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Dobri dupini (Tursiops truncatus) zbog svoje karizmatičnosti i popularnosti često se drže u zatočeništvu za istraživanje, konzervaciju i edukaciju. Zbog dinamične društvene strukture, mogu se pojaviti agresivne interakcije između dupina u obliku grube igre ili seksualnih povoda koji uzrokuju ogrebotine na tijelu koji su pokazatelji agresivnog ponašanja. Obogaćenje okoliša služi kao stimulacija i poticanje aktivnosti koji doprinose dobrobiti životinja u uvjetima zatočeništva. U delfinariju u Meksiku primijećen je veliki broj ogrebotina jednog dupina u grupi i uvedeni su plastični prstenovi s ciljem smanjenja ogrebotina i time smanjenju agresivnosti. Za istraživanje su se metodom kvantifikacije ogrebotina odredila ukupan broj ogrebotina u odsutnosti i prisutnosti prstenova, ali i na svakoj podijeljenoj regiji zasebno za dublju analizu i svrhu ogrebotina. Rezultati pokazuju općenito značajno smanjenje ogrebotina u prisutnosti prstenova, a pogotovo u području trbušnog pedunkuluma i trbuha, kao i na stražnjem dijelu tijela kod navedenog dupina. Stoga prstenovi mogu poslužiti kao alat za smanjenje agresivnih interakcija i smanjenju seksualnih agresija. Nadalje, rezultati se mogu koristiti za istraživanje agresije dupina u prirodnom staništu što daje važnost istraživanjima u kontroliranim uvjetima i suradnji između istraživača u kontroliranim i prirodnim uvjetima. Iako rezultati pokazuju vrijedne informacije potrebno je napraviti više istraživanja zbog malog uzorka životinja za dodatnu potvrdu zaključaka. Due to their charisma and popularity, bottlenose dolphins are often kept in captivity for research, conservation and education. Due to the dynamic social structure, aggressive interactions between dolphins can occur in the form of rough play or sexual occasions that cause rake marks on their body which are indicators of aggressive behavior. Environmental enrichment serves as a stimulation and encouragement of activities that improve the welfare of animals in captivity. In a dolphinarium in Mexico, a large number of rake marks on one dolphin in the group were noticed and plastic rings were introduced with the aim of reducing rake marks and thus reducing aggression. For research, the method of rake mark quantification determined the total number of rake marks in the absence and presence of rings, but also in each divided region separately for deeper analysis and purpose of rake marks. The results generally show a significant reduction in rake marks in the presence of rings, especially in ventral peduncle and belly area, as well as on the posterior side of the body in said dolphin. Therefore, rings can serve as a tool to reduce aggressive interactions and reduce sexual aggression. Furthermore, the results can be used to investigate dolphin aggression in a natural habitat, which gives importance to research in controlled environment and collaboration between researchers in controlled and natural environment. Although the results show that more research is needed due to the small sample of animals to further confirm the conclusions.

Influenza vaccines that confer broad and durable protection against diverse viral strains would have a major effect on global health, as they would lessen the need for annual vaccine reformulation and immunization1. Here we show that computationally designed, two-component nanoparticle immunogens2 induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens contain 20 haemagglutinin glycoprotein trimers in an ordered array, and their assembly in vitro enables the precisely controlled co-display of multiple distinct haemagglutinin proteins in defined ratios. Nanoparticle immunogens that co-display the four haemagglutinins of licensed quadrivalent influenza vaccines elicited antibody responses in several animal models against vaccine-matched strains that were equivalent to or better than commercial quadrivalent influenza vaccines, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved haemagglutinin stem. The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens makes them attractive candidates for a supraseasonal influenza vaccine candidate with the potential to replace conventional seasonal vaccines3. A nanoparticle influenza vaccine candidate is shown to induce broad cross-reactive antibody responses in animal models.

The Human Immunodeficiency Virus (HIV-1) type 1 viral protein is a life threatening virus causing HIV/AIDS in infected humans. The HIV-1 envelope (ENV) trimer glycoprotein GP160 (GP120-GP41) is gaining attention in recent years as a potential vaccine candidate for HIV-1/AIDS. However, the sequence variation and charge polarity at the interacting sites across clades is a shortcoming faced in the development of an effective HIV-1 vaccine. We analyzed the interfaces in terms of its interface area, interface size, and interface energies (van der Waals, hydrogen bonds, and electrostatics). The interfaces were divided as dominant (≥60%) and subdominant (

Alfvénic turbulence in the fast solar wind is imbalanced: the energy of the (dominant) waves propagating outward from the Sun is much larger than energy of inward-propagating (subdominant) waves. At large scales Alfvén waves are non-dispersive and turbulence is driven by non-linear interactions of counter-propagating waves. Contrary to this, at kinetic scales Alfvén waves become dispersive and non-linear interactions become possible among co-propagating waves as well. The study of the transition between these two regimes of Alfvénic turbulence is important for understanding of complicated dynamics of imbalanced Alfvénic turbulence. In this paper, we present a semiphenomenological model of the imbalanced Alfvénic turbulence accounting for the energy exchange between the dominant and subdominant wave fractions. The energy transfer becomes non-negligible at sufficiently small yet still larger than the ion gyroradius scales and is driven by the non-linear beatings between dispersive dominant(subdominant) waves pumping energy into the subdominant(dominant) component. Our results demonstrate that the turbulence imbalance should decrease significantly in the weakly dispersive wavenumber range.

Natural influenza virus infections and seasonal vaccinations often do not confer broadly neutralizing immunity across diverse influenza strains. In addition, the virus is capable of rapid antigenic drift in order to evade pre-existing immunity. The surface glycoproteins, hemagglutinin, and neuraminidase can easily mutate their immunodominant epitopes without impacting fitness. Skewing human antibody repertoires to target more conserved epitopes is thus an expanding area of research: Many groups are attempting to produce universal influenza vaccines that can protect across a wide variety of strains. Achieving this goal will require a detailed understanding of how infection history impacts humoral responses. It will also require the ability to manipulate or enhance B cell selection in order to expand clones that can recognize subdominant but protective epitopes. In this review, we will discuss what immune imprinting means to immunologists and describe efforts to overcome or silence imprinting in order to improve vaccination efficiency.

Background: Viral genetic variability presents a major challenge to the development of a prophylactic hepatitis C virus (HCV) vaccine. A promising HCV vaccine using chimpanzee adenoviral vectors (ChAd) encoding a genotype (gt) 1b non-structural protein (ChAd-Gt1b-NS) generated high magnitude T cell responses. However, these T cells showed reduced cross-recognition of dominant epitope variants and the vaccine has recently been shown to be ineffective at preventing chronic HCV. To address the challenge of viral diversity, we developed ChAd vaccines encoding HCV genomic sequences that are conserved between all major HCV genotypes and adjuvanted by truncated shark invariant chain (sIitr). Methods: Age-matched female mice were immunised intramuscularly with ChAd (108 infectious units) encoding gt-1 and -3 (ChAd-Gt1/3) or gt-1 to -6 (ChAd-Gt1-6) conserved segments spanning the HCV proteome, or gt-1b (ChAd-Gt1b-NS control), with immunogenicity assessed 14-days post-vaccination. Results: Conserved segment vaccines, ChAd-Gt1/3 and ChAd-Gt1-6, generated high-magnitude, broad, and functional CD4+ and CD8+ T cell responses. Compared to the ChAd-Gt1b-NS vaccine, these vaccines generated significantly greater responses against conserved non-gt-1 antigens, including conserved subdominant epitopes that were not targeted by ChAd-Gt1b-NS. Epitopes targeted by the conserved segment HCV vaccine induced T cells, displayed 96.6% mean sequence homology between all HCV subtypes (100% sequence homology for the majority of genotype-1, -2, -4 sequences and 94% sequence homology for gt-3, -6, -7, and -8) in contrast to 85.1% mean sequence homology for epitopes targeted by ChAd-Gt1b-NS induced T cells. The addition of truncated shark invariant chain (sIitr) increased the magnitude, breadth, and cross-reactivity of the T cell response. Conclusions: We have demonstrated that genetically adjuvanted ChAd vectored HCV T cell vaccines encoding genetic sequences conserved between genotypes are immunogenic, activating T cells that target subdominant conserved HCV epitopes. These pre-clinical studies support the use of conserved segment HCV T cell vaccines in human clinical trials.

Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus–negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse. Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays. Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.

Porcine epidemic diarrhea virus (PEDV) is the causative agent of PED, an enteric disease that causes high mortality rates in piglets. PEDV is an alphacoronavirus that has high genetic diversity. Insights into neutralizing B-cell epitopes of all genetically diverse PEDV strains are of importance, particularly for designing a vaccine that can provide broad protection against PEDV. In this work, we aimed to explore the landscape of linear B-cell epitopes on the spike (S) and membrane (M) proteins of global PEDV strains. All amino acid sequences of the PEDV S and M proteins were retrieved from the NCBI database and grouped. Immunoinformatics-based methods were next developed and used to identify putative linear B-cell epitopes from 14 and 5 consensus sequences generated from distinct groups of the S and M proteins, respectively. ELISA testing predicted peptides with PEDV-positive sera revealed nine novel immunodominant epitopes on the S protein. Importantly, seven of these novel immunodominant epitopes and other subdominant epitopes were demonstrated to be neutralizing epitopes by neutralization–inhibition assay. Our findings unveil important roles of the PEDV S2 subunit in both immune stimulation and virus neutralization. Additionally, our study shows the first time that the M protein is also the target of PEDV neutralization with seven neutralizing epitopes identified. Conservancy profiles of the epitopes are also provided. In this study, we offer immunoinformatics-based methods for linear B-cell epitope identification and a more complete profile of linear B-cell epitopes across the PEDV S and M proteins, which may contribute to the development of a greater next-generation PEDV vaccine as well as peptide-based immunoassays.

My dissertation examines several interconnected binaries in music theory: flat/sharp, subdominant/dominant, and minor/major. Traditional theory positions the marked member of each pair (flat, subdominant, and minor, respectively) conceptually LEFT, DOWN and OUTSIDE of the privileged term (sharp, dominant, and major), leading to further marginalization. In my theoretical, historical, analytical and aesthetic inquiry into the ‘musical left,’ I take on Riemannian dualism, mirroring, flat side transformations, stacked fourths, and the pentatonic scale. My deconstruction of 19th century major-minor dualism reveals the surprising “Othering” of the minor mode. Mirroring—from fugues to Riemannian dualism—cannot fully integrate with a ground-up, hierarchical practice like tonality; twentieth-century atonal musics constitute better vehicles for sustained, pure inversions. Unlike ‘structural’ authentic cadences, the subdominant is analyzed by Schenkerians as ‘surface-level’ embellishment, but I assert that composers use autonomous applied plagals to go the ‘wrong way’ around the circle of fifths. In contrast to applied dominants, secondary subdominants—the flatted seventh double plagal, the triple plagal “backdoor” cadence, and the flatted sixth quadruple subdominant—have rarely been studied. For composers of these structures, going flat serves revolutionary ends. Stacked fourths—commonly misinterpreted as purposeless for their tendency to “plane” non-functionally—are used by McCoy Tyner in “Blues on the Corner” to target the subdominant in what I term a “trapdoor cadence.” My taxonomy of stacked fourth chords leads to an analysis of Paul Hindemith’s ic-5 crossing over in Mathis der Maler. Motion in the flat direction is usually right to left—that is, it represents tracking back to the tonic-in-the-past, but by traveling 23 steps into the flatside, Hindemith transforms the past into the future. Quartals are the ideal vehicle for this kind of time travel, for they represent both the past (rustic antiquity) and the future (technological progress). Some theorists and composers have treated the ic-5/7 pentatonic scale as ‘incomplete’ or primitive, but I present compositions, such as John Coltrane’s A Love Supreme, that use segmented pentatonics as building blocks for ic-5 cyclic completion. Since pentatonic melodies are commonly accompanied by non-pentatonic harmonies (the so-called “melodic-harmonic divorce”), I propose a system of melodic-harmonic differentiation, as practiced by African-American musicians. I believe that this refusal to succumb to organic unity mimics heterophony, in which the individual stands out from the group.

Purpose Multiple anthropogenic disturbances, such as climate warming and nitrogen deposition are affecting terrestrial ecosystems. Different disturbances may have some consistent effects on the soil microbial community, which remains largely unexplored. Methods We mimicked 16 anthropogenic disturbances in a steppe ecosystem, and measured the absolute abundance and taxonomic composition of soil bacterial communities with qPCR and amplicon sequencing, respectively. Results We found that while the absolute abundance of each of the four dominant bacterial phyla did not show a consistent response to these disturbances, that of the five subdominant phyla showed a consistent increase. Meanwhile, these disturbances consistently stimulated the relative abundances of metabolic functions for high-growth-yield, including the transport/metabolism of amino acids and carbohydrates. Stochastic processes (e.g., random birth) played more critical roles in structuring the subdominant than dominant phyla, and the disturbances promoted the stochastic processes. Conclusions Overall, the high-yield traits and stochasticity of subdominant phyla led to their positive responses to disturbances. Furthermore, our findings indicate that the intensifying human activities are likely to cause a high-yield-strategies-toward shift in soil microbial composition in the Eurasian steppe ecosystem.

SummaryUnderstanding the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV-2) is critical to overcome the current coronavirus disease (COVID-19) pandemic. Efforts are being made to understand the potential cross-protective immunity of memory T cells, induced by prior encounters with seasonal coronaviruses, in providing protection against severe COVID-19. In this study we assessed T-cell responses directed against highly conserved regions of SARS-CoV-2. Epitope mapping revealed 16 CD8+ T-cell epitopes across the nucleocapsid (N), spike (S) and ORF3a proteins of SARS-CoV-2 and five CD8+ T-cell epitopes encoded within the highly conserved regions of the ORF1ab polyprotein of SARS-CoV-2. Comparative sequence analysis showed high conservation of SARS-CoV-2 ORF1ab T-cell epitopes in seasonal coronaviruses. Paradoxically, the immune responses directed against the conserved ORF1ab epitopes were infrequent and subdominant in both convalescent and unexposed participants. This subdominant immune response was consistent with a low abundance of ORF1ab encoded proteins in SARS-CoV-2 infected cells. Overall, these observations suggest that while cross-reactive CD8+ T cells likely exist in unexposed individuals, they are not common and therefore are unlikely to play a significant role in providing broad pre-existing immunity in the community.

Summary CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Aims Vegetation sampling typically involves the use of quadrats, often 1m2, to estimate species cover-abundance. Such surveys do not generally record small-scale vegetation patch structure at sub-quadrat scales, for example 10 cm2. Here we test a simple method to quantify patch structure that complements conventional techniques. We compare the two methods, and analyse metrics derived from small-scale patch surveys with environment / management data. Location Northumberland, United Kingdom Methods We recorded cover-abundance of all species in an upland moor with 1m2 quadrats. These were divided into 100 9sub-quadrats9, 10 x 10 cm, and the dominant and subdominant species identified. Patch metrics (number, area and shape) for individual species recorded as dominant or subdominant in the sub-quadrat survey were analysed using multivariate generalised linear models with environmental and management data. Sub-quadrat data were also aggregated for each quadrat, to create species composition data. The two sets of compositional data, from whole-quadrat and sub-quadrat aggregations, were compared via Procrustes rotation of ordination scores. Results Patch number, area and shape for dominant and subdominant species were all significantly affected by soil pH, soil water content, slope and elevation. Effects of proximity to sheep tracks and drainage ditches were less consistent amongst species. Ordinations of vegetation data from conventional and sub-quadrats were similar, with significant Procrustes R-squared of 67% and 70% for dominant and subdominant species respectively. Conclusions Sub-quadrat surveys can easily be used to complement existing whole-quadrat surveys at little cost in time or resources. Their patch metrics can provide additional insights into the environmental and management drivers that may affect the growth of individual plants or clumps, potentially in relation to plant traits, and thus alter the overall community composition. The methods we describe can readily be adapted to other sizes of quadrats and sub-quadrats in a wide range of vegetation communities.

Accurate crown detection and delineation of dominant and subdominant trees are crucial for accurate inventorying of forests at the individual tree level. The state-of-the-art tree detection and crown delineation methods have good performance mostly with dominant trees, whereas exhibits a reduced accuracy when dealing with subdominant trees. In this paper, we propose a novel approach to accurately detect and delineate both the dominant and subdominant tree crowns in conifer-dominated multistoried forests using small footprint high-density airborne Light Detection and Ranging data. Here, 3-D candidate cloud segments delineated using a canopy height model segmentation technique are projected onto a novel 3-D space where both the dominant and subdominant tree crowns can be accurately detected and delineated. Tree crowns are detected using 2-D features derived from the projected data. The delineation of the crown is performed at the voxel level with the help of both the 2-D features and 3-D texture information derived from the cloud segment. The texture information is modeled by using 3-D Gray Level Co-occurrence Matrix. The performance evaluation was done on a set of six circular plots for which reference data are available. The high detection and delineation accuracies obtained over the state of the art prove the performance of the proposed method.

AimsVegetation sampling typically involves the use of quadrats, often 1m2, to estimate species cover-abundance. Such surveys do not generally record small-scale vegetation patch structure at sub-quadrat scales, for example 10 cm2. Here we test a simple method to quantify patch structure that complements conventional techniques. We compare the two methods, and analyse metrics derived from small-scale patch surveys with environment / management data.LocationNorthumberland, United KingdomMethodsWe recorded cover-abundance of all species in an upland moor with 1m2 quadrats. These were divided into 100 ‘sub-quadrats’, 10 × 10 cm, and the dominant and subdominant species identified. Patch metrics (number, area and shape) for individual species recorded as dominant or subdominant in the sub-quadrat survey were analysed using multivariate generalised linear models with environmental and management data. Sub-quadrat data were also aggregated for each quadrat, to create species composition data. The two sets of compositional data, from whole-quadrat and sub-quadrat aggregations, were compared via Procrustes rotation of ordination scores.ResultsPatch number, area and shape for dominant and subdominant species were all significantly affected by soil pH, soil water content, slope and elevation. Effects of proximity to sheep tracks and drainage ditches were less consistent amongst species. Ordinations of vegetation data from conventional and sub-quadrats were similar, with significant Procrustes R-squared of 67% and 70% for dominant and subdominant species respectively.ConclusionsSub-quadrat surveys can easily be used to complement existing whole-quadrat surveys at little cost in time or resources. Their patch metrics can provide additional insights into the environmental and management drivers that may affect the growth of individual plants or clumps, potentially in relation to plant traits, and thus alter the overall community composition. The methods we describe can readily be adapted to other sizes of quadrats and sub-quadrats in a wide range of vegetation communities.

The interaction of the SARS–CoV–2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS–CoV–2 variants has revealed mutations arising in the RBD, the N–terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike–reactive monoclonal antibodies from SARS–CoV–2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD–specific. None of the S2–specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD–specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan–dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD–specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.

By and large, discussions on tonal pairing have been limited to works of the late nineteenth century whose competing key centers are a third apart. Even when we find tonal pairing earlier in the nineteenth century, the tonic is still most frequently in conflict with the mediant or the submediant. This chapter addresses a tonal pairing strategy found in certain songs by Fanny Hensel where the tonic is paired not with a third-related key but instead with the subdominant. In these cases, Hensel effectively transforms the tonic into V of iv, such that the subdominant key competes with, and even sometimes usurps, the tonic key. Using “Vorwurf” and “Die Äolsharfe auf dem Schlosse zu Baden” as examples, the author explores the harmonic strategies by which Hensel turns the tonic into V of iv, and the expressive implications that arise as the tonic’s function transforms is transformed in this way.

With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein., Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike.

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about their interplay and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we find that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens are enriched for a TCF1+ progenitor phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response does not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ progenitor cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets indicates CCR6+ TCF1+ cells exist across human cancers and correlate with poor ICB response. Vaccination eliminates CCR6+ TCF1+ cells and dramatically expands the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Minor and major keys/chords are arranged along the joint subdominant-dominant axis. For this purpose, the relative minor for a major tonic (e.g. Am regarding C major) is put between the tonic and its subdominant (F), being interpreted as the ‘semi-subdominant’. Correspondingly, the relative major for a minor key (C for Am) is called its ‘semi-dominant’. Thereby, two axes of fifths for major and minor keys are merged into one. To reflect the proximity of other types of key/chord relations (parallel major-minor keys, major dominants in minor keys and minor subdominants in major keys), this axis is closed by analogy with the circle of fifths and twisted, as if wrapping a torus. The torus unfolded results in a key/chord proximity map. Due to using the subdominant-dominant axis, it is free from inconsistencies inherent in some known maps.

Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.

SUMMARYVaccines work primarily by eliciting antibodies, even when recovery from natural infection depends on cellular immunity. Large efforts have therefore been made to identify microbial antigens that elicit protective antibodies, but these endeavors have encountered major difficulties, as witnessed by the lack of vaccines against many pathogens. This review summarizes accumulating evidence that subdominant protein regions, i.e., surface-exposed regions that elicit relatively weak antibody responses, are of particular interest for vaccine development. This concept may seem counterintuitive, but subdominance may represent an immune evasion mechanism, implying that the corresponding region potentially is a key target for protective immunity. Following a presentation of the concepts of immunodominance and subdominance, the review will present work on subdominant regions in several major human pathogens: the protozoan Plasmodium falciparum, two species of pathogenic streptococci, and the dengue and influenza viruses. Later sections are devoted to the molecular basis of subdominance, its potential role in immune evasion, and general implications for vaccine development. Special emphasis will be placed on the fact that a whole surface-exposed protein domain can be subdominant, as demonstrated for all of the pathogens described here. Overall, the available data indicate that subdominant protein regions are of much interest for vaccine development, not least in bacterial and protozoal systems, for which antibody subdominance remains largely unexplored. (Less)

Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people. CD8+ T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8+ T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified. These include HLA-A*02:01-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226, HLA-B*27:05-NP383-391 and HLA-B*57:01-NP199-207. The immunodominance hierarchies across these universal CD8+ T-cell epitopes were however unknown. Here, we probed immunodominance status of influenza-specific universal CD8+ T-cells in HLA-I heterozygote individuals expressing two or more universal HLAs for IAV. We found that while CD8+ T-cell responses directed towards A2/M158 were generally immunodominant, A2/M158+CD8+ T-cells were markedly diminished (subdominant) in HLA-A*02:01/B*27:05-expressing donors following ex vivo and in vitro analyses. A2/M158+CD8+ T-cells in non-HLA-B*27:05 individuals were immunodominant, contained optimal public TRBV19/TRAV27 TCRαβ clonotypes and displayed highly polyfunctional and proliferative capacity, while A2/M158+CD8+ T cells in HLA-B*27:05-expressing donors were subdominant, with largely distinct TCRαβ clonotypes and consequently markedly reduced avidity, proliferative and polyfunctional efficacy. Our data illustrate altered immunodominance patterns and immunodomination within human influenza-specific CD8+ T-cells. Accordingly, our work highlights the importance of understanding immunodominance hierarchies within individual donors across a spectrum of prominent virus-specific CD8+ T-cell specificities prior to designing T cell-directed vaccines and immunotherapies, for influenza and other infectious diseases., Author summary Annual influenza infections cause significant morbidity and morbidity globally. Established T-cell immunity directed at conserved viral regions provides some protection against influenza viruses and promotes rapid recovery, leading to better clinical outcomes. Killer CD8+ T-cells recognising viral peptides in a context of HLA-I glycoproteins, provide the broadest ever reported immunity across distinct influenza strains and subtypes. We asked whether the expression of certain HLA-I alleles affects CD8+ T cells responses. Our study clearly illustrates altered immunodominance hierarchies and immunodomination within broadly-cross-reactive influenza-specific CD8+ T-cells in individuals expressing two or more universal HLA-I alleles, key for T cell-directed vaccines and immunotherapies.

T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.

This paper examines analytic possibilities afforded by understanding exceptional uses of the subdominant as a hermeneutic signal of the past tense in contemporary Broadway megamusicals. While an emerging consensus in studies of pop music holds that the subdominant chord can comprise a variety of functions beyond its traditional predominant role, to suggest as much already betrays an approach that is steeped in the long shadow of common-practice tonality and the expectations that it entails. Rather than trying to develop a separate syntax from its common-practice antecedents, it is more fruitful to engage with common-practice perspectives in the analysis of certain styles of pop music. Through analysis of examples from Andrew Lloyd Webber'sSunset Boulevardand Boublil and Schönberg'sMiss Saigon, I argue that cases wherein the subdominant receives an unconventional (over-)emphasis might be better understood through the hermeneutics of tonal temporality, rather than through attempts to codify them as an entirely new syntax.

Upon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear. Here, we used publicly available TCR amino acid sequences to study which factors determine whether a response becomes immunodominance (ID) per donor; we classified the largest T cell clone as the epitope-specific dominant clone and all the other clones as subdominant responses (SD). We observed a distinctively hydrophobic CDR3 in ID responses against a dominant epitope from influenza A virus, compared to the SD responses. The common V-J combinations were shared between ID and SD responses, suggesting that the biased V-J recombination events are restricted by epitope specificity; thus, the immunodominance is not directly determined by a bias combination of V and J genetic segments. Our findings reveal a close similarity of global sequence properties between dominant and subdominant clones of epitope-specific responses but detectable distinctive amino acid enrichments in ID. Taken together, we believe this first comparative study of immunodominant and subdominant TCR sequences can guide further studies to resolve factors determining the immunodominance of antiviral as well as tumor-specific T cell responses. Electronic supplementary material The online version of this article (10.1007/s00251-019-01134-9) contains supplementary material, which is available to authorized users.

Summary Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSPRepeat) can protect against malaria. However, it has also been suggested that the CSPRepeat is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSPRepeat are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSPRepeat to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSPRepeat functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination., Graphical abstract, Highlights • The repeat domain is immunodominant within the circumsporozoite protein • High avidity responses by repeat-specific B cells inhibit subdominant responses • The number of naive B cell precursors does not predict immunodominance hierarchies • Vaccination with repeat-truncated circumsporozoite proteins induces robust protection, Chatterjee et al. show that avid B cell responses to repeating epitopes can suppress B cell responses to other regions of the same protein, driving immunodominance hierarchies. In the context of malaria vaccination, circumsporozoite-based immunogens carrying truncated repeat regions stimulated more diverse antibody responses and induced robust protection.

Herpes simplex virus 1 (HSV-1) causes a lifelong infection of neurons that innervate barrier sites like the skin and mucosal surfaces like the eye. After primary infection of the cornea, the virus enters latency within the trigeminal ganglion (TG), from which it can reactivate throughout the life of the host. Viral latency is maintained, in part, by virus-specific CD8+ T cells that nonlethally interact with infected neurons. When CD8+ T cell responses are inhibited, HSV-1 can reactivate, and these recurrent reactivation events can lead to blinding scarring of the cornea. In the C57BL/6 mouse, CD8+ T cells specific for the immunodominant epitope from glycoprotein B maintain functionality throughout latency, while CD8+ T cells specific for subdominant epitopes undergo functional impairment that is associated with the expression of the inhibitory checkpoint molecule programmed death 1 (PD-1). Here, we investigate the checkpoint molecule T cell immunoglobulin and mucin domain-containing 3 (Tim-3), which has traditionally been associated with CD8+ T cell exhaustion. Unexpectedly, we found that Tim-3 was preferentially expressed on highly functional ganglionic CD8+ T cells during acute and latent HSV-1 infection. This, paired with data that show that Tim-3 expression on CD8+ T cells in the latently infected TG is influenced by viral gene expression, suggests that Tim-3 is an indicator of recent T cell stimulation, rather than functional compromise, in this model. We conclude that Tim-3 expression is not sufficient to define functional compromise during latency; however, it may be useful in identifying activated cells within the TG during HSV-1 infection.IMPORTANCE Without an effective means of eliminating HSV-1 from latently infected neurons, efforts to control the virus have centered on preventing viral reactivation from latency. Virus-specific CD8+ T cells within the infected TG have been shown to play a crucial role in inhibiting viral reactivation, and with a portion of these cells exhibiting functional impairment, checkpoint molecule immunotherapies have presented a potential solution to enhancing the antiviral response of these cells. In pursuing this potential treatment strategy, we found that Tim-3 (often associated with CD8+ T cell functional exhaustion) is not upregulated on impaired cells but instead is upregulated on highly functional cells that have recently received antigenic stimulation. These findings support a role for Tim-3 as a marker of activation rather than exhaustion in this model, and we provide additional evidence for the hypothesis that there is persistent viral gene expression in the HSV-1 latently infected TG.

The ‘stress-gradient hypothesis’ predicts increasing facilitative interactions with increasing environmental stress, but it remains unclear if the prevailing type of interaction (i.e. facilitative or competitive) between dominant and subordinate plant species occurring in harsh environments is dependent on the plant functional type. In addition, most plant-species removal experiments in grasslands are short-term (1–2 years), which may imprecisely reflect transient effects arising from methodological limitations. We conducted a dominant species removal experiment in a subalpine ecosystem, containing a mosaic of grass-dominated and shrub-dominated community patches, both of which are common in the subalpine zone of the Qinghai-Tibetan Plateau. We examined the direction and magnitude of the effects of three co-dominant grass and a dominant shrub species on subordinate species richness and biomass over a 6-year period. Removal of the dominant grass species alleviated their competitive pressure on subdominant grasses, which resulted in similar total and grass biomass detected in the final year of the study. By contrast, shrub removal showed no effects on its subordinate species biomass. Furthermore, neither the removal of the dominant shrubs nor the grasses altered their respective subordinate species richness. Thus, in subalpine ecosystems that experience harsh environmental conditions, our results showed that the direction of interactive effects of dominant plant species on subordinate species may be dependent on the plant functional type and are not necessarily facilitative. Furthermore, we showed that longer-term plant-removal experiment observations may be required to better determine the effects of species removal for this subalpine and other montane ecosystem(s). Published version

We study the motion of an interface separating two regions with different electronic orders following a short duration pump that drives the system out of equilibrium. Using a generalized Ginzburg-Landau approach and assuming that the main effect of the nonequilibrium drive is to transiently heat the system we address the question of the direction of interface motion; in other words, which ordered region expands and which contracts after the pump. Our analysis includes the effects of differences in free energy landscape and in order parameter dynamics and identifies circumstances in which the drive may act to increase the volume associated with the subdominant order, for example when the subdominant order has a second order free energy landscape while the dominant order has a first order one., Comment: 8 pages, 7 figures

International audience; Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.

CMV is an obligate and persistent intracellular pathogen that continually drives the production of highly differentiated virus-specific CD8+ T cells in an Ag-dependent manner, a phenomenon known as memory inflation. Extensive proliferation is required to generate and maintain inflationary CD8+ T cell populations, which are counterintuitively short-lived and typically exposed to limited amounts of Ag during the chronic phase of infection. An apparent discrepancy therefore exists between the magnitude of expansion and the requirement for ongoing immunogenic stimulation. To address this issue, we explored the clonal dynamics of memory inflation. First, we tracked congenically marked OT-I cell populations in recipient mice infected with murine CMV (MCMV) expressing the cognate Ag OVA. Irrespective of numerical dominance, stochastic expansions were observed in each population, such that dominant and subdominant OT-I cells were maintained at stable frequencies over time. Second, we characterized endogenous CD8+ T cell populations specific for two classic inflationary epitopes, M38 and IE3. Multiple clonotypes simultaneously underwent Ag-driven proliferation during latent infection with MCMV. In addition, the corresponding CD8+ T cell repertoires were stable over time and dominated by persistent clonotypes, many of which also occurred in more than one mouse. Collectively, these data suggest that stochastic encounters with Ag occur frequently enough to maintain oligoclonal populations of inflationary CD8+ T cells, despite intrinsic constraints on epitope display at individual sites of infection with MCMV.

Anaplasma marginale is the most prevalent tick-borne livestock pathogen with worldwide distribution. Bovine anaplasmosis is a significant threat to cattle industry. Anaplasmosis outbreaks in endemic areas are prevented via vaccination with live A. centrale produced in splenectomized calves. Since A. centrale live vaccine can carry other pathogens and cause disease in adult cattle, research efforts are directed to develop safe recombinant subunit vaccines. Previous work found that the subdominant proteins of A. marginale type IV secretion system (T4SS) and the subdominant elongation factor-Tu (Ef-Tu) were involved in the protective immunity against the experimental challenge in cattle immunized with the A. marginale outer membrane (OM). This study evaluated the immunogenicity and protection conferred by recombinant VirB9.1, VirB9.2, VirB10, VirB11, and Ef-Tu proteins cloned and expressed in E. coli. Twenty steers were randomly clustered into four groups (G) of five animals each. Cattle from G1 and G2 were immunized with a mixture of 50 μg of each recombinant protein with Quil A® or Montanide™ adjuvants, respectively. Cattle from G3 and G4 (controls) were immunized with Quil A and Montanide adjuvants, respectively. Cattle received four immunizations at three-week intervals and were challenged with 107 A. marginale-parasitized erythrocytes 42 days after the fourth immunization. After challenge, all cattle showed clinical signs, with a significant drop of packed cell volume and a significant increase of parasitized erythrocytes (p

Various species of fish living in coral reef communities show sequential hermaphroditism, or sex change. In a typical case, an individual first matures as a female, and later, when it becomes dominant in the mating group, it becomes a male (i.e., protogynous sex change). Many species show only unidirectional changes but some of coral reef fishes exhibit bidirectional sex changes, in which even a dominant male may revert to female when a socially more dominant competitor arrives. However, bidirectional sex change has rarely been observed in natural conditions, even among those species exhibiting it under experimental conditions. Here we explain the rarity of bidirectional sex change by studying dynamics of hormones controlling sex expression. We consider social status factor, SF, which is elevated when the individual becomes more dominant in the mating group. When the SF level is high, the dynamics would culminate with low estradiol expression and high testosterone expression, suggesting a male phenotype. In contrast, when SF level is low, the system converges to an equilibrium with high estradiol expression and low testosterone expression, suggesting a female phenotype. There is a parameter region in which the dynamics exhibit bistability. The model demonstrates hysteresis: as SF increases smoothly, the system undergoes a sudden transition in the levels of sex hormones. The model can explain why species show unidirectional sex change, in that an individual's switch to a new sex is irreversible, even if the individual's social situation returns to the original subdominant status.

The paper considers a generalized Dickman equation t x ˙ ( t ) = − ∑ i = 1 s a i x ( t − τ i ) for t → ∞ where s ∈ N , ai > 0, τi > 0, i = 1 , … , s and ∑ i = 1 s a i = 1 . It is proved that there are two mutually disjoint sets of positive decreasing solutions such that, for every two solutions from different sets, the limit of their ratio for t → ∞ equals 0 or ∞. The asymptotic behavior of such solutions is derived and a structure formula utilizing such solutions and describing all the solutions of a given equation is discussed. In addition, a criterion is proved giving sufficient conditions for initial functions to generate solutions falling into the first or the second set. Illustrative examples are given. Some open problems are suggested to be solved.

The paper investigates large-time behaviour of positive solutions to a generalized Dickman equation. The asymptotic behaviour of dominant and subdominant positive solutions is analysed and a structure formula describing behaviour of all solutions is proved. A criterion is also given for sufficient conditions on initial functions to generate positive solutions with prescribed asymptotic behaviour with values of their weighted limits computed.

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27Gag and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIVmac239 which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8+ T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.

The influence of tonal modulation in pieces of music on the EEG parameters was studied. An EEG was recorded while subjects were listening to two series of fragments with modulations: controlled harmonic progressions and the fragments of classical musical compositions. Each series included modulations to the subdominant, the dominant, and the ascending minor sixth. The highly controlled and artistically impoverished harmonic progressions of the first series contrasted with the real music excerpts in the second series, which differed in tempo, rhythm, tessitura, duration, and style. Listening to harmonic progressions and musical fragments produced event-related synchronization in the α frequency band. Real musical fragments with modulation to the dominant generated lower synchronization in the α band as compared with other modulations. A lower decrease of synchronization in the α frequency band after listening was observed in the case of fragments of classical music compared with harmonic progressions.