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Human dengue viruses emerged from primate reservoirs, yet paradoxically dengue does not reach high titers in primate models. This presents a unique opportunity to examine the genetics of spillover versus reservoir hosts. The dengue virus 2 (DENV2) - encoded protease cleaves human STING, reducing type I interferon production and boosting viral titers in humans. We find that both human and sylvatic (reservoir) dengue viruses universally cleave human STING, but not the STING of primates implicated as reservoir species. The special ability of dengue to cleave STING is thus specific to humans and a few closely related ape species. Conversion of residues 78/79 to the human-encoded ‘RG’ renders all primate (and mouse) STINGs sensitive to viral cleavage. Dengue viruses may have evolved to increase viral titers in the dense and vast human population, while maintaining decreased titers and pathogenicity in the more rare animals that serve as their sustaining reservoir in nature. Dengue viruses are found in over 100 countries and cause the tropical disease known as dengue fever. Dengue viruses affect around 100 million people per year and can – in severe cases – lead to death. Unlike many other deadly diseases, there is currently no vaccine that completely prevents dengue fever. It is thought that dengue viruses that circulate in human populations were derived from monkey versions of that same virus. However, research suggests that both human and primate variations of dengue viruses appear to multiply much better in humans than in other species. Scientists believe that this is because some animals, including primates, have defense mechanisms that are ineffective in humans. To explore this idea, Stabell et al. looked at a protein called STING in humans and in three different primates: the chimpanzee, the rhesus macaque, and the common marmoset. STING plays an important role in the immune system and helps to fight infections caused by viruses and other microbes. During replication – the process by which a virus spreads through an organism’s cells – the dengue virus cuts and inactivates the human STING protein, and so helps the virus spread. Stabell et al. discovered that in most primates, dengue viruses cannot inactivate STING. This was found to be reliant on a small region in the STING protein that differed between humans and primates. This small difference may, in part, explain why dengue viruses replicate better in humans than other primates. Stabell et al. then searched for other animals whose STING protein would be susceptible to dengue virus inactivation. Using a database with genetic information of over 5,000 mammals, Stabell et al. identified STING proteins of three types of apes and three types of rodents that could also be deactivated by dengue viruses. To develop a vaccine or antiviral drug scientists generally need to study the disease in living animals. Since dengue viruses replicate more successfully in humans than they do in other animal models, it makes it more challenging to find an effective treatment. The results from Stabell et al. may help to identify animals that could be strong candidates for future research into dengue viruses, potentially paving the way for further therapeutic development.

Here, we develop a simple molecular test for SARS-CoV-2 in saliva based on reverse transcription loop-mediated isothermal amplification. The test has two steps: (1) heat saliva with a stabilization solution and (2) detect virus by incubating with a primer/enzyme mix. After incubation, saliva samples containing the SARS-CoV-2 genome turn bright yellow. Because this test is pH dependent, it can react falsely to some naturally acidic saliva samples. We report unique saliva stabilization protocols that rendered 295 healthy saliva samples compatible with the test, producing zero false positives. We also evaluated the test on 278 saliva samples from individuals who were infected with SARS-CoV-2 but had no symptoms at the time of saliva collection, and from 54 matched pairs of saliva and anterior nasal samples from infected individuals. The Saliva TwoStep test described herein identified infections with 94% sensitivity and >99% specificity in individuals with sub-clinical (asymptomatic or pre-symptomatic) infections.

Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

We analyze data from the fall 2020 pandemic response efforts at the University of Colorado Boulder, where more than 72,500 saliva samples were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using qRT-PCR. All samples were collected from individuals who reported no symptoms associated with COVID-19 on the day of collection. From these, 1,405 positive cases were identified. The distribution of viral loads within these asymptomatic individuals was indistinguishable from what has been previously observed in symptomatic individuals. Regardless of symptomatic status, ∼50% of individuals who test positive for SARS-CoV-2 seem to be in noninfectious phases of the disease, based on having low viral loads in a range from which live virus has rarely been isolated. We find that, at any given time, just 2% of individuals carry 90% of the virions circulating within communities, serving as viral “supercarriers” and possibly also superspreaders.

RNase L is widely thought to limit viral protein synthesis by cleaving host rRNA and viral mRNA, resulting in translation arrest and viral mRNA degradation. Herein, we show that the mRNAs of dengue virus and influenza A virus largely escape RNase L-mediated mRNA decay, and this permits viral protein production. However, activation of RNase L arrests nuclear mRNA export, which strongly inhibits influenza A virus protein synthesis and reduces cytokine production. Importantly, the heterogeneous and temporal nature of the mRNA export block in individual cells permits sufficient production of antiviral cytokines from transcriptionally induced host mRNAs. This defines RNase L-mediated arrest of mRNA export as a key antiviral shutoff and cytokine regulatory pathway. Competing Interest Statement Roy Parker is a founder and consultant of Faze Medicines.

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae . Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20–5.32) mg/L p  <  0.001 , 180 min 2.2 (1.58–3.25) mg/L p  <  0.001 ; free: 45 min 1.15 (0.88–1.42) mg/L p  <  0.001 , 180 min 0.5 (0.35–0.76) mg/L p  <  0.001 ). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5 , and for hepcidin at CHCHD7 / SDR16C5 . Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7 / SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron’s role in host-pathogen interactions.

Combination inhaled corticosteroid–formoterol reliever monotherapy reduces the rate of asthma attacks compared to short-acting β2-agonist (SABA) reliever monotherapy in adults. Its comparative efficacy in children has not been established. CARE was a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial in children aged 5–15 years with asthma using SABA reliever monotherapy at 15 clinical trials sites in New Zealand. Participants were randomly assigned (1:1) to either budesonide 50 μg–formoterol 3 μg, two actuations as needed, or salbutamol 100 μg, two actuations as needed. The primary outcome was asthma attacks as rate per participant per year. This trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12620001091998. From Jan 28, 2021, to June 23, 2023, we assessed 382 participants for eligibility. We randomly assigned 360 (94%) participants to treatment (179 [50%] to the budesonide–formoterol group and 181 [50%] to the salbutamol group). The annualised rate of asthma attacks was lower in the budesonide–formoterol group than in the salbutamol group—cluster-adjusted rates 0·23 versus 0·41 per participant per year (relative rate 0·55 [95% CI 0·35–0·86]; p=0·012). The number of participants with at least one adverse event was 162 (91%) in the budesonide–formoterol group and 167 (92%) in the salbutamol group (odds ratio 0·79 [95% CI 0·35–1·79]). In children aged 5–15 years with mild asthma, budesonide–formoterol reliever monotherapy is superior to salbutamol for preventing asthma attacks, with a similar safety profile. Health Research Council of New Zealand, Cure Kids New Zealand, and the Barbara Basham Medical Charitable Trust (managed by Perpetual Guardian).

Abstract Context Resistance exercise training (strength training) and aerobic exercise training are both recommended for people with type 1 diabetes, but it is unknown whether adding resistance exercise provides incremental benefits in people with this condition who already perform aerobic exercise regularly. Objective This work aimed to evaluate the incremental effect of resistance training on glycated hemoglobin A1c (HbA1c), fitness, body composition, and cardiometabolic risk factors in aerobically active people with type 1 diabetes. Methods The Resistance Exercise in Already-active Diabetic Individuals (READI) trial (NCT00410436) was a 4-center, randomized, parallel-group trial. After a 5-week run-in period with diabetes management optimization, 131 aerobically active individuals with type 1 diabetes were randomly assigned to resistance exercise (n = 71, intervention—INT) or control (n = 60, CON) for 22 additional weeks. Both groups maintained their aerobic activities and were provided dietary counseling throughout. Exercise training was 3 times per week at community-based facilities. The primary outcome was HbA1c, and secondary outcomes included fitness (peak oxygen consumption, muscle strength), body composition (anthropometrics, dual-energy x-ray absorptiometry, computed tomography), and cardiometabolic risk markers (lipids, apolipoproteins). Assessors were blinded to group allocation. Results There were no significant differences in HbA1c change between INT and CON. Declines in HbA1c (INT: 7.75 ± 0.10% [61.2 ± 1.1 mmol/mol] to 7.55 ± 0.10% [59 ± 1.1 mmol/mol]; CON: 7.70 ± 0.11% [60.7 ± 1.2 mmol/mol] to 7.57 ± 0.11% [59.6 ± 1.3 mmol/mol]; intergroup difference in change −0.07 [95% CI, −0.31 to 0.18]). Waist circumference decreased more in INT than CON after 6 months (P = .02). Muscular strength increased more in INT than in CON (P < .001). There were no intergroup differences in hypoglycemia or any other variables. Conclusion Adding resistance training did not affect glycemia, but it increased strength and reduced waist circumference, in aerobically active individuals with type 1 diabetes.

The theory, vision, and implementation of a multidisciplinary collaborative approach to social learning The academy is often described as an ivory tower, isolated from the community surrounding it. Presenting the theory, vision, and implementation of a socially engaged program for the Department of Human and Organizational Development (HOD) in Peabody's College of Education and Human Development at Vanderbilt University, Academics in Action! describes a more integrated model wherein students and faculty work with communities, learn from them, and bring to bear findings from theory and research to generate solutions to community problems. Offering examples of community-engaged theory, scholarship, teaching, and action, Academics in Action! describes the nuanced structures that foster and support their development within a research university. Theory and action span multiple ecological levels from individuals and small groups to organizations and social structures. The communities of engagement range from local neighborhoods and schools to arenas of national policy and international development. Reflecting the unique perspectives of research faculty, practitioners, and graduate students, Academics in Action! documents a specific philosophy of education that fosters and supports engagement; the potentially transformative nature of academic work for students, faculty, and the broader society; and some of the implications and challenges of action-oriented efforts in light of dynamics such as income inequality, racism, and global capitalism. This edited volume chronicles teaching, research, and community action that influences both inside and outside the classroom as well as presents dimensions of a participatory model that set such efforts into action.