ABSTRACT
Gene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries and are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects, e.g., when the product of two SNP effects and the linkage disequilibrium (LD) correlation is negative. Here, we introduce "mBAT-combo," a set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,273 gene-trait pairs, indicating that masking effects is common in complex traits. We further validate the improved power of our method in height, body mass index, and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with a 1.7-fold increase in sample sizes. Eleven genes significant only in mBAT-combo for schizophrenia are confirmed by functionally informed fine-mapping or Mendelian randomization integrating gene expression data. The framework of mBAT-combo can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.
Subject(s)
Genome-Wide Association Study , Multifactorial Inheritance , Humans , Genome-Wide Association Study/methods , Phenotype , Linkage Disequilibrium , Genomics , Polymorphism, Single Nucleotide/geneticsABSTRACT
Multiple myeloma (MM) is a rarely curable malignancy of plasma cells. MM expresses B cell maturation antigen (BCMA). We developed a fully human anti-BCMA chimeric antigen receptor (CAR) with a heavy-chain-only antigen-recognition domain, a 4-1BB domain, and a CD3ζ domain. The CAR was designated FHVH33-CD8BBZ. We conducted the first-in-humans clinical trial of T cells expressing FHVH33-CD8BBZ (FHVH-T). Twenty-five patients with relapsed MM were treated. The stringent complete response rate (sCR) was 52%. Median progression-free survival (PFS) was 78 weeks. Of 24 evaluable patients, 6 (25%) had a maximum cytokine-release syndrome (CRS) grade of 3; no patients had CRS of greater than grade 3. Most anti-MM activity occurred within 2-4 weeks of FHVH-T infusion as shown by decreases in the rapidly changing MM markers serum free light chains, urine light chains, and bone marrow plasma cells. Blood CAR+ cell levels peaked during the time that MM elimination was occurring, between 7 and 15 days after FHVH-T infusion. C-C chemokine receptor type 7 (CCR7) expression on infusion CD4+ FHVH-T correlated with peak blood FHVH-T levels. Single-cell RNA sequencing revealed a shift toward more differentiated FHVH-T after infusion. Anti-CAR antibody responses were detected in 4 of 12 patients assessed. FHVH-T has powerful, rapid, and durable anti-MM activity.
Subject(s)
Multiple Myeloma , Receptors, Chimeric Antigen , Humans , Multiple Myeloma/genetics , Receptors, Chimeric Antigen/metabolism , T-Lymphocytes , Immunotherapy, Adoptive , Bone Marrow/metabolismABSTRACT
To explore the effect of micro ribonucleic acid (miR)-20b on knee osteoarthritis rats by regulating the bone morphogenetic protein 2 (BMP2)/Smad1 pathway, a total of 36 SD rats were randomly divided into normal group (n=12), model group (n=12) and miR-20b mimics group (n=12). The rats in normal group were fed normally, while those in model group and miR-20b mimics group were used to establish knee osteoarthritis models. After modeling, model group was not given any intervention, but miR-20b mimics group received intra-articular injection of miR-20b mimics once a day for 2 weeks. Basso, Beattie and Bresnahan (BBB) limb motor function scoring was performed at 1, 5, 7 and 14 days after the modeling, and samples were obtained after 2 weeks of intervention. Next, hematoxylin and eosin (H&E) staining was applied to observe tissue morphology, Markin's scoring was utilized to evaluate articular cartilage degeneration, and immunohistochemistry was employed to detect the expressions of BMP2 and Smad1. Thereafter, the expression of miR-20b was detected via qPCR, the content of cartilage oligomeric matrix protein (COMP) and C-telopeptide of type II collagen (CTX-II) was measured via enzyme-linked immunosorbent assay (ELISA), and the expressions of BMP2 and Smad1 proteins were examined via Western blotting (WB). BBB limb motor function scoring showed that compared with that in normal group, the BBB limb motor function score of rats in the other two groups was reduced (P<0.05). In comparison with that in model group, the BBB limb motor function score in miR-20b mimics group was increased from the 7th day after intervention (P<0.05). In addition, H&E staining results manifested that the articular surface in normal group was smooth and flat, with normal morphology, clear structure and no obvious damage. In model group, the articular surface was not smooth and uneven, and more articular cartilage fractures, morphological disorders and structural damages could be observed. Moreover, the articular surface in miR-20b mimics group was slightly damaged and smoother, and its morphology and structure were markedly improved in contrast to that in model group. The Markin's score in normal group was lower than that in model group and miR-20b mimics group (P<0.05), and it was overtly decreased in miR-20b mimics group in comparison with that in model group (P<0.05). Next, immunohistochemistry demonstrated that compared with normal group, the other two groups had lowered positive expressions of BMP2 and Smad1 (P<0.05). In comparison with model group, miR-20b mimics group exhibited notably raised positive expressions of BMP2 and Smad1 (P<0.05). Then it was found from qPCR results that the expression level of miR-20b in the other two groups was overtly reduced compared with that in normal group (P<0.05), and it was prominently elevated in miR-20b mimics group in contrast to that in model group (P<0.05). Besides, ELISA illustrated that the content of COMP and CTX-II in the cartilage tissues in the other two groups was evidently reduced compared with that in normal group (P<0.05), and it was increased prominently in miR-20b mimics group compared with that in model group (P<0.05). Finally, it was revealed by WB examination that the relative expression levels of BMP2 and Smad1 proteins in the other two groups markedly declined in comparison with those in normal group (P<0.05), and they were elevated in contrast to those in model group (P<0.05). MiR-20b can promote cartilage repair and improve articular function in knee osteoarthritis rats by up-regulating the BMP2/Smad1 signaling pathway.
Subject(s)
Cartilage, Articular , MicroRNAs , Osteoarthritis, Knee , Rats , Animals , Osteoarthritis, Knee/genetics , Rats, Sprague-Dawley , Bone Morphogenetic Protein 2/genetics , Bone Morphogenetic Protein 2/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Signal Transduction , Cartilage, Articular/metabolism , Smad1 Protein/genetics , Smad1 Protein/metabolismABSTRACT
Immune checkpoint inhibitors are effective in treating a variety of malignancies, including metastatic bladder cancer. A generally accepted hypothesis suggests that immune checkpoint inhibitors induce tumor regressions by reactivating a population of endogenous tumor-infiltrating lymphocytes (TILs) that recognize cancer neoantigens. Although previous studies have identified neoantigen-reactive TILs from several types of cancer, no study to date has shown whether neoantigen-reactive TILs can be found in bladder tumors. To address this, we generated TIL cultures from patients with primary bladder cancer and tested their ability to recognize tumor-specific mutations. We found that CD4+ TILs from one patient recognized mutated C-terminal binding protein 1 in an MHC class II-restricted manner. This finding suggests that neoantigen-reactive TILs reside in bladder cancer, which may help explain the effectiveness of immune checkpoint blockade in this disease and also provides a rationale for the future use of adoptive T cell therapy targeting neoantigens in bladder cancer.
Subject(s)
Alcohol Oxidoreductases/metabolism , Antigens, Neoplasm/metabolism , Cancer Vaccines/immunology , DNA-Binding Proteins/metabolism , Immunotherapy, Adoptive/methods , Lymphocytes, Tumor-Infiltrating/immunology , Urinary Bladder Neoplasms/immunology , Adult , Aged , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/immunology , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cells, Cultured , Cytokines/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/immunology , Humans , Lymphocyte Activation , Male , Middle Aged , Mutation/geneticsABSTRACT
Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in â¼250000 European participants have led to the discovery of â¼700 and â¼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in â¼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N â¼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P < 1 × 10-8), including 1185 height-associated SNPs and 751 BMI-associated SNPs located within loci not previously identified by these two GWAS. The near-independent genome-wide significant SNPs explain â¼24.6% of the variance of height and â¼6.0% of the variance of BMI in an independent sample from the Health and Retirement Study (HRS). Correlations between polygenic scores based upon these SNPs with actual height and BMI in HRS participants were â¼0.44 and â¼0.22, respectively. From analyses of integrating GWAS and expression quantitative trait loci (eQTL) data by summary-data-based Mendelian randomization, we identified an enrichment of eQTLs among lead height and BMI signals, prioritizing 610 and 138 genes, respectively. Our study demonstrates that, as previously predicted, increasing GWAS sample sizes continues to deliver, by the discovery of new loci, increasing prediction accuracy and providing additional data to achieve deeper insight into complex trait biology. All summary statistics are made available for follow-up studies.
Subject(s)
Body Height/genetics , Body Mass Index , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Body Weight/genetics , Female , Genome, Human , Genome-Wide Association Study , Humans , Male , White People/geneticsABSTRACT
The recent availability of large-scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex-wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey-matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case-control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex-wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex-wise complexity; (b) comparison of the information retained by different MRI processings.
Subject(s)
Body Size/physiology , Gray Matter/anatomy & histology , Gray Matter/diagnostic imaging , Neuroimaging/methods , Phenotype , Age Factors , Aged , Aged, 80 and over , Connectome , Databases, Factual , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Sex FactorsABSTRACT
Fast wavefront reconstruction is crucial for improving the temporal frequency of adaptive optics systems, in which a mass of subapertures is used. In this paper, we present a novel block zonal reconstruction algorithm based on Southwell geometry to speed up the wavefront reconstruction from Shack-Hartmann wavefront sensor measurements. Therein, we use the theory of computational complexity to install a novel optimal block zonal strategy to get the best size of the subwavefront and give the verification through simulations. Compared with the classical Southwell entire wavefront reconstruction algorithm, the algorithm based on the optimal block zonal strategy needs only a few milliseconds to finish the reconstruction process from 100×100 subapertures. Moreover, we analyze the superiority to use our algorithm to realize the phase reconstruction of the unconnected subwavefront, which cannot be reconstructed via traditional methods. Further, the simulation and experiments show that the precision of the algorithm based on the proposed optimal block zonal strategy is comparable with the commercial wavefront sensor HASO, the time consumption is much less than that of the traditional zonal reconstruction, and it is applicable to the square wavefront, circular wavefront, and local unconnected wavefront. Our proposed algorithm can be widely utilized in astronomical observation, laser transmission, and remote sensing.
ABSTRACT
Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.
Subject(s)
Adaptation, Physiological , Altitude , Ethnicity/genetics , Genetic Markers , Genome-Wide Association Study , Selection, Genetic , Alleles , Female , Humans , Male , Phenotype , TibetABSTRACT
The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to -6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in as-yet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.
Subject(s)
Basigin/genetics , Exome , Genetic Predisposition to Disease , Mutation , Myopia/genetics , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Myopia/pathology , Pedigree , Phenotype , Sequence Analysis, DNAABSTRACT
We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×1011 HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.
Subject(s)
CD8-Positive T-Lymphocytes , Colorectal Neoplasms/pathology , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Colorectal Neoplasms/immunology , Colorectal Neoplasms/therapy , Female , Flow Cytometry , Humans , Lung/diagnostic imaging , Lung Neoplasms/immunology , Lymphocyte Count , Middle Aged , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
The adoptive transfer of neoantigen-reactive tumor-infiltrating lymphocytes (TILs) can result in tumor regression in patients with metastatic cancer. To improve the efficacy of adoptive T cell therapy targeting these tumor-specific mutations, we have proposed a new therapeutic strategy, which involves the genetic modification of autologous T cells with neoantigen-specific T cell receptors (TCRs) and the transfer of these modified T cells back to cancer patients. However, the current techniques to isolate neoantigen-specific TCRs are labor intensive, time consuming, and technically challenging, not suitable for clinical applications. To facilitate this process, a new approach was developed, which included the co-culture of TILs with tandem minigene (TMG)-transfected or peptide-pulsed autologous antigen-presenting cells (APCs) and the single-cell RNA sequencing (RNA-seq) analysis of T cells to identify paired TCR sequences associated with cells expressing high levels of interferon-γ (IFN-γ) and interleukin-2 (IL-2). Following this new approach, multiple TCRs were identified, synthesized, cloned into a retroviral vector, and then transduced into donor T cells. These transduced T cells were shown to specifically recognize the neoantigens presented by autologous APCs. In conclusion, this approach provides an efficient procedure to isolate neoantigen-specific TCRs for clinical applications, as well as for basic and translational research.
Subject(s)
Antigens, Neoplasm/immunology , High-Throughput Nucleotide Sequencing , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Single-Cell Analysis , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Cell Line, Tumor , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/immunology , T-Cell Antigen Receptor Specificity/genetics , T-Cell Antigen Receptor Specificity/immunologyABSTRACT
Recently, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in human cancer biology. LncRNA CCAT2 is a novel identified lncRNA that was previously reported to be up-regulated in different cancers, however, its role in prostate cancer remains unclear. The aim of this study was to investigate the expression and role of lncRNA CCAT2 in prostate cancer. The expression levels of lncRNA CCAT2 in PCa tissues and cell lines (DU145 and 22RV1) were evaluated by quantitative real-time PCR (qRT-PCR), and its association with prognosis of patients was analyzed by statistical analysis. Furthermore, the effect of CCAT2 on proliferation, migration, and invasion was studied in PCa cells. We found that the expression level of CCAT2 was higher in PCa tissues and cells compared to adjacent non-tumor tissues and normal prostate stromal immortalized cells WPMY-1. Kaplan-Meier survival analysis revealed that patients with high CCAT2 expression level had poorer overall survival and progression-free survival than those with low CCAT2 expression. Furthermore, multivariate analysis showed that the status of CCAT2 expression was an independent prognostic indicator for this disease. We also found that knockdown of CCAT2 could inhibit cell growth, migration, and invasion in vitro. In addition, knockdown of CCAT2 stimulated epithelial-mesenchymal transition (EMT) through abrogating N-cadherin, vimentin expression and intensifing the expression levels of E-cadherin. In conclusion, our data suggested that lncRNA CCAT2 was a novel molecule involved in PCa progression, which provided a potential prognostic biomarker and therapeutic target for new therapies in patients with prostate cancer.
Subject(s)
Biomarkers, Tumor/genetics , Epithelial-Mesenchymal Transition/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/secondary , RNA, Long Noncoding/genetics , Aged , Aged, 80 and over , Cell Line, Tumor , Genetic Markers/genetics , Humans , Incidence , Male , Middle Aged , Prognosis , Prostatic Neoplasms/mortality , Risk Factors , Survival Rate , Up-Regulation/geneticsABSTRACT
UNLABELLED: Adoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding. We compared a standard CD4 CAR with CD4-17b CARs where the polypeptide linker between the CD4 and 17b moieties is sufficiently long (CD4-35-17b CAR) versus too short (CD4-10-17b) to permit simultaneous binding of the two moieties to a single gp120 subunit. When transduced into a peripheral blood mononuclear cell (PBMC) or T cells thereof, all three CD4-based CARs displayed specific functional activities against HIV-1 Env-expressing target cells, including stimulation of gamma interferon (IFN-γ) release, specific target cell killing, and suppression of HIV-1 pseudovirus production. In assays of spreading infection of PBMCs with genetically diverse HIV-1 primary isolates, the CD4-10-17b CAR displayed enhanced potency compared to the CD4 CAR whereas the CD4-35-17b CAR displayed diminished potency. Importantly, both CD4-17b CARs were devoid of a major undesired activity observed with the CD4 CAR, namely, rendering the transduced CD8(+) T cells susceptible to HIV-1 infection. Likely mechanisms for the superior potency of the CD4-10-17b CAR over the CD4-35-17b CAR include the greater potential of the former to engage in the serial antigen binding required for efficient T cell activation and the ability of two CD4-10-17b molecules to simultaneously bind a single gp120 subunit. IMPORTANCE: HIV research has been energized by prospects for a cure for HIV infection or, at least, for a "functional cure" whereby antiretroviral therapy can be discontinued without virus rebound. This report describes a novel CD4-based "chimeric antigen receptor" (CAR) which, when genetically engineered into T cells, gives them the capability to selectively respond to and kill HIV-infected cells. This CAR displays enhanced features compared to previously described CD4-based CARs, namely, increased potency and avoidance of the undesired rendering of the genetically modified CD8 T cells susceptible to HIV infection. When adoptively transferred back to the individual, the genetically modified T cells will hopefully provide durable killing of infected cells and sustained virus suppression without continued antiretroviral therapy, i.e., a functional cure.
Subject(s)
Anti-HIV Agents/metabolism , HIV-1/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Receptors, Antigen/metabolism , Receptors, HIV/metabolism , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/metabolism , CD4 Antigens/genetics , CD4 Antigens/metabolism , HIV Antibodies/genetics , HIV Antibodies/metabolism , HIV Envelope Protein gp120/metabolism , Humans , Protein Binding , Receptors, Antigen/genetics , Receptors, HIV/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Single-Chain Antibodies/genetics , Single-Chain Antibodies/metabolism , Transduction, GeneticABSTRACT
Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9-84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFα, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500-2,000-fold in vitro. Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted.
Subject(s)
Endoribonucleases/genetics , Gene Expression Regulation, Neoplastic , Lymphocytes, Tumor-Infiltrating/immunology , Melanoma/therapy , Programmed Cell Death 1 Receptor/genetics , Zinc Fingers , Alleles , Animals , Cell Separation , Cytokines/metabolism , Female , Flow Cytometry , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Green Fluorescent Proteins/metabolism , Humans , Immunologic Memory , Immunotherapy, Adoptive , Interferon-gamma/metabolism , Lymphocyte Activation/immunology , Mice , Neoplasm Metastasis , Neoplasm Transplantation , Phenotype , Programmed Cell Death 1 Receptor/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
MXenes are a recently emerging class of two-dimensional nanomaterials that have gained considerable interest in the field of environmental protection. Owing to their high surface area, abundant terminal groups, and unique two-dimensional layered structures, MXenes have demonstrated high efficacy as adsorbents for various pollutants. Here we focused on the latest developments in the field of MXene-based adsorbents, including the structure and properties of MXenes, their synthesis and modification methods, and their adsorption performance and mechanisms for various pollutants. Among the pollutants that have been reported to be adsorbed by MXenes are radionuclides (U(VI), Sr(II), Cs(I), Eu(III), Ba(II), Th(IV), and Tc(VII)/Re(VII)), heavy metals (Hg(II), Cu(II), Cr(VI), and Pb(II)), dyes, per- and polyfluoroalkyl substances (PFAS), antibiotics (tetracycline, ciprofloxacin, and sulfonamides), antibiotic resistance genes (ARGs), and other contaminates. Moreover, future directions in MXene research are also suggested in this review.
ABSTRACT
Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic segments without considering the global genetic architecture. Here, we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods in error control, mapping power and precision, replication rate, and trans-ancestry phenotype prediction. For 48 well-powered traits in the UK Biobank, we identify causal variants that collectively explain 17% of the SNP-based heritability, and predict that fine-mapping 50% of that would require 2 million samples on average. We pinpoint a known causal variant, as proof-of-principle, at FTO for body mass index, unveil a hidden secondary variant with evolutionary conservation, and identify new missense causal variants for schizophrenia and Crohn's disease. Overall, we analyse 600 complex traits with 13 million SNPs, highlighting the efficacy of GWFM with functional annotations.
ABSTRACT
Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic segments without considering the global genetic architecture. Here, we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods in error control, mapping power and precision, replication rate, and trans-ancestry phenotype prediction. For 48 well-powered traits in the UK Biobank, we identify causal variants that collectively explain 17% of the SNP-based heritability, and predict that fine-mapping 50% of that would require 2 million samples on average. We pinpoint a known causal variant, as proof-of-principle, at FTO for body mass index, unveil a hidden secondary variant with evolutionary conservation, and identify new missense causal variants for schizophrenia and Crohn's disease. Overall, we analyse 599 complex traits with 13 million SNPs, highlighting the efficacy of GWFM with functional annotations.
ABSTRACT
We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using â¼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP density and annotation information, suggesting whole-genome sequence variants with annotations may further improve prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from nonsynonymous SNPs.
Subject(s)
Genome-Wide Association Study , Molecular Sequence Annotation , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Multifactorial Inheritance/genetics , Genome-Wide Association Study/methods , Humans , Molecular Sequence Annotation/methods , Genomics/methods , Genome, Human , Models, GeneticABSTRACT
Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer's disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders.
Subject(s)
Alzheimer Disease , Autistic Disorder , Brain , DNA Methylation , Schizophrenia , Humans , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Schizophrenia/genetics , Schizophrenia/pathology , Brain/metabolism , Brain/pathology , Autistic Disorder/genetics , Autistic Disorder/pathology , Male , Female , Genome-Wide Association Study , Aged , Endothelial Cells/metabolism , Endothelial Cells/pathology , Epigenomics/methods , Middle Aged , Aged, 80 and overABSTRACT
DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.