SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.

Support for management actions to protect night sky quality: Insights from visitors to state and national park units in the U.S.

Light pollution is a global phenomenon where anthropogenic light sources continue to grow unabated, affecting both social and ecological systems. This is leaving parks and protected areas as some of the last vestiges of naturally dark environments for protecting views of the night sky. Yet, even parks and protected areas have outdoor lighting. Alternative lighting practices are needed to reduce or prevent light pollution from within parks. However, making parks darker may not be desirable for some visitors if they believe it will reduce navigability, safety, or restrict how they recreate (e.g., requiring the use of red-light flashlights after dark and before dawn). How visitors will respond to alternative lighting practices that park managers can implement is still unknown. We used an on-site intercept survey at nine state and national park units in Utah, U.S., to investigate nighttime visitors' support or opposition to management actions to protect night sky quality and their interest in learning about topics related to night skies. Further, this study also segmented visitors into two groups: those 'dependent' on the dark sky as a resource and those whose activities did not depend on a dark sky. Defining what a 'dark sky dependent' visitor is, which has yet to be done in the literature, is a fundamental step to furthering night sky research and management efforts. Across nine parks and protected areas, 62% of nighttime visitors participated in dark sky dependent activities. Findings indicate broad support for management actions designed to improve night sky quality, with between 74% and 89% of all visitors supporting seven different management actions. There was stronger support from dark sky dependent visitors for some elements of alternative lighting practices, but there was still strong support for those who do not participate in dark sky dependent outdoor recreation. Additionally, between 57% and 75% of visitors were interested in learning more about topics related to night skies. This research indicates most visitors would welcome actions to preserve the quality of the rapidly dwindling naturally dark experiences offered by parks and protected areas.

Public and manager perceptions about prescribed fire in the Mid-Atlantic, United States.

Firescapes of the Mid-Atlantic are understudied compared to other ecosystems in the United States, and little is known about the acceptance of prescribed fire as a forest management tool. Yet, this region harbors high levels of wildland-urban interface (WUI), has a close intermingling of land ownerships, and reflects substantial regional heterogeneity in burning histories and fire hazards. As prescribed fire is increasingly applied in the Mid-Atlantic as a critical tool to meet various land management objectives, research is needed to help managers understand community perceptions of prescribed fire implementation. Through intercept surveys of forest recreationists and online surveys of fire managers, this study investigates perceptions about prescribed fire use in the Mid-Atlantic, in addition to the critical contributing factors of public support toward prescribed fires. Two states, Pennsylvania and New Jersey, were selected as case studies to explore regional differences in social perception due to their contrasts in fire history, policy, management objectives, and social exposure. Our results show moderate social awareness of local prescribed fires, moderate to high familiarity with prescribed burning, high agency trust, and strong community support toward prescribed fires. However, the perceived concerns and benefits differed between managers and forest recreationists and between recreationists from Pennsylvania and New Jersey. The factors influencing the support of prescribed burning practices included forest management beliefs, concern about prescribed fire effects, familiarity with prescribed fires as a forest management tool, and awareness of local prescribed fires. Collectively, these results highlighted needs in public outreach to strengthen education, build broader community awareness, engage critical stakeholder groups such as forest recreationists, and re-align public outreach messages based on community-level concerns and perceived benefits. Additionally, it will be vital for the scientific community to help monitor critical shifts in forest value orientations and fill in significant research gaps regarding prescribed fire benefits.

Acceptability factors for wildlife approach in park and protected area settings.

Human-wildlife conflicts are a challenge in parks and protected areas around the world. Facilitating quality wildlife viewing experiences that minimize negative impacts to people and animals is often complicated by distance-related human behaviors. The purpose of this study was to examine how people's distance-related norms varied as a function of proximity from wildlife, wildlife species, and physical landscape features. By using virtual reality technology and simulations, this study assessed how physical landscape features (i.e., an open field, deadfall, and a paved road) impact wildlife viewing norms and also compared norms among three different wildlife species (i.e., bison, bear, and elk). Data were analyzed with repeated measures ANOVA to explore how these factors influenced acceptability ratings of distances between people and wildlife. Results revealed a significant interaction between distance to wildlife and landscape features. Recommendations for improving the management of humanwildlife conflicts and future research directions are discussed.

Mutualism Wildlife Value Orientations Predict Support for Messages About Distance-Related Wildlife Conflict.

Wildlife value orientations (WVOs) are used to address human-wildlife conflicts by developing value-framed messaging. However, little is known about whether WVOs (i.e., mutualism, domination) are useful in distance-related wildlife safety communication strategies. This study explores the predictive ability of mutualism and domination value orientations on study participants' levels of agreement with distance-related safety messages. Distance-related wildlife safety messages were crafted to appeal to the four WVO typologies (i.e., traditionalist, mutualist, pluralist, and distanced). Undergraduate students were asked to rate their levels of agreement with a series of distance-related messages. Confirmatory factor analyses were used to create domination and mutualism dimension scores. Multiple regressions predicted levels of agreement with each of the messages from domination and mutualism. Study results indicated that in this sample of undergraduate student participants, only mutualism values predicted distance-related wildlife safety message agreement. This information can be used to help frame communications about distance-related wildlife issues.

The phantom chorus: birdsong boosts human well-being in protected areas.

Spending time in nature is known to benefit human health and well-being, but evidence is mixed as to whether biodiversity or perceptions of biodiversity contribute to these benefits. Perhaps more importantly, little is known about the sensory modalities by which humans perceive biodiversity and obtain benefits from their interactions with nature. Here, we used a 'phantom birdsong chorus' consisting of hidden speakers to experimentally increase audible birdsong biodiversity during 'on' and 'off' (i.e. ambient conditions) blocks on two trails to study the role of audition in biodiversity perception and self-reported well-being among hikers. Hikers exposed to the phantom chorus reported higher levels of restorative effects compared to those that experienced ambient conditions on both trails; however, increased restorative effects were directly linked to the phantom chorus on one trail and indirectly linked to the phantom chorus on the other trail through perceptions of avian biodiversity. Our findings add to a growing body of evidence linking mental health to nature experiences and suggest that audition is an important modality by which natural environments confer restorative effects. Finally, our results suggest that maintaining or improving natural soundscapes within protected areas may be an important component to maximizing human experiences.

Extracellular histones induce calcium signals in the endothelium of resistance-sized mesenteric arteries and cause loss of endothelium-dependent dilation.

Histone proteins are elevated in the circulation after traumatic injury owing to cellular lysis and release from neutrophils. Elevated circulating histones in trauma contribute to coagulopathy and mortality through a mechanism suspected to involve endothelial cell (EC) dysfunction. However, the functional consequences of histone exposure on intact blood vessels are unknown. Here, we sought to understand the effects of clinically relevant concentrations of histones on the endothelium in intact, resistance-sized, mesenteric arteries (MAs). EC Ca2+ was measured with high spatial and temporal resolution in MAs from mice selectively expressing the EC-specific, genetically encoded ratiometric Ca2+ indicator, Cx40-GCaMP-GR, and vessel diameter was measured by edge detection. Application of purified histone protein directly to the endothelium of en face mouse and human MA preparations produced large Ca2+ signals that spread within and between ECs. Surprisingly, luminal application of histones had no effect on the diameter of pressurized arteries. Instead, after prolonged exposure (30 min), it reduced dilations to endothelium-dependent vasodilators and ultimately caused death of ~25% of ECs, as evidenced by markedly elevated cytosolic Ca2+ levels (793 ± 75 nM) and uptake of propidium iodide. Removal of extracellular Ca2+ but not depletion of intracellular Ca2+ stores prevented histone-induced Ca2+ signals. Histone-induced signals were not suppressed by transient receptor potential vanilloid 4 (TRPV4) channel inhibition (100 nM GSK2193874) or genetic ablation of TRPV4 channels or Toll-like receptor receptors. These data demonstrate that histones are robust activators of noncanonical EC Ca2+ signaling, which cause vascular dysfunction through loss of endothelium-dependent dilation in resistance-sized MAs. NEW & NOTEWORTHY We describe the first use of the endothelial cell (EC)-specific, ratiometric, genetically encoded Ca2+ indicator, Cx40-GCaMP-GR, to study the effect of histone proteins on EC Ca2+ signaling. We found that histones induce an influx of Ca2+ in ECs that does not cause vasodilation but instead causes Ca2+ overload, EC death, and vascular dysfunction in the form of lost endothelium-dependent dilation.

Merging elaboration and the theory of planned behavior to understand bear spray behavior of day hikers in Yellowstone National Park.

This research empirically merges together two related theories: the elaboration likelihood model and the theory of planned behavior. A structural equation modeling approach is used to evaluate the relationship between the two theories and their collective impacts on behavioral intentions. The results suggest elaboration predicts the components of the theory of planned behavior (attitudes, subjective norms, and perceived behavior control), which in turn all predicted behavior intentions. Furthermore, results showed that the components of the theory of planned behavior partially meditated the relationship between elaboration and behavioral intentions, indicating that elaboration works mostly through the components of the theory of planned behavior to impact behavioral intentions. This study represents an improved understanding of the influence of communication techniques on visitor behaviors in sustainable tourism settings. Additionally, the discussion exemplifies how these techniques can be used to improve communications and evaluate communication strategies.

Enantioselective Crossed Photocycloadditions of Styrenic Olefins by Lewis Acid Catalyzed Triplet Sensitization.

The synthesis of unsymmetrical cyclobutanes by controlled heterodimerization of olefins remains a substantial challenge, particularly in an enantiocontrolled fashion. Shown herein is that chiral Lewis acid catalyzed triplet sensitization enables the synthesis of highly enantioenriched diarylcyclobutanes by photocycloaddition of structurally varied 2'-hydroxychalcones with a range of styrene coupling partners. The utility of this reaction is demonstrated through the direct synthesis of a representative norlignan cyclobutane natural product.

Regiodivergent and Stereoselective Hydrosilylation of 1,3-Disubstituted Allenes.

Methods for the highly stereoselective and regiodivergent hydrosilylation of 1,3-disubstituted allenes have been developed. The synthesis of E allylsilanes is accomplished with palladium NHC catalysts, and trisubstituted Z alkenylsilanes are accessed with nickel NHC catalysts. Unsymmetrically substituted allenes are well tolerated with nickel catalysis and afford Z alkenylsilanes. Evidence for a plausible mechanism was obtained through an isotopic double-labeling crossover study.

Regioselective allene hydrosilylation catalyzed by N-heterocyclic carbene complexes of nickel and palladium.

Regioselective methods for allene hydrosilylation have been developed, with regioselectivity being governed primarily by the choice of metal. Alkenylsilanes are produced via nickel catalysis with larger N-heterocyclic carbene (NHC) ligands, and allylsilanes are produced via palladium catalysis with smaller NHC ligands. These complementary methods allow either regioisomeric product to be obtained with exceptional regiocontrol.

Beyond uterine atony: characterizing postpartum hemorrhage coagulopathy.

BACKGROUND: Postpartum hemorrhage is a leading cause of morbidity and mortality worldwide, yet the associated early coagulopathy is not well defined. OBJECTIVE: We hypothesized that women who develop postpartum hemorrhage have a distinct derangement of thrombin generation and coagulation factors compared with postpartum women without postpartum hemorrhage. STUDY DESIGN: This prospective study of pregnant patients with postpartum hemorrhage was completed at a single urban hospital. Blood was drawn on postpartum hemorrhage diagnosis and 2 and 4 hours later. Assays of patients with postpartum hemorrhage included thrombelastography, whole blood thrombin generation, coagulation factor activity, tissue factor levels and activity, and tissue factor pathway inhibitor levels, which were compared with that of patients without postpartum hemorrhage. RESULTS: A total of 81 patients were included in this study. Of those patients, 66 had postpartum hemorrhage, and 15 served as controls. Compared with patients without PPH, patients with postpartum hemorrhage had lower fibrinogen levels (469.0 mg/dL vs 411.0 mg/dL; P=.02), increased tissue plasminogen activator resistance (fibrinolysis 30 minutes after maximal clot strength: 8.7% vs 4.2%; P=.02), decreased peak thrombin concentration (150.2 nM vs 40.7 nM; P=.01), and decreased maximal rate of thrombin generation (60.1 nM/minute vs 2.8 nM/minute; P=.02). Furthermore, compared with patients without postpartum hemorrhage, patients with postpartum hemorrhage had decreased tissue factor levels (444.3 pg/mL vs 267.1 pg/mL; P=.02) and increased tissue factor pathway inhibitor levels (0.6 U/mL vs 0.8 U/mL; P=.04), with decreased tissue factor pathway inhibitor ratios (624 vs 299; P=.01). CONCLUSION: PPH is not only an issue of uterine tone and mechanical bleeding but also a distinct coagulopathy that is characterized by decreased fibrinogen level, clot breakdown resistance, and markedly low thrombin generation. This pathology seemed to be driven by low tissue factor and high tissue factor pathway inhibitor levels.

A multi-dimensional measure of pro-environmental behavior for use across populations with varying levels of environmental involvement in the United States.

Researchers continue to explore ways to understand and promote pro-environmental behavior (PEB) amongst various populations. Despite this shared goal, much debate exists on the operationalization and the dimensionality of PEB and how it is measured. This piecemeal approach to measurement has limited the ability to draw conclusions across studies. We address limitations associated with previous measures of PEB by developing a multi-dimensional scale that is validated across both a general population of individuals residing in the United States as well as a group of individuals associated with a pro-environmental organization. Exploratory and confirmatory factor analyses and reliability estimation were conducted for the developed measure across these two populations. Measurement invariance testing was also utilized to assess the psychometric stability of the scale across the two groups. Results indicated an 11 item scale was best fitting with two sub-scales: private and public behaviors. Implications for research and practice are discussed.

Observing COVID-19 related behaviors in a high visitor use area of Arches National Park.

INTRODUCTION: Visitation to parks and protected areas is a common COVID-19 coping strategy promoted by state and national public health officials and political leadership. Crowding and congestions in parks has been a perennial problem and the ability to socially distance within them is an unproven assumption. Is it possible to socially distance in a busy national park that has been designed to concentrate use? METHODOLOGY/PRINCIPAL FINDINGS: An observational study was conducted in July 2020 at the outside foyer of the Visitor Center of Arches National Park. Motion sensor cameras were placed to record one-minute videos when a person entered the field of view. Number of groups, group size, facial coverings and encounters within 6 feet (1.83 meters) of other groups were recorded. Groups were smaller on average than recorded in previous studies. Approximately 61% of the visitors wore masks. Most groups (69%) were able to experience the visitor center with no intergroup encounters. We model the probability of intergroup encounters and find as group size and number of groups increases, the probability of encounters rises. With four groups present, the probability of one or more encounters ranges from 19% to 40% for common group sizes, while if eight groups are present, the probability of one or more encounters increases from 34% to 64% for common group sizes. CONCLUSIONS/SIGNIFICANCE: Under conditions in which park visitors have the physical space to avoid close encounters with other groups they are taking advantage of the opportunity. Visitors are minimizing group size, wearing masks, and remaining socially distant. However, encounters increase as the number or the size of the groups increases. In other areas of the parks this ability to avoid encounters may not be as possible. We recommend that park managers continue to appeal for compliance with CDC guidelines, especially the wearing of masks and encouraging visitors to split up into small groups when visiting.

An oropharyngeal device for airway management of conscious and semiconscious patients: A randomized clinical trial.

OBJECTIVE: No oropharyngeal devices exist for use in conscious and semiconscious trauma patients during emergency evacuation, transport, or resuscitation. We aimed to test the hypotheses that the ManMaxAirway (MMA) is better tolerated than the standard Guedel-style device in awake volunteers and that it produces a jaw thrust and improves air flow. METHODS: This was a randomized cross-over study of healthy volunteers with either the MMA or standard device. The primary outcome of tolerability was defined as maintaining the device in place for 60 seconds. Secondary outcomes included respiratory system function and jaw thrust. Resistance to airflow through the device lumen was measured in situ and when placed in subjects in the pulmonary laboratory alone. Jaw thrust was quantified as displacement between the mandibular condyle and condylar fossa apex relative to baseline visualized with magnetic resonance imaging (MRI). RESULTS: We enrolled 19 subjects. Of these, a convenience sample of 5 individuals was selected for MRI; the remaining individuals (n = 14) were randomized for the cross-over study. All 14 subjects were able to maintain the MMA for 60 seconds compared with 2/14 (14%) with the standard device (odds ratio, 145; 95% confidence interval, 6.3-3314). Subjects reported that the experimental device was more comfortable and its placement did not trigger the gag reflex. Airway resistance produced by the MMA in an oscillatory flow model was nearly an order of magnitude lower than that of the standard device (experimental vs standard, 8 Hz-0.092 vs 0.786 cmH20·s/L; 15 Hz-0.193 vs 1.321 cmH20·s/L). Rapid induction of the gag reflex precluded further measurements with the standard device. Forced oscillation pulmonary testing in conscious volunteers with and without the MMA demonstrated that the device decreased respiratory system resistance to airflow and reduced respiratory elastance (31% ± 8% and 44% ± 13.4%, respectively; P < 0.05). MRIs of the subjects (n = 5) with the MMA in place showed a significant jaw thrust compared with baseline (7 ± 1 mm). CONCLUSIONS: The MMA proved well tolerated in conscious subjects, resulting in an opening of the anatomic airway and a decreased resistance to airflow.

Interspecies Organogenesis for Human Transplantation.

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.

Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer.

Relatively few catalytic systems are able to control the stereochemistry of electronically excited organic intermediates. Here we report the discovery that a chiral Lewis acid complex can catalyze triplet energy transfer from an electronically excited photosensitizer. We applied this strategy to asymmetric [2 + 2] photocycloadditions of 2'-hydroxychalcones, using tris(bipyridyl) ruthenium(II) as a sensitizer. A variety of electrochemical, computational, and spectroscopic data rule out substrate activation by means of photoinduced electron transfer and instead support a mechanism in which Lewis acid coordination dramatically lowers the triplet energy of the chalcone substrate. We expect that this approach will enable chemists to more broadly apply their detailed understanding of chiral Lewis acid catalysis to stereocontrol in reactions involving electronically excited states.

Regioselective allene hydroarylation via one-pot allene hydrosilylation/Pd-catalyzed cross-coupling.

Advances in hydroarylation have been achieved by the development of a one-pot regioselective allene hydrosilylation/Pd(0)-catalyzed cross-coupling protocol. The regioselectivity is primarily governed by N-heterocyclic carbene (NHC) ligand identity in the hydrosilylation step and is preserved in the subsequent cross-coupling reaction. This methodology affords streamlined access to functionalized 1,1-disubstituted alkenes with excellent regiocontrol.