The devastating effects of the coronavirus disease 2019 (COVID-19) pandemic have made clear a global necessity for antiviral strategies. Most fatalities associated with infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result at least partially from uncontrolled host immune response. Here, we use an antisense compound targeting a previously identified microRNA (miRNA) linked to severe cases of COVID-19. The compound binds specifically to the miRNA in question, miR-2392, which is produced by human cells in several disease states. The safety and biodistribution of this compound were tested in a mouse model via intranasal, intraperitoneal, and intravenous administration. The compound did not cause any toxic responses in mice based on measured parameters, including body weight, serum biomarkers for inflammation, and organ histopathology. No immunogenicity from the compound was observed with any administration route. Intranasal administration resulted in excellent and rapid biodistribution to the lungs, the main site of infection for SARS-CoV-2. Pharmacokinetic and biodistribution studies reveal delivery to different organs, including lungs, liver, kidneys, and spleen. The compound was largely cleared through the kidneys and excreted via the urine, with no accumulation observed in first-pass organs. The compound is concluded to be a safe potential antiviral treatment for COVID-19.

Biliary atresia (BA) is a progressive, inflammatory cholangiopathy that culminates in fibrosis of extrahepatic and intrahepatic bile ducts. A leading theory on the pathogenesis of BA is that the bile duct damage is initiated by a virus infection, followed by a bile duct-targeted autoimmune response. One mechanism of autoimmunity entails diminished number or function of regulatory T cells (Tregs). The aim of this study was to identify potential virus-specific liver T cells from infants with BA at the time of diagnosis, implicating the virus involved in early bile duct damage. A subaim was to determine if presence of virus infection was associated with quantitative changes in Tregs. Results: Liver T cells from BA and control patients were cultured with antigen presenting cells in the presence of a variety of viral or control proteins. 56% of BA patients had significant increases in IFN-γ-producing liver T cells in response to cytomegalovirus (CMV), compared to minimal BA responses to other viruses or the control group CMV response. In addition, a positive correlation between BA plasma CMV IgM and liver T cell CMV reactivity was identified. Investigation of peripheral blood Tregs revealed significant deficits in Tregs frequencies in BA compared to controls, with marked deficits in those BA patients who were positive for CMV. Conclusions: Liver T cell responses to CMV were identified in the majority of BA patients at diagnosis, suggesting perinatal CMV infection as a plausible initiator of bile duct damage. Deficiency of Tregs in BA implies decreased inhibition of inflammation and autoreactivity, potentially allowing for exaggerated bile duct injury.

BACKGROUND & AIMS Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology. The bile duct injury that occurs in patients with BA might result from a hepatobiliary viral infection followed by an autoimmune response against the bile duct epithelia. We aimed to identify autoantigens recognized by serum antibodies in the Rhesus rotavirus (RRV)-induced mouse model of BA; findings were correlated with BA in humans. METHODS Bile duct epithelial proteins were screened for their reactivity with serum antibodies from the mouse model of BA using immunoblot assays. Unique proteins that reacted with sera antibodies were identified by mass spectrometry and verified using enzyme-linked immunosorbent assay (ELISA) and immunoblot analyses. Candidate autoantibodies in BA patient sera were analyzed by ELISA. RESULTS A bile duct epithelial antigen that reacted strongly with serum immunoglobulin (Ig) G from the mouse model of BA was identified as α-enolase. α-Enolase autoantibody specificity was confirmed by ELISA and immunoblot analyses. Anti-RRV and anti-enolase antibodies cross-reacted with enolase and RRV proteins; we identified regions of sequence homology between RRV and enolase. Serum samples from patients with BA had increased levels of anti-enolase IgM and IgG. CONCLUSIONS We have identified autoantibodies against α-enolase in a mouse model of BA (infected with RRV) and in serum samples from patients, indicating a role of humoral autoimmunity in disease pathogenesis. The cross-reactivity between an anti-enolase antibody and RRV proteins indicates that molecular mimicry might activate humoral autoimmunity in BA patients; further studies are required.

Cretaceous ichthyosaurs have typically been considered a small, homogeneous assemblage sharing a common Late Jurassic ancestor. Their low diversity and disparity have been interpreted as indicative of a decline leading to their Cenomanian extinction. We describe the first post-Triassic ichthyosaur from the Middle East, Malawania anachronus gen. et sp. nov. from the Early Cretaceous of Iraq, and re-evaluate the evolutionary history of parvipelvian ichthyosaurs via phylogenetic and cladogenesis rate analyses. Malawania represents a basal grade in thunnosaurian evolution that arose during a major Late Triassic radiation event and was previously thought to have gone extinct during the Early Jurassic. Its pectoral morphology appears surprisingly archaic, retaining a forefin architecture similar to that of its Early Jurassic relatives. After the initial latest Triassic radiation of early thunnosaurians, two subsequent large radiations produced lineages with Cretaceous representatives, but the radiation events themselves are pre-Cretaceous. Cretaceous ichthyosaurs therefore include distantly related lineages, with contrasting evolutionary histories, and appear more diverse and disparate than previously supposed.

As the world braces to enter its fourth year of the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to the treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer, a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed using three separate administration methods, namely, intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound K D of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.

Public concern about oil and gas (O&G) operations in residential areas is substantial. Noise from construction and drilling related to O&G operations may be greater than other phases of O&G operations; yet the impacts of audible and low-frequency noise during these operations are not extensively explored nor the effects on health well understood. This study documents the noise levels at a multi-well O&G well pad during construction and drilling in a residential area in Colorado. A-weighted (dBA) and C-weighted (dBC) noise measurements were collected at four locations during development over a 3-month period. The maximum 1-min equivalent continuous sound levels over a 1-month period were 60.2 dBA and 80.0 dBC. Overall, 41.1% of daytime and 23.6% of nighttime dBA 1-min equivalent continuous noise measurements were found to exceed 50 dBA, and 97.5% of daytime and 98.3% of nighttime measurements were found to exceed 60 dBC. Noise levels exceeding 50 dBA or 60 dBC may cause annoyance and be detrimental to health; thus, these noise levels have the potential to impact health and noise levels and associated health effects warrant further investigation.

Unconventional oil and gas development (UOGD) in the United States is increasingly being conducted on multiwell pads (MWPs) and in residential areas. We measured air pollution, noise, and truck traffic during four distinct phases of UOGD: drilling, hydraulic fracturing, flowback, and production. We monitored particulate matter (PM2.5), black carbon (BC), A-weighted (dBA), and C-weighted (dBC) noise using real-time instruments on 1 and 5 min time scales, and truck traffic for 4–7 days per phase at a large 22-well pad sited in a residential area of Weld County, Colorado. Hydraulic fracturing, which requires frequent truck trips to move supplies and diesel engines to power the process, had the highest median air pollution levels of PM2.5 and BC and experienced the greatest number of heavy trucks per hour compared to other phases. Median air pollution was lowest during drilling at this MWP, possibly because an electric drill rig was used. The equivalent continuous noise level (L eq) exceeded guidelines of 50 dBA and 65 dBC for A-weighted and C-weighted noise, respectively, during all development phases. Our data show that these multiple stressors are present around the clock at these sites, and this work provides baseline measurements on likely human exposure levels near similarly sized MWPs.

Background: Oil and natural gas (O&G) extraction emits pollutants that are associated with cardiovascular disease, the leading cause of mortality in the United States. Objective: We evaluated associations between intensity of O&G activity and cardiovascular disease indicators. Methods: Between October 2015 and May 2016, we conducted a cross-sectional study of 97 adults living in Northeastern Colorado. For each participant, we collected 1-3 measurements of augmentation index, systolic and diastolic blood pressure (SBP and DBP), and plasma concentrations of interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). We modelled the intensity of O&G activity by weighting O&G well counts within 16 km of a participant's home by intensity and distance. We used linear models accounting for repeated measures within person to evaluate associations. Results: Adjusted mean augmentation index differed by 6.0% (95% CI: 0.6, 11.4%) and 5.1% (95%CI: −0.1, 10.4%) between high and medium, respectively, and low exposure tertiles. The