Understanding and minimizing coronavirus disease 2019 (COVID‐19) vaccine hesitancy is critical to population health and minimizing health inequities, which continue to be brought into stark relief by ...the pandemic. We investigate questions regarding vaccine hesitancy in a sample (n = 1205) of Arkansas adults surveyed online in July/August of 2020. We examine relationships among sociodemographics, COVID‐19 health literacy, fear of COVID‐19 infection, general trust in vaccines, and COVID‐19 vaccine hesitancy using bivariate analysis and a full information maximum likelihood (FIML) logistic regression model. One in five people (21,21.86%) reported hesitancy to take a COVID‐19 vaccine. Prevalence of COVID‐19 vaccine hesitancy was highest among Black/African Americans (50.00%), respondents with household income less than $25K (30.68%), some college (32.17%), little to no fear of infection from COVID‐19 (62.50%), and low trust in vaccines in general (55.84%). Odds of COVID‐19 vaccine hesitancy were 2.42 greater for Black/African American respondents compared to White respondents (p < 0.001), 1.67 greater for respondents with some college/technical degree compared to respondents with a 4‐year degree (p < 0.05), 5.48 greater for respondents with no fear of COVID‐19 infection compared to those who fear infection to a great extent (p < 0.001), and 11.32 greater for respondents with low trust in vaccines (p < 0.001). Sociodemographic differences in COVID‐19 vaccine hesitancy raise concerns about the potential of vaccine implementation to widen existing health disparities in COVID‐19 related infections, particularly among Black/African Americans. Fear of infection and general mistrust in vaccines are significantly associated with vaccine hesitancy.
The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. ...However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein–DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain–promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.
The CRISPR-Cas9 nuclease has been widely repurposed as a molecular and cell biology tool for its ability to programmably target and cleave DNA. Cas9 recognizes its target site by unwinding the DNA ...double helix and hybridizing a 20-nucleotide section of its associated guide RNA to one DNA strand, forming an R-loop structure. A dynamic and mechanical description of R-loop formation is needed to understand the biophysics of target searching and develop rational approaches for mitigating off-target activity while accounting for the influence of torsional strain in the genome. Here we investigate the dynamics of Cas9 R-loop formation and collapse using rotor bead tracking (RBT), a single-molecule technique that can simultaneously monitor DNA unwinding with base-pair resolution and binding of fluorescently labeled macromolecules in real time. By measuring changes in torque upon unwinding of the double helix, we find that R-loop formation and collapse proceed via a transient discrete intermediate, consistent with DNA:RNA hybridization within an initial seed region. Using systematic measurements of target and off-target sequences under controlled mechanical perturbations, we characterize position-dependent effects of sequence mismatches and show how DNA supercoiling modulates the energy landscape of R-loop formation and dictates access to states competent for stable binding and cleavage. Consistent with this energy landscape model, in bulk experiments we observe promiscuous cleavage under physiological negative supercoiling. The detailed description of DNA interrogation presented here suggests strategies for improving the specificity and kinetics of Cas9 as a genome engineering tool and may inspire expanded applications that exploit sensitivity to DNA supercoiling.
The delivery of CRISPR ribonucleoproteins (RNPs) for genome editing in vitro and in vivo has important advantages over other delivery methods, including reduced off-target and immunogenic effects. ...However, effective delivery of RNPs remains challenging in certain cell types due to low efficiency and cell toxicity. To address these issues, we engineer self-deliverable RNPs that can promote efficient cellular uptake and carry out robust genome editing without the need for helper materials or biomolecules. Screening of cell-penetrating peptides (CPPs) fused to CRISPR-Cas9 protein identifies potent constructs capable of efficient genome editing of neural progenitor cells. Further engineering of these fusion proteins establishes a C-terminal Cas9 fusion with three copies of A22p, a peptide derived from human semaphorin-3a, that exhibits substantially improved editing efficacy compared to other constructs. We find that self-deliverable Cas9 RNPs generate robust genome edits in clinically relevant genes when injected directly into the mouse striatum. Overall, self-deliverable Cas9 proteins provide a facile and effective platform for genome editing in vitro and in vivo.
Today, insular Southeast Asia is important for both its remarkably rich biodiversity and globally significant roles in atmospheric and oceanic circulation. Despite the fundamental importance of ...environmental history for diversity and conservation, there is little primary evidence concerning the nature of vegetation in north equatorial Southeast Asia during the Last Glacial Period (LGP). As a result, even the general distribution of vegetation during the Last Glacial Maximum is debated. Here we show, using the stable carbon isotope composition of ancient cave guano profiles, that there was a substantial forest contraction during the LGP on both peninsular Malaysia and Palawan, while rainforest was maintained in northern Borneo. These results directly support rainforest "refugia" hypotheses and provide evidence that environmental barriers likely reduced genetic mixing between Borneo and Sumatra flora and fauna. Moreover, it sheds light on possible early human dispersal events.
Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-024-45998-2, published online 26 February 2024. In the Acknowledgements section of this article, the grant number relating to ...National Institutes of Health funding to J.A.D. was incorrectly given as RM1HG009490 and should have been U19NS132303. The grant number 2334028 relating to the National Science Foundation funding to J.A.D. was omitted. Funding from Hampton University Summer Undergraduate Research Program, Mr. Li Ka Shing, Emerson Collective and the Innovative Genomics Institute (IGI) were omitted. The original article has been corrected.
Objectives
To report our success and complication rates with emergency department (ED) technician–performed ultrasound (US)‐guided peripheral intravenous (IV) catheter placement and to compare our ...results to similar studies in the literature.
Methods
We conducted a retrospective review of a prospective database of patients who underwent US‐guided peripheral IV catheter placement attempts for clinical care in the ED. All patients meeting difficult IV access criteria who had a US‐guided peripheral IV catheter placement attempted by a trained ED technician were included. Average attempts per success and overall success rates were compared to similar published studies.
Results
There were 830 participants, with an overall success rate of ED technician– performed US‐guided peripheral IV catheter placement of 97.5%. Clinicians categorized 82.6% of participants as having difficult IV access and reported that in 46.5%, a central venous catheter would have been necessary if the US‐guided peripheral IV catheter failed. Of successful catheter attempts, 86.8% were placed on the first attempt; 11.6% were placed on the second attempt; and 1.6% were placed on the third attempt. For this study, the average number of attempts per success was 1.15 (95% confidence interval, 1.12–1.18), which was lower than in 6 other published studies, ranging from 1.27 to 1.70. The overall success rate of our ED technician‐performed attempts was 0.970 (95% confidence interval, 0.956–0.983), which was higher than that reported in previous ED technician studies (0.79–0.80), and closer to that reported for physicians or nurses (0.87–0.97). The arterial puncture complication rate was 0.8%, which was also lower than in other published studies (1.25%–9.80%).
Conclusions
With brief but comprehensive training, ED technicians can successfully obtain US‐guided peripheral IV catheter access in patients with difficult IV access.
We administered a survey during the fifteen-minute wait time after the COVID-19 vaccine was given (N = 1475) to examine attitudes towards COVID-19 vaccines among adults who were vaccinated in ...Arkansas between April 22nd and July 6th, 2021. We found 60% of those who had just been vaccinated reported some level of hesitancy, including 10% who reported being “very hesitant.” Hesitancy was not evenly distributed across sociodemographic groups (age, sex, race/ethnicity, and education) and was associated with whether a non-English language is spoken in the home, health care coverage, and flu vaccination over the past five years in bivariate analysis. Generalized ordered logistic regression results reveal associations between the log-ordered odds of COVID-19 vaccine hesitancy and age, sex, race/ethnicity, health care coverage, health literacy, and flu vaccination over the past five years. Surprisingly, a prior COVID-19 diagnosis was not significantly associated with COVID-19 vaccine hesitancy. These results can inform health care and communication strategies. Further attention to “hesitant adopters” can provide insights into the process of overcoming vaccine hesitancy that are critical to vaccine uptake.
Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we ...demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.
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