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Background: Most patients in specialty drug treatment programs that are not federally licensed Opioid Treatment Programs (OTPs) programs do not receive medications for opioid use disorder (MOUD)., Methods: We linked results from a survey of non-OTP treatment program directors in New Jersey (n = 81) to statewide administrative records of admissions for opioid use to those programs between July 2021-June 2022. Using multi-level regression, we examined the association of three types of factors with planned MOUD use: program survey responses, client-level factors, and program-level client characteristic mix., Results: Of 9583 opioid treatment admissions in non-OTP settings, 41 % included treatment plans involving MOUD. Programs where directors reported staff concerns about buprenorphine's efficacy or diversion had a lower proportion of clients with planned MOUD, as did programs reporting too little physical space to prescribe. Being self-referred to treatment, unemployed and not looking for work, aged 30-49, heroin use (vs. prescription opioid use), and stimulant use in addition to opioids, were positively associated with planned MOUD; while non-Medicaid insurance, and Black and Hispanic race/ethnicity, were negatively associated with planned MOUD. Clients were more likely to have planned MOUD if their programs had a higher proportion of clients aged 30 or older, heroin as primary "drug of abuse," stimulant use, and not working but actively looking for work., Conclusion: Findings suggest addressing program staff attitudes toward buprenorphine could help increase planned MOUD. There is also a need to improve access for clients with non-Medicaid insurance, address within-program race and ethnic disparities, and address employment-related barriers to medication., Competing Interests: Declaration of competing interest This research was supported by a grant from Bloomberg Philanthropies. The authors have no interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epitopes, we generated an influenza virus particle where the full-length hemagglutinin protein was replaced with a membrane-anchored, "headless" variant while retaining the normal complement of other viral structural proteins such as the neuraminidase as well as viral RNAs. We found that a single administration of a headless virus particle-based vaccine elicited high titers of antibodies that recognized more conserved epitopes on the major viral glycoproteins. Furthermore, the vaccine could elicit these responses even in the presence of pre-existing, hemagglutinin (HA) head-focused influenza immunity. Importantly, these antibody responses mediated protective, but non-neutralizing functions such as neuraminidase inhibition and antibody-dependent cellular cytotoxicity. Additionally, we show the vaccine can provide protection from homologous and heterologous challenges in mouse models of severe influenza without any measurable HA head-directed antibody responses. Thus, headless hemagglutinin containing viral particles may represent a tool to drive the types of antibody responses predicted to increase influenza vaccine breadth and durability.IMPORTANCECurrent seasonal influenza vaccines provide incomplete protection from disease. This is partially the result of the antibody response being directed toward parts of the virus that are tolerant of mutations. Redirecting the immune response to more conserved regions of the virus has been a central strategy of next-generation vaccine designs and approaches. Here, we develop and test a vaccine based on a modified influenza virus particle that expresses a partially deleted hemagglutinin protein along with the other viral structural proteins. We demonstrate this vaccine elicits antibodies that recognize the more conserved viral epitopes of the hemagglutinin stalk and neuraminidase protein to facilitate protection against influenza viruses despite a lack of classical viral neutralization activity., Competing Interests: Duke University has filed for intellectual property protection of the vaccine production approaches and antigen designs described in this work.

Influenza viruses cause substantial morbidity and mortality every year despite seasonal vaccination. mRNA-based vaccines have the potential to elicit more protective immune responses, but for maximal breadth and durability, it is desirable to deliver both the viral hemagglutinin and neuraminidase glycoproteins. Delivering multiple antigens individually, however, complicates manufacturing and increases cost, thus it would be beneficial to express both proteins from a single mRNA. Here, we develop an mRNA genetic configuration that allows the simultaneous expression of unmodified, full-length NA and HA proteins from a single open reading frame. We apply this approach to glycoproteins from contemporary influenza A and B viruses and, after vaccination, observe high levels of functional antibodies and protection from disease in female mouse and male ferret challenge models. This approach may further efforts to utilize mRNA technology to improve seasonal vaccine efficacy by efficiently delivering multiple viral antigens simultaneously and in their native state., (© 2024. The Author(s).)

The CRISPR-Cas13 system has been proposed as an alternative treatment of viral infections. However, for this approach to be adopted as an antiviral, it must be optimized until levels of efficacy rival or exceed the performance of conventional approaches. To take steps toward this goal, we evaluated the influenza viral RNA degradation patterns resulting from the binding and enzymatic activity of mRNA-encoded LbuCas13a and two crRNAs from a prior study, targeting PB2 genomic and messenger RNA. We found that the genome targeting guide has the potential for significantly higher potency than originally detected, because degradation of the genomic RNA is not uniform across the PB2 segment, but it is augmented in proximity to the Cas13 binding site. The PB2 genome targeting guide exhibited high levels (>1 log) of RNA degradation when delivered 24 hours post-infection in vitro and maintained that level of degradation over time, with increasing multiplicity of infection (MOI), and across modern influenza H1N1 and H3N2 strains. Chemical modifications to guides with potent LbuCas13a function, resulted in nebulizer delivered efficacy (>1-2 log reduction in viral titer) in a hamster model of influenza (Influenza A/H1N1/California/04/09) infection given prophylactically or as a treatment (post-infection). Maximum efficacy was achieved with two doses, when administered both pre- and post-infection. This work provides evidence that mRNA-encoded Cas13a can effectively mitigate Influenza A infections opening the door to the development of a programmable approach to treating multiple respiratory infections., Competing Interests: D.V. and P.J.S. have a patent applied for regarding the polymer used in this work. D.V., C.Z. and P.J.S. have a provisional patent filed for the guides described in this work, and are co-founders of Tether Therapeutics. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. All other authors declare no competing interests., (Copyright: © 2024 Chaves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Medications for opioid use disorder (MOUD), including buprenorphine, reduce overdose risk and improve outcomes for individuals with opioid use disorder (OUD). However, historically, most non-opioid treatment program (non-OTP) specialty substance use treatment programs have not offered buprenorphine. Understanding barriers to offering buprenorphine in specialty substance use treatment settings is critical for expanding access to buprenorphine. This study aims to examine program-level attitudinal, financial, and regulatory factors that influence clients' access to buprenorphine in state-licensed non-OTP specialty substance use treatment programs., Methods: We surveyed leadership from state-licensed non-OTP specialty substance use treatment programs in New Jersey about organizational characteristics, including medications provided on- and off-site and percentage of OUD clients receiving any type of MOUD, and perceived attitudinal, financial, and regulatory barriers and facilitators to buprenorphine. The study estimated prevalence of barriers and compared high MOUD reach (n = 36, 35 %) and low MOUD reach (n = 66, 65 %) programs., Results: Most responding organizations offered at least one type of MOUD either on- or off-site (n = 80, 78 %). However, 71 % of organizations stated that fewer than a quarter of their clients with OUD use any type of MOUD. Endorsement of attitudinal, financial, and institutional barriers to buprenorphine were similar among high and low MOUD reach programs. The most frequently endorsed government actions suggested to increase use of buprenorphine were facilitating access to long-acting buprenorphine (n = 95, 96 %), education and stigma reduction for clients and families (n = 95, 95 %), and financial assistance to clients to pay for medications (n = 90, 90 %)., Conclusions: Although non-OTP specialty substance use programs often offer clients access to MOUD, including buprenorphine, most OUD clients do not actually receive MOUD. Buprenorphine uptake in these settings may require increased financial support for programs and clients, more robust education and training for providers, and efforts to reduce the stigma associated with medication among clients and their families., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Current seasonal influenza virus vaccines induce responses primarily against immunodominant but highly plastic epitopes in the globular head of the hemagglutinin (HA) glycoprotein. Because of viral antigenic drift at these sites, vaccines need to be updated and readministered annually. To increase the breadth of influenza vaccine-mediated protection, we developed an antigenically complex mixture of recombinant HAs designed to redirect immune responses to more conserved domains of the protein. Vaccine-induced antibodies were disproportionally redistributed to the more conserved stalk of the HA without hindering, and in some cases improving, antibody responses against the head domain. These improved responses led to increased protection against homologous and heterologous viral challenges in both mice and ferrets compared with conventional vaccine approaches. Thus, antigenically complex protein mixtures can at least partially overcome HA head domain antigenic immunodominance and may represent a step toward a more universal influenza vaccine.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

NASA's first asteroid sample return mission, OSIRIS-REx, collected a sample from the surface of near-Earth asteroid Bennu in October 2020 and will deliver it to Earth in September 2023. Selecting a sample collection site on Bennu's surface was challenging due to the surprising lack of large ponded deposits of regolith particles exclusively fine enough ( ≤ 2 cm diameter) to be ingested by the spacecraft's Touch-and-Go Sample Acquisition Mechanism (TAGSAM). Here we describe the Sampleability Map of Bennu, which was constructed to aid in the selection of candidate sampling sites and to estimate the probability of collecting sufficient sample. "Sampleability" is a numeric score that expresses the compatibility of a given area's surface properties with the sampling mechanism. The algorithm that determines sampleability is a best fit functional form to an extensive suite of laboratory testing outcomes tracking the TAGSAM performance as a function of four observable properties of the target asteroid. The algorithm and testing were designed to measure and subsequently predict TAGSAM collection amounts as a function of the minimum particle size, maximum particle size, particle size frequency distribution, and the tilt of the TAGSAM head off the surface. The sampleability algorithm operated at two general scales, consistent with the resolution and coverage of data collected during the mission. The first scale was global and evaluated nearly the full surface. Due to Bennu's unexpected boulder coverage and lack of ponded regolith deposits, the global sampleability efforts relied heavily on additional strategies to find and characterize regions of interest based on quantifying and avoiding areas heavily covered by material too large to be collected. The second scale was site-specific and used higher-resolution data to predict collected mass at a given contact location. The rigorous sampleability assessments gave the mission confidence to select the best possible sample collection site and directly enabled successful collection of hundreds of grams of material., (© The Author(s) 2022.)

Spacecraft missions have observed regolith blankets of unconsolidated subcentimetre particles on stony asteroids 1-3 . Telescopic data have suggested the presence of regolith blankets also on carbonaceous asteroids, including (101955) Bennu 4 and (162173) Ryugu 5 . However, despite observations of processes that are capable of comminuting boulders into unconsolidated materials, such as meteoroid bombardment 6,7 and thermal cracking 8 , Bennu and Ryugu lack extensive areas covered in subcentimetre particles 7,9 . Here we report an inverse correlation between the local abundance of subcentimetre particles and the porosity of rocks on Bennu. We interpret this finding to mean that accumulation of unconsolidated subcentimetre particles is frustrated where the rocks are highly porous, which appears to be most of the surface 10 . The highly porous rocks are compressed rather than fragmented by meteoroid impacts, consistent with laboratory experiments 11,12 , and thermal cracking proceeds more slowly than in denser rocks. We infer that regolith blankets are uncommon on carbonaceous asteroids, which are the most numerous type of asteroid 13 . By contrast, these terrains should be common on stony asteroids, which have less porous rocks and are the second-most populous group by composition 13 . The higher porosity of carbonaceous asteroid materials may have aided in their compaction and cementation to form breccias, which dominate the carbonaceous chondrite meteorites 14 ., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Influenza A viruses encode their genomes across eight, negative sense RNA segments. The six largest segments produce mRNA transcripts that do not generally splice; however, the two smallest segments are actively spliced to produce the essential viral proteins NEP and M2. Thus, viral utilization of RNA splicing effectively expands the viral coding capacity without increasing the number of genomic segments. As a first step towards understanding why splicing is not more broadly utilized across genomic segments, we designed and inserted an artificial intron into the normally nonsplicing NA segment. This insertion was tolerated and, although viral mRNAs were incompletely spliced, we observed only minor effects on viral fitness. To take advantage of the unspliced viral RNAs, we encoded a reporter luciferase gene in frame with the viral ORF such that when the intron was not removed the reporter protein would be produced. This approach, which we also show can be applied to the NP encoding segment and in different viral genetic backgrounds, led to high levels of reporter protein expression with minimal effects on the kinetics of viral replication or the ability to cause disease in experimentally infected animals. These data together show that the influenza viral genome is more tolerant of splicing than previously appreciated and this knowledge can be leveraged to develop viral genetic platforms with utility for biotechnology applications., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Duke University has filed for intellectual property protection for the technology described in this report.

Antiviral therapeutics are a front-line defense against virally induced diseases. Because viruses frequently mutate to escape direct inhibition of viral proteins, there is interest in targeting the host proteins that the virus must co-opt to complete its replication cycle. However, a detailed understanding of the interactions between the virus and the host cell is necessary in order to facilitate development of host-directed therapeutics. As a first step, we performed a genome-wide loss of function screen using the alphacoronavirus HCoV-229E to better define the interactions between coronaviruses and host factors. We report the identification and validation of an ER-resident host protein, TMEM41B, as an essential host factor for not only HCoV-229E but also genetically distinct coronaviruses including the pandemic betacoronavirus SARS-CoV-2. We show that the protein is required at an early, but post-receptor engagement, stage of the viral lifecycle. Further, mechanistic studies revealed that although the protein was not enriched at replication complexes, it likely contributes to viral replication complex formation via mobilization of cholesterol and other lipids to facilitate host membrane expansion and curvature. Continued study of TMEM41B and the development of approaches to prevent its function may lead to broad spectrum anti-coronavirus therapeutics., Competing Interests: The authors have declared that no competing interests exist.

While vaccines are vital for preventing COVID-19 infections, it is critical to develop new therapies to treat patients who become infected. Pharmacological targeting of a host factor required for viral replication can suppress viral spread with a low probability of viral mutation leading to resistance. In particular, host kinases are highly druggable targets and a number of conserved coronavirus proteins, notably the nucleoprotein (N), require phosphorylation for full functionality. In order to understand how targeting kinases could be used to compromise viral replication, we used a combination of phosphoproteomics and bioinformatics as well as genetic and pharmacological kinase inhibition to define the enzymes important for SARS-CoV-2 N protein phosphorylation and viral replication. From these data, we propose a model whereby SRPK1/2 initiates phosphorylation of the N protein, which primes for further phosphorylation by GSK-3a/b and CK1 to achieve extensive phosphorylation of the N protein SR-rich domain. Importantly, we were able to leverage our data to identify an FDA-approved kinase inhibitor, Alectinib, that suppresses N phosphorylation by SRPK1/2 and limits SARS-CoV-2 replication. Together, these data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases.

The composition of asteroids and their connection to meteorites provide insight into geologic processes that occurred in the early Solar System. We present spectra of the Nightingale crater region on near-Earth asteroid Bennu with a distinct infrared absorption around 3.4 micrometers. Corresponding images of boulders show centimeters-thick, roughly meter-long bright veins. We interpret the veins as being composed of carbonates, similar to those found in aqueously altered carbonaceous chondrite meteorites. If the veins on Bennu are carbonates, fluid flow and hydrothermal deposition on Bennu's parent body would have occurred on kilometer scales for thousands to millions of years. This suggests large-scale, open-system hydrothermal alteration of carbonaceous asteroids in the early Solar System., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Visible-wavelength color and reflectance provide information about the geologic history of planetary surfaces. Here we present multispectral images (0.44 to 0.89 micrometers) of near-Earth asteroid (101955) Bennu. The surface has variable colors overlain on a moderately blue global terrain. Two primary boulder types are distinguishable by their reflectance and texture. Space weathering of Bennu surface materials does not simply progress from red to blue (or vice versa). Instead, freshly exposed, redder surfaces initially brighten in the near-ultraviolet region (i.e., become bluer at shorter wavelengths), then brighten in the visible to near-infrared region, leading to Bennu's moderately blue average color. Craters indicate that the time scale of these color changes is ~10 5 years. We attribute the reflectance and color variation to a combination of primordial heterogeneity and varying exposure ages., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Thermal inertia and surface roughness are proxies for the physical characteristics of planetary surfaces. Global maps of these two properties distinguish the boulder population on near-Earth asteroid (NEA) (101955) Bennu into two types that differ in strength, and both have lower thermal inertia than expected for boulders and meteorites. Neither has strongly temperature-dependent thermal properties. The weaker boulder type probably would not survive atmospheric entry and thus may not be represented in the meteorite collection. The maps also show a high-thermal inertia band at Bennu's equator, which might be explained by processes such as compaction or strength sorting during mass movement, but these explanations are not wholly consistent with other data. Our findings imply that other C-complex NEAs likely have boulders similar to those on Bennu rather than finer-particulate regoliths. A tentative correlation between albedo and thermal inertia of C-complex NEAs may be due to relative abundances of boulder types., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The shapes of asteroids reflect interplay between their interior properties and the processes responsible for their formation and evolution as they journey through the Solar System. Prior to the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) mission, Earth-based radar imaging gave an overview of (101955) Bennu's shape. Here, we construct a high-resolution shape model from OSIRIS-REx images. We find that Bennu's top-like shape, considerable macroporosity, and prominent surface boulders suggest that it is a rubble pile. High-standing, north-south ridges that extend from pole to pole, many long grooves, and surface mass wasting indicate some low levels of internal friction and/or cohesion. Our shape model indicates that, similar to other top-shaped asteroids, Bennu formed by reaccumulation and underwent past periods of fast spin leading to its current shape. Today, Bennu might follow a different evolutionary pathway, with interior stiffness permitting surface cracking and mass wasting.