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Tebentafusp is a gp100xCD3 bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage specific antigen gp100 on HLA-A*02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions, yet the mechanisms are unknown. Here we analysed clinical data from the randomised phase 3 trial (NCT03070392) of tebentafusp (n=252) versus investigator's choice (n=126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced and expression of melanocytic genes decreased, while gene expression related to immunity and cytokine signalling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.
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The design of digital health information systems around a conflated gender/sex binary contributes to health inequities. Lack of specific information that supports affirming communication lead to inappropriate care, disrespectful encounters with healthcare staff, and avoidance of health services by clients who have been harmed by misgendering, deadnaming and being outed. The HL7 International Gender Harmony Model (HL7 GHM) supports the design, implementation and use of DHIS that enable affirming clinical interactions and care. This case study will demonstrate how applying the HL7 GHM can address the harms reported in a recently published account of one patient in Canada.
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Informática Aplicada a la Enfermería , Humanos , Femenino , Masculino , Canadá , Estándar HL7 , Identidad de GéneroRESUMEN
Deep learning models have been shown to accurately predict protein structure from sequence, allowing researchers to explore protein space from the structural viewpoint. In this paper we explore whether "novel" features, such as distinct loop conformations can arise from these predictions despite not being present in the training data. Here we have used ABodyBuilder2, a deep learning antibody structure predictor, to predict the structures of ~1.5M paired antibody sequences. We examined the predicted structures of the canonical CDR loops and found that most of these predictions fall into the already described CDR canonical form structural space. We also found a small number of "new" canonical clusters composed of heterogeneous sequences united by a common sequence motif and loop conformation. Analysis of these novel clusters showed their origins to be either shapes seen in the training data at very low frequency or shapes seen at high frequency but at a shorter sequence length. To evaluate explicitly the ability of ABodyBuilder2 to extrapolate, we retrained several models whilst withholding all antibody structures of a specific CDR loop length or canonical form. These "starved" models showed evidence of generalisation across CDRs of different lengths, but they did not extrapolate to loop conformations which were highly distinct from those present in the training data. However, the models were able to accurately predict a canonical form even if only a very small number of examples of that shape were in the training data. Our results suggest that deep learning protein structure prediction methods are unable to make completely out-of-domain predictions for CDR loops. However, in our analysis we also found that even minimal amounts of data of a structural shape allow the method to recover its original predictive abilities. We have made the ~1.5 M predicted structures used in this study available to download at https://doi.org/10.5281/zenodo.10280181.
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Regiones Determinantes de Complementariedad , Aprendizaje Profundo , Regiones Determinantes de Complementariedad/química , Conformación Proteica , Modelos Moleculares , AnticuerposRESUMEN
The optical properties of light-absorbing materials in optical shutter devices are critical to the use of such platforms for optical applications. We demonstrate switchable optical properties of dyes and nanoparticles in liquid-based electrowetting-on-dielectric (EWOD) devices. Our work uses narrow-band-absorbing dyes and nanoparticles, which are appealing for spectral-filtering applications targeting specific wavelengths while maintaining device transparency at other wavelengths. Low-voltage actuation of boron dipyromethene (BODIPY) dyes and nanoparticles (Ag and CdSe) was demonstrated without degradation of the light-absorbing materials. Three BODIPY dyes were used, namely Abs 503 nm, 535 nm and 560 nm for dye 1 (BODIPY-core), 2 (I2BODIPY) and 3 (BODIPY-TMS), respectively. Reversible and low-voltage (≤20 V) switching of dye optical properties was observed as a function of device pixel dimensions (300 × 900, 200 × 600 and 150 × 450 µm). Low-voltage and reversible switching was also demonstrated for plasmonic and semiconductor nanoparticles, such as CdSe nanotetrapods (abs 508 nm), CdSe nanoplatelets (Abs 461 and 432 nm) and Ag nanoparticles (Abs 430 nm). Nanoparticle-based devices showed minimal hysteresis as well as faster relaxation times. The study presented can thus be extended to a variety of nanomaterials and dyes having the desired optical properties.
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CD4+ T cells recognize a broad range of peptide epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which contribute to immune memory and limit COVID-19 disease. We demonstrate that the immunogenicity of SARS-CoV-2 peptides, in the context of the model allotype HLA-DR1, does not correlate with their binding affinity to the HLA heterodimer. Analyzing six epitopes, some with very low binding affinity, we solve X-ray crystallographic structures of each bound to HLA-DR1. Further structural definitions reveal the precise molecular impact of viral variant mutations on epitope presentation. Omicron escaped ancestral SARS-CoV-2 immunity to two epitopes through two distinct mechanisms: (1) mutations to TCR-facing epitope positions and (2) a mechanism whereby a single amino acid substitution caused a register shift within the HLA binding groove, completely altering the peptide-HLA structure. This HLA-II-specific paradigm of immune escape highlights how CD4+ T cell memory is finely poised at the level of peptide-HLA-II presentation.
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COVID-19 , SARS-CoV-2 , Humanos , Antígeno HLA-DR1 , Epítopos de Linfocito T , Péptidos , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivosRESUMEN
Malaria-causing Plasmodium parasites have a complex life cycle and present numerous antigen targets that may contribute to protective immune responses. The currently recommended vaccine-RTS,S-functions by targeting the Plasmodium falciparum circumsporozoite protein (CSP), which is the most abundant surface protein of the sporozoite form responsible for initiating infection of the human host. Despite showing only moderate efficacy, RTS,S has established a strong foundation for the development of next-generation subunit vaccines. Our previous work characterizing the sporozoite surface proteome identified additional non-CSP antigens that may be useful as immunogens individually or in combination with CSP. In this study, we examined eight such antigens using the rodent malaria parasite Plasmodium yoelii as a model system. We demonstrate that despite conferring weak protection individually, coimmunizing each of several of these antigens alongside CSP could significantly enhance the sterile protection achieved by CSP immunization alone. Thus, our work provides compelling evidence that a multiantigen preerythrocytic vaccine approach may enhance protection compared to CSP-only vaccines. This lays the groundwork for further studies aimed at testing the identified antigen combinations in human vaccination trials that assess efficacy with controlled human malaria infection. IMPORTANCE The currently approved malaria vaccine targets a single parasite protein (CSP) and results in only partial protection. We tested several additional vaccine targets in combination with CSP to identify those that could enhance protection from infection upon challenge in the mouse malaria model. In identifying several such enhancing vaccine targets, our work indicates that a multiprotein immunization approach may be a promising avenue to achieving higher levels of protection from infection. Our work identified several candidate leads for follow-up in the models relevant for human malaria and provides an experimental framework for efficiently carrying out such screens for other combinations of vaccine targets.
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Importance: Immune-related adverse events (irAEs) due to immune checkpoint blockade (ICB) have been shown to be positively associated with survival. Among patients with metastatic melanoma, evidence supporting this association has been conflicting, while ipilimumab-nivolumab combination ICB has been examined only in small clinical cohorts. Objective: To examine the association between irAEs and survival among patients with metastatic melanoma, in particular for those receiving combination ICB. Design, Setting, and Participants: A retrospective cohort of 492 consecutive patients with metastatic melanoma treated with ICB at 2 tertiary and 4 regional cancer centers in Alberta, Canada, from August 1, 2013, to May 31, 2020, was observed. Patients were aged 18 years or older with metastatic melanoma agnostic to primary site, who received 1 or more doses of an anti-programmed cell death protein 1 agent as single or combination ICB. Clinically significant irAEs requiring systemic corticosteroids and/or treatment delay were captured. To minimize immortal time bias, only patients surviving 12 weeks after ICB initiation were included in survival analyses. Statistical analysis was conducted on December 10, 2021. Exposures: Development of irAEs requiring systemic corticosteroids and/or treatment delay. Main Outcomes and Measures: The primary outcome was overall survival (OS), with the association of irAE development with OS assessed via Kaplan-Meier and Cox proportional hazards regression analyses. The association of hospitalization for irAEs and ICB resumption after irAE with OS was examined. Results: Among 492 patients, the median age of those with irAEs was 61.8 years (IQR, 52.9-72.1 years), and the median age of those without irAEs was 65.5 years (IQR, 56.5-76.9 years), while sex distribution was comparable (137 of 198 men [69.2%] with irAEs vs 183 of 294 men [62.2%] without irAEs). There was an association between irAEs and OS both in the overall cohort (with irAEs: median OS, 56.3 months [95% CI, 38.2 months to not evaluable] vs without irAEs: median OS, 18.5 months [95% CI, 14.4-23.2 months]; P < .001) and in the 124 patients (25.2%) receiving combination ICB (with irAEs: median OS, 56.2 months [95% CI, 52.2 months to not evaluable] vs without irAEs: median OS, 19.0 months [95% CI, 6.6 months to not evaluable]; P < .001). Hospitalization for irAE did not alter this positive association with OS compared with outpatient treatment (median OS, not evaluable [95% CI, 31.5 months to not evaluable] vs median OS, 52.2 months [95% CI, 35.2 months to not evaluable]; P = .53), while resumption of ICB was associated with longer OS than not resuming ICB (median, 56.3 months [95% CI, 40.8 months to not evaluable] vs 31.5 months [95% CI, 21.0 months to not evaluable]; P = .009). A favorable independent association of irAEs with OS was confirmed in multivariable analysis (hazard ratio for death, 0.382 [95% CI, 0.254-0.576]; P < .001). Conclusions and Relevance: This study suggests an association between irAEs and OS for patients with metastatic melanoma, including those treated with combination ICB and those with severe irAEs requiring hospitalization. The potential benefit associated with ICB resumption after irAEs warrants further investigation.
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Melanoma , Humanos , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Distribución por Sexo , Alberta , Melanoma/tratamiento farmacológicoRESUMEN
While they are often encountered as reaction intermediates, phosphenium cations are not commonly incorporated into π-conjugated systems. We report the synthesis and characterization of donor-stabilized phosphenium cations supported by pyridylhydrazonide ligands. The preparation of these cations relies on precise control of ligand E-Z isomerism. The heterocycles were treated with a variety of transition metals, with [Rh(COD)Cl]2 yielding the only well-defined organometallic products. The optoelectronic properties of the phosphenium heterocycles and their transition-metal complexes were examined using UV-vis absorption spectroscopy, cyclic voltammetry, and modeling by density functional theory (DFT). Computations support the description of these compounds as phosphenium cations and corroborate our observation of a weak P-Npyridine bond, which was manifested experimentally as the Rh adducts undergo selective insertion of Rh into the P-Npyridine bond, depending on the substituent at phosphorus. The reported compounds provide a framework for further study of π-conjugated, N,N'-chelated phosphenium cations and their transition-metal adducts.
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BACKGROUND: For post-docetaxel treatment of metastatic castrate-resistant prostate cancer (mCRPC), cabazitaxel has demonstrated superior third line PFS and OS compared to androgen receptor pathway inhibitors (ARPIs) in patients who progress within 12 months on first ARPI. The impact of first ARPI response, in particular responses beyond 12 months, on cabazitaxel outcomes in real-world populations is uncertain, as are other factors impacting cabazitaxel use. MATERIALS AND METHODS: mCRPC patients in Alberta, Canada who received docetaxel from October 1, 2012 to December 31, 2017 were included. We reviewed mCRPC therapies, correlating cabazitaxel use with patient characteristics and TROPIC trial inclusion/exclusion criteria. OS and PFS were evaluated in patients who received cabazitaxel, stratified by time to progression on first ARPI ≤ 12 months (poor ARPI responders, PAR) or >12 months (strong ARPI responders, SAR), using the Kaplan-Meier method. RESULTS: PAR patients had inferior OS compared to SAR patients (12.3 vs. 24.8 months, P < .001). OS was longer in PAR patients receiving cabazitaxel compared to those not treated with cabazitaxel (16.9 vs. 10.3 months, P = .015), but this benefit was not seen in the SAR group (17.1 vs. 32 months, P = .084). Cabazitaxel use was associated with reduced PFS first line post-docetaxel in SAR (3.5 vs. 14.7 months, P < .001) but not PAR patients. Of 592 patients, 170 (29%) received cabazitaxel post-docetaxel, compared to 280 (47%) and 250 (42%) for abiraterone and enzalutamide. 238 patients (40%) did not have a discussion of cabazitaxel documented. Cabazitaxel use was increased in patients who fit TROPIC trial criteria (P < .001). CONCLUSIONS: In a real-world mCRPC cohort, cabazitaxel use was associated with longer OS among PAR patients, but crucially not among strong ARPI responders. Cabazitaxel was used less frequently and later than ARPIs post-docetaxel. These data help support first ARPI progression time as a consideration in treatment sequencing.
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Neoplasias de la Próstata Resistentes a la Castración , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Masculino , Nitrilos , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Taxoides , Resultado del TratamientoRESUMEN
Both subunit and attenuated whole-sporozoite vaccination strategies against Plasmodium infection have shown promising initial results in malaria-naive westerners but less efficacy in malaria-exposed individuals in endemic areas. Here, we demonstrate proof of concept by using a rodent malaria model in which non-neutralizing antibodies (nNAbs) can directly interfere with protective anti-circumsporozoite protein (CSP) humoral responses. We characterize a monoclonal antibody, RAM1, against Plasmodium yoelii sporozoite major surface antigen CSP. Unlike the canonical PyCSP repeat domain binding and neutralizing antibody (NAb) 2F6, RAM1 does not inhibit sporozoite traversal or entry of hepatocytes in vitro or infection in vivo. Although 2F6 and RAM1 bind non-overlapping regions of the CSP-repeat domain, pre-treatment with RAM1 abrogates the capacity of NAb to block sporozoite traversal and invasion in vitro. Importantly, RAM1 reduces the efficacy of the polyclonal humoral response against PyCSP in vivo. Collectively, our data provide a proof of concept that nNAbs can alter the efficacy of malaria vaccination.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antiprotozoarios/inmunología , Inmunidad Humoral , Estadios del Ciclo de Vida , Hígado/parasitología , Plasmodium yoelii/crecimiento & desarrollo , Plasmodium yoelii/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Línea Celular , Epítopos/inmunología , Femenino , Cinética , Vacunas contra la Malaria/inmunología , Ratones Endogámicos BALB C , Modelos Biológicos , Unión Proteica , Dominios Proteicos , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Esporozoítos/inmunología , Vacunas Sintéticas/inmunologíaRESUMEN
Immune checkpoint inhibitors (antibodies that block the T cell co-inhibitory receptors PD-1/PD-L1 or CTLA-4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co-inhibitory receptor lymphocyte activation gene-3 (LAG-3), which is upregulated on T cells extracted from tumor sites that have suppressive or exhausted phenotypes. However, the molecular rules that govern the function of LAG-3 are still not understood. Using surface plasmon resonance combined with a novel bead-based assay (AlphaScreenTM ), we demonstrate that LAG-3 can directly and specifically interact with intact human leukocyte antigen class II (HLA-II) heterodimers. Unlike the homologue CD4, which has an immeasurably weak affinity using these biophysical approaches, LAG-3 binds with low micromolar affinity. We further validated the interaction at the cell surface by staining LAG-3+ cells with pHLA-II-multimers. These data provide new insights into the mechanism by which LAG-3 initiates T cell inhibition.
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Antígenos CD/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Antígenos HLA/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Antígenos CD4/inmunología , Línea Celular Tumoral , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Células Jurkat , Neoplasias/inmunología , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Polymers that exhibit aggregation-induced emission (AIE) find use, for example, as cell-imaging agents and as fluorometric sensors due to their unique optical properties. However, the structural diversity of AIE-active polymers has not necessarily advanced at the same rate as their applications. In this work, ring-opening metathesis polymerization is used to synthesize the first example of a polymer (Mn = 61,600 g mol-1 , D = 1.32) containing boron difluoride hydrazone (BODIHY) heterocycles in its repeating unit. The BODIHY monomer and polymer described absorb and emit in the visible region in solution (λabs = 428 and 429 nm, λem = 528 and 526 nm) and as thin films (λabs = 443 and 440 nm, λem = 535 and 534 nm). Monomer (ΦFilm = 10%) and polymer (ΦFilm = 6%) exhibit enhanced emission as thin films compared to solution (ΦSoln ≤ 1%) as well as AIE upon the addition of water to DMF solutions as a result of restriction of intramolecular motion. Enhancement factors for the monomer and polymer are determined to be 58 and 15, respectively. The title BODIHY polymer exhibited an earlier onset of AIE and enhanced sensitivity to solution viscosity when compared to the parent monomer.
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Hidrazonas , Polímeros , Compuestos de Boro , PolimerizacionRESUMEN
HYPOTHESIS: The electrowetting behavior of droplets can be altered by the inclusion of salts, surfactants, or nanoparticles. We propose that varying the properties of cadmium selenide/zinc sulfide quantum dots will affect the electrowetting behavior of fluorescent nanofluids. Information gathered will allow for greater control of fluid properties when designing a colloidal system in an electrowetting environment. EXPERIMENTS: Aqueous-based quantum dots were functionalized with mercaptocarboxylic acid ligands of various chain length and binding motifs by a room temperature phase transfer method. The size and concentration of the quantum dot were varied, and droplets of the resulting nanofluids were exposed to increasing amounts of voltage. The change in contact angle was evaluated and correlated to the surface chemistry, size, and concentration of the quantum dots. FINDINGS: Quantum dot nanofluids with longer alkyl chains have the most pronounced change in contact angle and were the most stable under applied voltage. The size of the nanoparticles does not significantly impact the electrowetting behavior at low concentration (3 µM), but nanofluids containing smaller diameter quantum dots show enhanced electrowetting behavior at higher concentration (27 µM). The fluorescent properties of the QD nanofluids studied were not affected after repeated electrowetting cycles.
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The nature of the tumor microenvironment (TME) influences the ability of tumor-specific T cells to control tumor growth. In this study, we performed an unbiased comparison of the TME of regulatory T-cell (Treg)-replete and Treg-depleted carcinogen-induced tumors, including Treg-depleted responding (regressing) and non-responding (growing) tumors. This analysis revealed an inverse relationship between extracellular matrix (ECM) and T-cell infiltrates where responding tumors were T-cell rich and ECM poor, whereas the converse was observed in non-responder tumors. For this reason, we hypothesized that the ECM acted as a barrier to successful T-cell infiltration and tumor rejection. However, further experiments revealed that this was not the case but instead showed that an effective T-cell response dramatically altered the density of ECM in the TME. Along with loss of ECM and high numbers of infiltrating T cells, responder tumors were distinguished by the development of lymphatic and blood vessel networks with specialized immune function. ECM-rich tumors exhibited a stem cell-like gene expression profile and superior tumor-initiating capacity, whereas such features were absent in responder tumors. Overall, these findings define an extended role for an effective immune response, not just in direct killing of tumor cells but in widescale remodeling of the TME to favor loss of ECM, elimination of cancer stem cells, and propagation of adaptive immunity.
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Neoplasias/etiología , Células Madre Neoplásicas/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Matriz Extracelular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias/metabolismo , Neoplasias/patología , Microambiente Tumoral/genéticaRESUMEN
The purpose of this study was to determine whether the type and direction of postural perturbation threat differentially affect anticipatory postural control. Healthy young adults stood on a force plate fixed to a translating platform and completed a series of rise-to-toes movements without (No Threat) and with (Threat) the potential of receiving a postural perturbation to either their feet (15 participants) or torso (16 participants). Each type of perturbation threat was presented along the anteroposterior (A-P) or mediolateral (M-L) axis. For each condition, the A-P center of pressure (COP) signal and tibialis anterior (TA) and soleus (SOL) electromyographical (EMG) recordings were used to quantify the anticipatory postural adjustment (APA). Results indicated that across both threat types and directions, postural threat induced a 40.2% greater TA activation (p < 0.001), a 18.5% greater backward COP displacement (p < 0.001) and a 23.9% greater backward COP velocity (p < 0.001), leading to larger and faster APAs than the No Threat condition. Subsequently, a 7.7% larger forward COP displacement (p = 0.001), a 20.4% greater forward COP velocity (p < 0.001) and 43.2% greater SOL activation (p = 0.009) were observed during the execution phase of the rise-to-toes for the Threat compared to the No Threat condition. Despite these threat effects, there were no differences in the magnitude or velocity of APAs between the threat directsion conditions. Since the type and direction of perturbation-induced postural threat had minimal differential effects on anticipatory postural control, these factors are unlikely to explain the discrepancy of previous findings.
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Músculo Esquelético/fisiología , Equilibrio Postural , Postura , Adulto , Ansiedad , Intervalos de Confianza , Electromiografía , Miedo , Femenino , Pie/fisiología , Humanos , Masculino , Presión , Autoimagen , Dedos del Pie , Torso/fisiología , Adulto JovenRESUMEN
T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated by the highly variable T cell receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes by using identical or highly related TCRs expressed on CD8+ T cells. Characterization of these TCRs has extended our understanding of the molecular mechanisms that govern the recognition of peptide-HLA. However, few examples exist for CD4+ T cells. Here, we investigate CD4+ T cell responses to the internal proteins of the influenza A virus that correlate with protective immunity. We identify five internal epitopes that are commonly recognized by CD4+ T cells in five HLA-DR1+ subjects and show conservation across viral strains and zoonotic reservoirs. TCR repertoire analysis demonstrates several shared gene usage biases underpinned by complementary biochemical features evident in a structural comparison. These epitopes are attractive targets for vaccination and other T cell therapies.
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Linfocitos T CD4-Positivos/inmunología , Epítopos/inmunología , Región Variable de Inmunoglobulina/genética , Virus de la Influenza A/inmunología , Adulto , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Aves/virología , Regiones Determinantes de Complementariedad/química , Secuencia Conservada , Epítopos/química , Femenino , Células Germinativas/metabolismo , Antígeno HLA-DR1/inmunología , Humanos , Epítopos Inmunodominantes/química , Epítopos Inmunodominantes/inmunología , Masculino , Persona de Mediana Edad , Péptidos/química , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Porcinos/virología , Donantes de Tejidos , Proteínas Virales/inmunología , Adulto Joven , Zoonosis/inmunología , Zoonosis/virologíaRESUMEN
Research indicates that threat-induced changes in standing balance are associated with shifts in attention focus. This study investigated whether distracting attention modifies threat-induced changes in standing balance. Twenty-five healthy young adults stood without (No Threat) and with (Threat) the possibility of receiving a temporally unpredictable anteroposterior support surface translation. In both conditions, participants completed a distractor task that consisted of counting how often a pre-selected letter occurred in an auditory sequence, or no distractor task. Emotional responses to threat were quantified using electrodermal activity and self-report measures, while attention focus was quantified using self-report. Centre of pressure (COP) was measured to assess changes in standing balance. Results indicate that postural threat induced an emotional response, as well as broad shifts in attention focus and changes in standing balance. Distracting attention with a cognitive task mitigated threat-induced increases in medium-frequency COP displacements (0.5-1.8 Hz). These results provide support for a relationship between threat-related changes in balance control and attention focus.
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Atención/fisiología , Miedo/fisiología , Equilibrio Postural/fisiología , Femenino , Humanos , Masculino , Posición de Pie , Adulto JovenRESUMEN
Here, we report an update of the VDJdb database with a substantial increase in the number of T-cell receptor (TCR) sequences and their cognate antigens. The update further provides a new database infrastructure featuring two additional analysis modes that facilitate database querying and real-world data analysis. The increased yield of TCR specificity identification methods and the overall increase in the number of studies in the field has allowed us to expand the database more than 5-fold. Furthermore, several new analysis methods are included. For example, batch annotation of TCR repertoire sequencing samples allows for annotating large datasets on-line. Using recently developed bioinformatic methods for TCR motif mining, we have built a reduced set of high-quality TCR motifs that can be used for both training TCR specificity predictors and matching against TCRs of interest. These additions enhance the versatility of the VDJdb in the task of exploring T-cell antigen specificities. The database is available at https://vdjdb.cdr3.net.
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Biología Computacional/métodos , Bases de Datos Genéticas , Motivos de Nucleótidos , Receptores de Antígenos de Linfocitos T/genética , Recombinación V(D)J , Secuencia de Aminoácidos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Posición Específica de Matrices de Puntuación , Receptores de Antígenos de Linfocitos T/química , Análisis de Secuencia de ADN , Programas Informáticos , Navegador WebRESUMEN
CD4+ T-cells recognize peptide antigens, in the context of human leukocyte antigen (HLA) class II molecules (HLA-II), which through peptide-flanking residues (PFRs) can extend beyond the limits of the HLA binding. The role of the PFRs during antigen recognition is not fully understood; however, recent studies have indicated that these regions can influence T-cell receptor (TCR) affinity and pHLA-II stability. Here, using various biochemical approaches including peptide sensitivity ELISA and ELISpot assays, peptide-binding assays and HLA-II tetramer staining, we focused on CD4+ T-cell responses against a tumor antigen, 5T4 oncofetal trophoblast glycoprotein (5T4), which have been associated with improved control of colorectal cancer. Despite their weak TCR-binding affinity, we found that anti-5T4 CD4+ T-cells are polyfunctional and that their PFRs are essential for TCR recognition of the core bound nonamer. The high-resolution (1.95 Å) crystal structure of HLA-DR1 presenting the immunodominant 20-mer peptide 5T4111-130, combined with molecular dynamic simulations, revealed how PFRs explore the HLA-proximal space to contribute to antigen reactivity. These findings advance our understanding of what constitutes an HLA-II epitope and indicate that PFRs can tune weak affinity TCR-pHLA-II interactions.