, and river discharge are essential indicators of river ecosystem health and reflect watershed‐scale processes. Monitoring these variables is labor‐intensive, leading to a lack of global data. In this work, we build a new type of model that can use multiple data sources to predict all three of these variables, compared to existing models that generally use one data source to predict one of the variables. We find that combining data sources and predicting multiple physically related variables improves model accuracy. We develop a model that uses daily meteorological data and irregularly timed optical satellite imagery to predict daily fluvial sediment flux Our model performs as well as existing models with the benefit of predicting daily sediment flux, concentration, and discharge at once This model approach can be extended to other Earth systems processes that need to integrate diverse and sparse data sets for daily estimates We develop a model that uses daily meteorological data and irregularly timed optical satellite imagery to predict daily fluvial sediment flux Our model performs as well as existing models with the benefit of predicting daily sediment flux, concentration, and discharge at once This model approach can be extended to other Earth systems processes that need to integrate diverse and sparse data sets for daily estimate