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Frontiers in Immunology 2022To examine the production time, type, and MFI of post-transplantation HLA antibodies, and their effects on haplo-HSCT outcomes, we retrospectively included 116 patients...
To examine the production time, type, and MFI of post-transplantation HLA antibodies, and their effects on haplo-HSCT outcomes, we retrospectively included 116 patients who were negative for pre-existing HLA antibodies. In total, 322 serum samples from pre-transplantation to post-transplantation were dynamically tested by Luminex and single-antigen bead reagents. Patients were divided into: HLA antibody persistently negative group (group 1), the HLA antibody transiently positive group (group 2), the HLA antibody non-persistently positive group (group 3), and the HLA antibody persistently positive group (group 4). Group 4 included DSA+non-DSA (NDSA) (group 4a) and NDSA (group 4b) groups. The detection rate of HLA antibodies was 75.9% (88/116). The median MFI for HLA antibodies was 2439 (1033-20162). The incidence of II-IV aGvHD was higher in group 2 than in group 1 (52.6% vs 17.9%, P < 0.01); in group 4a than in group 1 (87.5% vs 17.9%, P < 0.001); and in group 4a than in group 4b (87.5% vs 40.0%, P = 0.001). The DFS (37.5% vs 85.7%, P < 0.01) and OS (37.5% vs 85.7%, P < 0.01) of group 4a were lower than those of group 1. The DFS (48.0% vs 85.7%, P < 0.01) and OS (56.0% vs 85.7%, P = 0.03) of group 4b were lower than those of group 1. Multivariate analysis showed that HLA antibody being transiently positive (HR: 5.30; 95% CI: 1.71-16.42, P = 0.01) and persistently positive (HR: 5.67; 95% CI: 2.00-16.08, P < 0.01) were both associated with a higher incidence of II-IV aGvHD. Persistently positive HLA antibodies were a risk factor for reduced DFS (HR: 6.57; 95% CI: 2.08-20.70, P < 0.01) and OS (HR: 5.51; 95% CI: 1.73-17.53, P < 0.01). DSA and NDSA can be detected since 15 days after haplo-HSCT in patients without pre-existing HLA antibodies, and affect aGvHD, DFS, and OS. Haplo-HSCT patients must be monitored for HLA antibodies changes for appropriate preventive clinical management, and we recommend that 1-month post-transplantation is the best test time point.
Topics: Humans; Retrospective Studies; Hematologic Neoplasms; Antibodies; Risk Factors; Hematopoietic Stem Cell Transplantation
PubMed: 36532004
DOI: 10.3389/fimmu.2022.1047200 -
ArXiv Apr 2024Deep generative models that produce novel molecular structures have the potential to facilitate chemical discovery. Diffusion models currently achieve state of the art...
Deep generative models that produce novel molecular structures have the potential to facilitate chemical discovery. Diffusion models currently achieve state of the art performance for 3D molecule generation. In this work, we explore the use of flow matching, a recently proposed generative modeling framework that generalizes diffusion models, for the task of de novo molecule generation. Flow matching provides flexibility in model design; however, the framework is predicated on the assumption of continuously-valued data. 3D de novo molecule generation requires jointly sampling continuous and categorical variables such as atom position and atom type. We extend the flow matching framework to categorical data by constructing flows that are constrained to exist on a continuous representation of categorical data known as the probability simplex. We call this extension SimplexFlow. We explore the use of SimplexFlow for de novo molecule generation. However, we find that, in practice, a simpler approach that makes no accommodations for the categorical nature of the data yields equivalent or superior performance. As a result of these experiments, we present FlowMol, a flow matching model for 3D de novo generative model that achieves improved performance over prior flow matching methods, and we raise important questions about the design of prior distributions for achieving strong performance in flow matching models. Code and trained models for reproducing this work are available at https://github.com/dunni3/FlowMol.
PubMed: 38745704
DOI: No ID Found -
Frontiers in Genetics 2023Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1,...
Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1, are commonly associated with ID. The aim of this study was to identify novel gene variants in Chinese individuals with ID and evaluate the pathogenicity of the detected variants. Whole exome sequencing (WES) was performed on 113 patients diagnosed with ID. In the study, two variants in were identified. Sanger sequencing was used to confirm these variants. Minigene assays were used to verify whether the intronic variant in influenced the normal splicing of mRNA. Two heterozygous pathogenic variants in c.333del and c.664-2A>G, were identified in two ID patients separately. The c.333del variant has been reported previously as a finding in a child with ID, while the c.664-2A>G variant was novel intronic variant, which has not been reported in the literature. Functional studies showed that c.664-2A>G could cause aberrant splicing, resulting in exon 7 skipping and a 16bp deletion within exon 7. We identified two pathogenic heterozygous variants in in two patients with ID, among which the c.664-2A>G variant was a novel pathogenic variant. Our findings further enrich the variant spectrum of the gene and provide a research basis for the genetic diagnosis of ID.
PubMed: 37928246
DOI: 10.3389/fgene.2023.1270175 -
Human Molecular Genetics Dec 2014An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported...
An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. Copy number variants were called by PennCNV and filtered for frequency (<1%) and size (>10 kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios (LRR) and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared with SZ. Patients with a positive family history can also harbour de novo mutations.
Topics: Adolescent; Adult; Algorithms; Bipolar Disorder; Case-Control Studies; Child; Chromosomes, Human, Pair 16; DNA Copy Number Variations; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotyping Techniques; Humans; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Pedigree; Schizophrenia
PubMed: 25055870
DOI: 10.1093/hmg/ddu379 -
The Plant Journal : For Cell and... Aug 2022De novo genes are derived from non-coding sequences, and they can play essential roles in organisms. Cultivated peanut (Arachis hypogaea) is a major oil and protein crop...
De novo genes are derived from non-coding sequences, and they can play essential roles in organisms. Cultivated peanut (Arachis hypogaea) is a major oil and protein crop derived from a cross between Arachis duranensis and Arachis ipaensis. However, few de novo genes have been documented in Arachis. Here, we identified 381 de novo genes in A. hypogaea cv. Tifrunner based on comparison with five closely related Arachis species. There are distinct differences in gene expression patterns and gene structures between conserved and de novo genes. The identified de novo genes originated from ancestral sequence regions associated with metabolic and biosynthetic processes, and they were subsequently integrated into existing regulatory networks. De novo paralogs and homoeologs were identified in A. hypogaea cv. Tifrunner. De novo paralogs and homoeologs with conserved expression have mismatching cis-acting elements under normal growth conditions. De novo genes potentially have pluripotent functions in responses to biotic stresses as well as in growth and development based on quantitative trait locus data. This work provides a foundation for future research examining gene birth processes and gene function in Arachis and related taxa.
Topics: Arachis; Evolution, Molecular; Quantitative Trait Loci
PubMed: 35748398
DOI: 10.1111/tpj.15875 -
Frontiers in Endocrinology 2022iPPSD2 (which includes PHP1A and PPHP/POH) is a rare inherited autosomal dominant endocrine disorder caused by inactivating pathogenic variants. A high percentage of...
OBJECTIVE
iPPSD2 (which includes PHP1A and PPHP/POH) is a rare inherited autosomal dominant endocrine disorder caused by inactivating pathogenic variants. A high percentage of cases has been suggested. In rare cases, parental mosaicism has been described, but its real frequency is unknown.
DESIGN
A retrospective study including a series of 95 genetically confirmed iPPSD2 probands.
METHODS
The frequency of cases was evaluated and the distribution of the type of variants was compared according to the type of inheritance. The putative involved allele was determined by reverse transcriptase PCR (RT-PCR) or allele specific oligonucleotide RT-PCR (ASO-RT-PCR). The possibility of mosaicism was studied by next-generation sequencing (NGS) on the corresponding parental DNA.
RESULTS
In 41 patients the variant was of origin and in 24 the origin could not be established. In both cases 66.67% of variants generated a truncated or absent protein whereas the rest of the variants were missense or in-frame deletion/duplication. Parental origin was studied in 45 of those patients and determined in 35. Curiously, the percentage of variants at the paternal allele was higher than when paternally inherited (31.1% vs 6.67%). NGS detected mosaicism in three independent families: one from paternal DNA (allelic ratio 10%) and two from maternal DNA (allelic ratio 10% and 2%).
CONCLUSION
pathogenic variants are frequent in iPPSD2 (around 45%). Parental mosaicism is infrequent (8.11%) but should be analyzed with NGS, taking into account its importance in genetic counselling.
Topics: Humans; Mosaicism; Parathyroid Hormone-Related Protein; Retrospective Studies; Mutation; Parents; DNA
PubMed: 36686455
DOI: 10.3389/fendo.2022.1055431 -
Journal of Hepatocellular Carcinoma 2021Hepatocellular carcinoma (HCC) is one of the most common and serious types of cancer in the world. Currently, the treatment options for patients with HCC are limited....
Hepatocellular carcinoma (HCC) is one of the most common and serious types of cancer in the world. Currently, the treatment options for patients with HCC are limited. Lipid metabolic alterations are being recognized as a therapeutic target in the past few years. De novo lipogenesis has been frequently observed in HCC. Fatty acid synthase (FASN) is the key enzyme of de novo lipogenesis. Previous studies have indicated that loss of FASN suppresses the growth of HCC cells, but it cannot completely prevent HCC formation in vivo. Thus, other mechanisms that can support HCC tumor formation in the absence of de novo lipogenesis maybe existed. In a study recently published in Gut, Che and colleague investigated the functions of Fasn in HCC mouse model and explore the crosstalk between de novo lipogenesis and cholesterol biosynthesis-associated pathway during HCC development. These findings highlight the simultaneous inhibition of de novo lipogenesis and cholesterol biosynthesis as a novel therapeutic and prevention strategy for HCC.
PubMed: 33537248
DOI: 10.2147/JHC.S278517 -
World Journal of Transplantation Sep 2018Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either or recurrent TMA... (Review)
Review
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, ., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, ., purified products of the deficient genes, though promising in theory, are not yet of proven value.
PubMed: 30211021
DOI: 10.5500/wjt.v8.i5.122 -
World Journal of Hepatology May 2015Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between... (Review)
Review
Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.
PubMed: 25954477
DOI: 10.4254/wjh.v7.i7.942 -
Protein Science : a Publication of the... Jun 2024De novo protein design expands the protein universe by creating new sequences to accomplish tailor-made enzymes in the future. A promising topology to implement diverse...
De novo protein design expands the protein universe by creating new sequences to accomplish tailor-made enzymes in the future. A promising topology to implement diverse enzyme functions is the ubiquitous TIM-barrel fold. Since the initial de novo design of an idealized four-fold symmetric TIM barrel, the family of de novo TIM barrels is expanding rapidly. Despite this and in contrast to natural TIM barrels, these novel proteins lack cavities and structural elements essential for the incorporation of binding sites or enzymatic functions. In this work, we diversified a de novo TIM barrel by extending multiple βα-loops using constrained hallucination. Experimentally tested designs were found to be soluble upon expression in Escherichia coli and well-behaved. Biochemical characterization and crystal structures revealed successful extensions with defined α-helical structures. These diversified de novo TIM barrels provide a framework to explore a broad spectrum of functions based on the potential of natural TIM barrels.
Topics: Models, Molecular; Escherichia coli; Crystallography, X-Ray; Protein Folding; Protein Engineering; Proteins
PubMed: 38723111
DOI: 10.1002/pro.5001