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  • Oxford University Press (OUP)  (10)
  • Nelson, Karen E  (10)
  • 1
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    Online Resource
    Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 3 ( 2022-07-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 3 ( 2022-07-01)
    Abstract: Human leukocyte antigen class I (HLA-I) molecules bind and present peptides at the cell surface to facilitate the induction of appropriate CD8+ T cell-mediated immune responses to pathogen- and self-derived proteins. The HLA-I peptide-binding cleft contains dominant anchor sites in the B and F pockets that interact primarily with amino acids at peptide position 2 and the C-terminus, respectively. Nonpocket peptide–HLA interactions also contribute to peptide binding and stability, but these secondary interactions are thought to be unique to individual HLA allotypes or to specific peptide antigens. Here, we show that two positively charged residues located near the top of peptide-binding cleft facilitate interactions with negatively charged residues at position 4 of presented peptides, which occur at elevated frequencies across most HLA-I allotypes. Loss of these interactions was shown to impair HLA-I/peptide binding and complex stability, as demonstrated by both in vitro and in silico experiments. Furthermore, mutation of these Arginine-65 (R65) and/or Lysine-66 (K66) residues in HLA-A*02:01 and A*24:02 significantly reduced HLA-I cell surface expression while also reducing the diversity of the presented peptide repertoire by up to 5-fold. The impact of the R65 mutation demonstrates that nonpocket HLA-I/peptide interactions can constitute anchor motifs that exert an unexpectedly broad influence on HLA-I-mediated antigen presentation. These findings provide fundamental insights into peptide antigen binding that could broadly inform epitope discovery in the context of viral vaccine development and cancer immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac124
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3120703-0
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  • 2
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    Online Resource
    Reimagine fire science for the anthropocene
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 3 ( 2022-07-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 3 ( 2022-07-01)
    Abstract: Fire is an integral component of ecosystems globally and a tool that humans have harnessed for millennia. Altered fire regimes are a fundamental cause and consequence of global change, impacting people and the biophysical systems on which they depend. As part of the newly emerging Anthropocene, marked by human-caused climate change and radical changes to ecosystems, fire danger is increasing, and fires are having increasingly devastating impacts on human health, infrastructure, and ecosystem services. Increasing fire danger is a vexing problem that requires deep transdisciplinary, trans-sector, and inclusive partnerships to address. Here, we outline barriers and opportunities in the next generation of fire science and provide guidance for investment in future research. We synthesize insights needed to better address the long-standing challenges of innovation across disciplines to (i) promote coordinated research efforts; (ii) embrace different ways of knowing and knowledge generation; (iii) promote exploration of fundamental science; (iv) capitalize on the “firehose” of data for societal benefit; and (v) integrate human and natural systems into models across multiple scales. Fire science is thus at a critical transitional moment. We need to shift from observation and modeled representations of varying components of climate, people, vegetation, and fire to more integrative and predictive approaches that support pathways toward mitigating and adapting to our increasingly flammable world, including the utilization of fire for human safety and benefit. Only through overcoming institutional silos and accessing knowledge across diverse communities can we effectively undertake research that improves outcomes in our more fiery future.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac115
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 4 ( 2022-09-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 4 ( 2022-09-01)
    Abstract: Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker—Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac147
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 4
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    An intranasally administrated SARS-CoV-2 beta variant subunit booster vaccine prevents beta variant replication in rhesus macaques
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 3 ( 2022-07-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 3 ( 2022-07-01)
    Abstract: Emergence of SARS-CoV-2 variants and waning of vaccine/infection-induced immunity pose threats to curbing the COVID-19 pandemic. Effective, safe, and convenient booster vaccines are in need. We hypothesized that a variant-modified mucosal booster vaccine might induce local immunity to prevent SARS-CoV-2 infection at the port of entry. The beta-variant is one of the hardest to cross-neutralize. Herein, we assessed the protective efficacy of an intranasal booster composed of beta variant-spike protein S1 with IL-15 and TLR agonists in previously immunized macaques. The macaques were first vaccinated with Wuhan strain S1 with the same adjuvant. A total of 1 year later, negligibly detectable SARS-CoV-2-specific antibody remained. Nevertheless, the booster induced vigorous humoral immunity including serum- and bronchoalveolar lavage (BAL)-IgG, secretory nasal- and BAL-IgA, and neutralizing antibody against the original strain and/or beta variant. Beta-variant S1-specific CD4+ and CD8+ T cell responses were also elicited in PBMC and BAL. Following SARS-CoV-2 beta variant challenge, the vaccinated group demonstrated significant protection against viral replication in the upper and lower respiratory tracts, with almost full protection in the nasal cavity. The fact that one intranasal beta-variant booster administrated 1 year after the first vaccination provoked protective immunity against beta variant infections may inform future SARS-CoV-2 booster design and administration timing.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac091
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 5
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    Gender and ethnicity bias in medicine: a text analysis of 1.8 million critical care records
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 4 ( 2022-09-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 4 ( 2022-09-01)
    Abstract: Gender and ethnicity biases are pervasive across many societal domains including politics, employment, and medicine. Such biases will facilitate inequalities until they are revealed and mitigated at scale. To this end, over 1.8 million caregiver notes (502 million words) from a large US hospital were evaluated with natural language processing techniques in search of gender and ethnicity bias indicators. Consistent with nonlinguistic evidence of bias in medicine, physicians focused more on the emotions of women compared to men and focused more on the scientific and bodily diagnoses of men compared to women. Content patterns were relatively consistent across genders. Physicians also attended to fewer emotions for Black/African and Asian patients compared to White patients, and physicians demonstrated the greatest need to work through diagnoses for Black/African women compared to other patients. Content disparities were clearer across ethnicities, as physicians focused less on the pain of Black/African and Asian patients compared to White patients in their critical care notes. This research provides evidence of gender and ethnicity biases in medicine as communicated by physicians in the field and requires the critical examination of institutions that perpetuate bias in social systems.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac157
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
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    Crop genetic diversity uncovers metabolites, elements, and gene networks predicted to be associated with high plant biomass yields in maize
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 3 ( 2022-07-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 3 ( 2022-07-01)
    Abstract: Rapid population growth and increasing demand for food, feed, and bioenergy in these times of unprecedented climate change require breeding for increased biomass production on the world's croplands. To accelerate breeding programs, knowledge of the relationship between biomass features and underlying gene networks is needed to guide future breeding efforts. To this end, large-scale multiomics datasets were created with genetically diverse maize lines, all grown in long-term organic and conventional cropping systems. Analysis of the datasets, integrated using regression modeling and network analysis revealed key metabolites, elements, gene transcripts, and gene networks, whose contents during vegetative growth substantially influence the build-up of plant biomass in the reproductive phase. We found that S and P content in the source leaf and P content in the root during the vegetative stage contributed the most to predicting plant performance at the reproductive stage. In agreement with the Gene Ontology enrichment analysis, the cis-motifs and identified transcription factors associated with upregulated genes under phosphate deficiency showed great diversity in the molecular response to phosphate deficiency in selected lines. Furthermore, our data demonstrate that genotype-dependent uptake, assimilation, and allocation of essential nutrient elements (especially C and N) during vegetative growth under phosphate starvation plays an important role in determining plant biomass by controlling root traits related to nutrient uptake. These integrative multiomics results revealed key factors underlying maize productivity and open new opportunities for efficient, rapid, and cost-effective plant breeding to increase biomass yield of the cereal crop maize under adverse environmental factors.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac068
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    Experimental reductions in subdaily flow fluctuations increased gross primary productivity for 425 river kilometers downstream
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 3 ( 2022-07-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 3 ( 2022-07-01)
    Abstract: Aquatic primary production is the foundation of many river food webs. Dams change the physical template of rivers, often driving food webs toward greater reliance on aquatic primary production. Nonetheless, the effects of regulated flow regimes on primary production are poorly understood. Load following is a common dam flow management strategy that involves subdaily changes in water releases proportional to fluctuations in electrical power demand. This flow regime causes an artificial tide, wetting and drying channel margins and altering river depth and water clarity, all processes that are likely to affect primary production. In collaboration with dam operators, we designed an experimental flow regime whose goal was to mitigate negative effects of load following on ecosystem processes. The experimental flow contrasted steady-low flows on weekends with load following flows on weekdays. Here, we quantify the effect of this experimental flow on springtime gross primary production (GPP) 90-to-425 km downstream of Glen Canyon Dam on the Colorado River, AZ, USA. GPP during steady-low flows was 41% higher than during load following flows, mostly owing to nonlinear reductions in sediment-driven turbidity. The experimental flow increased weekly GPP even after controlling for variation in weekly mean discharge, demonstrating a negative effect of load following on GPP. We estimate that this environmental flow increased springtime carbon fixation by 0.27 g C m−2 d−1, which is ecologically meaningful considering median C fixation in 356 US rivers of 0.44 g C m−2 d−1 and the fact that native fish populations in this river are food-limited.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac094
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 8
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    Differential network analysis of oral microbiome metatranscriptomes identifies community scale metabolic restructuring in dental caries
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 5 ( 2022-11-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 5 ( 2022-11-01)
    Abstract: Dental caries is a microbial disease and the most common chronic health condition, affecting nearly 3.5 billion people worldwide. In this study, we used a multiomics approach to characterize the supragingival plaque microbiome of 91 Australian children, generating 658 bacterial and 189 viral metagenome-assembled genomes with transcriptional profiling and gene-expression network analysis. We developed a reproducible pipeline for clustering sample-specific genomes to integrate metagenomics and metatranscriptomics analyses regardless of biosample overlap. We introduce novel feature engineering and compositionally-aware ensemble network frameworks while demonstrating their utility for investigating regime shifts associated with caries dysbiosis. These methods can be applied when differential abundance modeling does not capture statistical enrichments or the results from such analysis are not adequate for providing deeper insight into disease. We identified which organisms and metabolic pathways were central in a coexpression network as well as how these networks were rewired between caries and caries-free phenotypes. Our findings provide evidence of a core bacterial microbiome that was transcriptionally active in the supragingival plaque of all participants regardless of phenotype, but also show highly diagnostic changes in the ways that organisms interact. Specifically, many organisms exhibit high connectedness with central carbon metabolism to Cardiobacterium and this shift serves a bridge between phenotypes. Our evidence supports the hypothesis that caries is a multifactorial ecological disease.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac239
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    Temporal analysis of Lassa virus infection and transmission in experimentally infected Mastomys natalensis
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 3 ( 2022-07-01)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 3 ( 2022-07-01)
    Abstract: Little is known about the temporal patterns of infection and transmission of Lassa virus (LASV) within its natural reservoir (Mastomys natalensis). Here, we characterize infection dynamics and transmissibility of a LASV isolate (Soromba-R) in adult lab-reared M. natalensis originating from Mali. The lab-reared M. natalenesis proved to be highly susceptible to LASV isolates from geographically distinct regions of West Africa via multiple routes of exposure, with 50% infectious doses of  & lt; 1 TCID50. Postinoculation, LASV Soromba-R established a systemic infection with no signs of clinical disease. Viral RNA was detected in all nine tissues examined with peak concentrations detected between days 7 and 14 postinfection within most organs. There was an overall trend toward clearance of virus within 40 days of infection in most organs. The exception is lung specimens, which retained positivity throughout the course of the 85-day study. Direct (contact) and indirect (fomite) transmission experiments demonstrated 40% of experimentally infected M. natalensis were capable of transmitting LASV to naïve animals, with peak transmissibility occurring between 28 and 42 days post-inoculation. No differences in patterns of infection or transmission were noted between male and female experimentally infected rodents. Adult lab-reared M. natalensis are highly susceptible to genetically distinct LASV strains developing a temporary asymptomatic infection associated with virus shedding resulting in contact and fomite transmission within a cohort.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac114
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 10
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    Declaration of common standards for the preregistration of animal research—speeding up the scientific progress
    Oxford University Press (OUP) ; 2022
    In:  PNAS Nexus Vol. 1, No. 1 ( 2022-03-02)
    Details
    In: PNAS Nexus, Oxford University Press (OUP), Vol. 1, No. 1 ( 2022-03-02)
    Abstract: Preregistration of studies is a recognized tool in clinical research to improve the quality and reporting of all gained results. In preclinical research, preregistration could boost the translation of published results into clinical breakthroughs. When studies rely on animal testing or form the basis of clinical trials, maximizing the validity and reliability of research outcomes becomes in addition an ethical obligation. Nevertheless, the implementation of preregistration in animal research is still slow. However, research institutions, funders, and publishers start valuing preregistration, and thereby level the way for its broader acceptance in the future. A total of 3 public registries, the OSF registry, preclinicaltrials.eu, and animalstudyregistry.org already encourage the preregistration of research involving animals. Here, they jointly declare common standards to make preregistration a valuable tool for better science. Registries should meet the following criteria: public accessibility, transparency in their financial sources, tracking of changes, and warranty and sustainability of data. Furthermore, registration templates should cover a minimum set of mandatory information and studies have to be uniquely identifiable. Finally, preregistered studies should be linked to any published outcome. To ensure that preregistration becomes a powerful instrument, publishers, funders, and institutions should refer to registries that fulfill these minimum standards.
    Type of Medium: Online Resource
    ISSN: 2752-6542
    URL: Article
    DOI: 10.1093/pnasnexus/pgac016
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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