TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, ...but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.
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•Force-enhanced peptide-TCR interactions determine TCR-pMHC-I catch bonds•Force-strengthened TCR-MHC binding interface contributes to TCR-pMHC-I catch bonds•Force-induced MHC-I rotation allosterically enhances TCR-pMHC-I catch bonds•Tumor-associated somatic mutations in HLA-A2 impair TCR-pHLA-A2 catch bonds
Wu et al. report that a dynamic structural mechanism of mechano-chemical coupling for TCR antigen recognition—that is, mechanical force-induced conformational changes in the agonist peptide-MHC-I—allosterically activates TCR-pMHC-I catch bonds to determine TCR antigen recognition and trigger T cell signaling.
Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can ...overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.
The tumor microenvironment (TME) is an ecosystem that contains various cell types, including cancer cells, immune cells, stromal cells, and many others. In the TME, cancer cells aggressively ...proliferate, evolve, transmigrate to the circulation system and other organs, and frequently communicate with adjacent immune cells to suppress local tumor immunity. It is essential to delineate this ecosystem’s complex cellular compositions and their dynamic intercellular interactions to understand cancer biology and tumor immunology and to benefit tumor immunotherapy. But technically, this is extremely challenging due to the high complexities of the TME. The rapid developments of single-cell techniques provide us powerful means to systemically profile the multiple omics status of the TME at a single-cell resolution, shedding light on the pathogenic mechanisms of cancers and dysfunctions of tumor immunity in an unprecedently resolution. Furthermore, more advanced techniques have been developed to simultaneously characterize multi-omics and even spatial information at the single-cell level, helping us reveal the phenotypes and functionalities of disease-specific cell populations more comprehensively. Meanwhile, the connections between single-cell data and clinical characteristics are also intensively interrogated to achieve better clinical diagnosis and prognosis. In this review, we summarize recent progress in single-cell techniques, discuss their technical advantages, limitations, and applications, particularly in tumor biology and immunology, aiming to promote the research of cancer pathogenesis, clinically relevant cancer diagnosis, prognosis, and immunotherapy design with the help of single-cell techniques.
Severe early childhood caries (SECC) is an inflammatory disease with complex pathology. Although changes in the oral microbiota and metabolic profile of patients with SECC have been identified, the ...salivary metabolites and the relationship between oral bacteria and biochemical metabolism remains unclear. We aimed to analyse alterations in the salivary microbiome and metabolome of children with SECC as well as their correlations. Accordingly, we aimed to explore potential salivary biomarkers in order to gain further insight into the pathophysiology of dental caries.
We collected 120 saliva samples from 30 children with SECC and 30 children without caries. The microbial community was identified through 16S ribosomal RNA (rRNA) gene high-throughput sequencing. Additionally, we conducted non-targeted metabolomic analysis through ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry to determine the relative metabolite levels and their correlation with the clinical caries status.
There was a significant between-group difference in 8 phyla and 32 genera in the microbiome. Further, metabolomic and enrichment analyses revealed significantly altered 32 salivary metabolites in children with dental caries, which involved pathways such as amino acid metabolism, pyrimidine metabolism, purine metabolism, ATP-binding cassette transporters, and cyclic adenosine monophosphate signalling pathway. Moreover, four in vivo differential metabolites (2-benzylmalate, epinephrine, 2-formaminobenzoylacetate, and 3-Indoleacrylic acid) might be jointly applied as biomarkers (area under the curve = 0.734). Furthermore, the caries status was correlated with microorganisms and metabolites. Additionally, Spearman's correlation analysis of differential microorganisms and metabolites revealed that Veillonella, Staphylococcus, Neisseria, and Porphyromonas were closely associated with differential metabolites.
This study identified different microbial communities and metabolic profiles in saliva, which may be closely related to caries status. Our findings could inform future strategies for personalized caries prevention, detection, and treatment.
The clinical characteristics and risk factors of infusion reactions (IRs) are inadequately described in clinical practice due to underreported cases. In the present study, we reported the current ...status of IRs based on an in-hospital pharmacovigilance database of a tertiary care hospital.
Our study conducted a retrospective analysis of drug-induced IRs recorded at an in-hospital pharmacovigilance center between January 2015 to December 2019. The descriptive statistical analysis encompassed main causative agents, clinical manifestations, organ/system involvement and outcome. The severity of IRs was assessed with reference to the CTCAE version 5.0 criteria and we investigated risk factors associated with severe IRs.
During the study period, a total of 505 cases of inpatient drug-induced IRs were detected, of which 79.2% (400 cases) were classified as general IRs and 20.8% (105 cases) were categorized as severe IRs. The primary drugs responsible for these reactions were antibiotics (23%, 116 cases), with piperacillin sodium-sulbactam sodium being the most prevalent, followed by antineoplastic agents (18.4%, 93 cases) and traditional Chinese medicine injections (TCMIs) (12.9%, 65 cases). The administration of cefoperazone - sulbactam, mannatide, Shenqi Fuzheng, elemene, and diterpene ginkgolides meglumine resulted in a higher incidence of critical IRs. Among all cases of IRs, 43.2%, 41.2%, and 23.4% showed signs and symptoms of circulation, skin mucosa, and respiratory organs/systems, respectively. 9.1% of cases experienced systemic damage, while 7.1% and 5.9% of cases reported neurological and gastrointestinal related adverse reactions, respectively. The multivariate analysis revealed that alcohol consumption (OR = 2.389%, 95% CI 1.141-5.002,
= 0.021), age over 65 (OR = 1.814%, 95% CI 1.052-3.127,
= 0.032) and the utilization of contrast media (OR = 4.072%, 95% CI 1.903-8.713,
< 0.001) were identified as risk factors for the development of severe IRs.
Understanding the clinical characteristics of IRs helps to implement effective pharmaceutical monitoring and appropriate preventive measures for susceptible populations with risk factors.
Leiomyosarcoma (LMS) is an uncommon and aggressive form of cancer that originates in the smooth muscles. It possesses the capacity for rapid growth and often manifests with general, nonspecific ...symptoms arising from the displacement of nearby structures rather than direct invasion. In this particular instance, an 81-year-old woman presented with right lower abdominal pain, leading to the discovery of a mass adjacent to the right external iliac artery. In this case, the patient was misdiagnosed initially because of her nonspecific and poorly distinguished clinical symptoms. The laboratory results were within normal ranges. A well-defined tumor was detected through laparoscopic operation and subsequently surgically excised. The histopathological analysis of the tumor revealed the presence of malignant spindle cells, nuclear pleomorphism, and tumor giant cells. Immunohistochemistry tests indicated positive results for CD34 and Desmin, while CD117 and DOG1 showed adverse effects. It is worth noting that LMS of the right external iliac artery is an infrequent occurrence, potentially resulting in delayed diagnosis and misidentification. To enhance our comprehension of this uncommon cancer, more cases with detailed information are essential.
I explored the correlations of psychological capital, job burnout, and emotional labor strategies. Participants were 434 teachers at two universities in China, who completed scales to measure the ...three variables. Results showed that both deep acting and expression of natural emotion
were negatively correlated with college teachers' job burnout, and surface acting was positively correlated with job burnout. Additionally, psychological capital significantly moderated these effects: For teachers with high psychological capital, expression of natural emotion and deep acting
were both significantly correlated with job burnout, but the correlation between surface acting and burnout was not significant; however, for teachers with low psychological capital, surface acting and burnout were significantly correlated, but the correlations between expression of natural
emotion and burnout, and between deep acting and burnout were not significant. The results shed light on how to reduce and prevent job burnout among college teachers.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study I explored the relationships among the locus of control, self-efficacy, and subjective well-being (SWB) of elementary school teachers in China, with a focus on the mediating effect of ...self-efficacy in the relationship between external locus of control and SWB. A survey
was conducted with 305 elementary school teachers using the Adult Nowicki-Strickland Internal-External Locus of Control Scale, the General Self-Efficacy Scale, and SWB measurements. External locus of control was found to be negatively correlated with SWB, and selfefficacy was positively correlated
with SWB. Structural equation modeling analysis showed that self-efficacy partially mediated the effect of external locus of control on SWB, with the indirect effect accounting for 36.34% of the total explained variance. Promoting a sense of control and self-efficacy may be effective in improving
elementary school teachers' SWB.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study aimed to analyze the effects of factors on cystocele and the Green classification.
We conducted a cross-sectional study on 357 primiparous women examined at our hospital from ...January 2019 to May 2021. The following data were recorded: maternal characteristics, neonatal characteristics, and factors of childbirth. It was added to the multivariate logistic regression model to determine the independent predictors of the cystocele and the Green classification.
A total of 242 women had cystocele, including 71 women with Green type I cystocele, 134 women with Green type II cystocele, and 37 women with Green type III cystocele. In multivariate logistic regression analysis, body mass index (BMI) at delivery was associated with cystocele, while BMI at delivery and the second stage of labor (SSL) > 1 h were independently with the distance from the symphysis pubis to the bladder neck (SPBN) abnormal (
< 0.05). BMI at examination was associated with the large retrovesical angle (RVA) (
< 0.05). BMI at delivery and the fetal right occiput anterior position (ROA) were independently associated with the distance from the symphysis pubis to the posterior wall of the bladder (SPBP) abnormal (
< 0.05), while epidural anesthesia (EDA) was the protective factor (
< 0.05).
Primipara women should strive to avoid exposure to modifiable risk factors such as controlling weight during pregnancy, reducing weight after delivery, and shortening SSL to reduce the occurrence of cystocele.
Resumo Fundamento A influência do volume do apêndice atrial esquerdo (VAAE) na recorrência de fibrilação atrial (FA) após ablação por cateter de radiofrequência permanece obscura. Objetivos ...Realizamos uma metanálise para avaliar se o VAAE é um preditor independente de recorrência de FA após ablação por cateter de radiofrequência. Métodos Os bancos de dados PubMed e Cochrane Library foram pesquisados até março de 2022 para identificar publicações avaliando o VAAE em associação com a recorrência de FA após ablação por cateter por radiofrequência. Foram encontrados 7 estudos que preencheram os critérios especificados de nossa análise. Usamos a Escala de Newcastle-Ottawa para avaliar a qualidade dos estudos. Os efeitos agrupados foram avaliados dependendo das diferenças médias padronizadas (DMPs) ou hazard ratios (HRs) com intervalos de confiança (ICs) de 95%. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados Um total de 1.017 pacientes de 7 estudos de coorte com um seguimento médio de 16,3 meses foram incluídos na metanálise. Dados de 6 estudos (943 indivíduos) comparando VAAE mostraram que o VAAE basal foi significativamente maior em pacientes com recorrência de FA em comparação com aqueles sem FA (DMP: −0,63; IC de 95%: −0,89 a −0,37; todos os valores de p < 0,05; I 2 = 62,6%). Além disso, maior VAAE foi independentemente associado a um risco significativamente maior de recorrência de FA após ablação por cateter de radiofrequência (HR: 1,10; IC de 95%: 1,02 a 1,18). Conclusões A metanálise mostrou que existe uma correlação significativa entre o VAAE e a recorrência de FA após ablação por cateter de radiofrequência, e o papel do VAAE em pacientes com FA não deve ser ignorado na prática clínica.
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