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IntroductionAdoption of allogeneic T cells directly supplements the number of T cells and rapidly induces T-cell immunity, which has good efficacy for treating some tumors and immunodeficiency diseases. However, poor adoptive T-cell engraftment and graft-versus-host disease (GVHD) limit the application of these methods. Alloreactive T-cell clones were eliminated from the donor T-cell repertoire, and the remaining T-cell clones were prepared as Tscm for T-cell adoptive treatment to reconstruct recipient T-cell immunity without GVHD.MethodsThe subjects in this study included three different strains of mice. Lymphocytes from mice (C57BL/6) were used as the donor T-cell repertoire, from which the Tscm allo-reactive T cell clone was depleted (ATD-Tscm). This was confirmed by showing that the Tscm was not responsive to the alloantigen of the recipient (BALB/c). To prepare ATD-Tscm cells, we used recipient lymphocytes as a simulator, and coculture of mouse and recipient lymphocytes was carried out for 7 days. Sorting of non-proliferative cells ensured that the prepared Tscm cells were nonresponsive. The sorted lymphocytes underwent further expansion by treatment with TWS119 and cytokines for an additional 10 days, after which the number of ATD-Tscm cells increased. The prepared Tscm cells were transferred into recipient mice to observe immune reconstitution and GVHD incidence.ResultsOur protocol began with the use of 1×107 donor lymphocytes and resulted in 1 ×107 ATD-Tscm cells after 17 days of preparation. The prepared ATD-Tscm cells exhibited a nonresponse upon restimulation of the recipient lymphocytes. Importantly, the prepared ATD-Tscm cells were able to bind long and reconstitute other T-cell subsets in vivo, effectively recognizing and answering the “foreign” antigen without causing GVHD after they were transferred into the recipients.DiscussionOur strategy was succeeded to prepare ATD-Tscm cells from the donor T-cell repertoire. The prepared ATD-Tscm cells were able to reconstitute the immune system and prevent GVHD after transferred to the recipients. This study provides a good reference for generating ATD-Tscm for T-cell adoptive immunotherapy.

BackgroundPreeclampsia (PE) is a pregnancy complication defined by new onset hypertension and proteinuria or other maternal organ damage after 20 weeks of gestation. Although non-invasive prenatal testing (NIPT) has been widely used to detect fetal chromosomal abnormalities during pregnancy, its performance in combination with maternal risk factors to screen for PE has not been extensively validated. Our aim was to develop and validate classifiers that predict early- or late-onset PE using the maternal plasma cell-free DNA (cfDNA) profile and clinical risk factors.MethodsWe retrospectively collected and analyzed NIPT data of 2,727 pregnant women aged 24–45 years from four hospitals in China, which had previously been used to screen for fetal aneuploidy at 12 + 0 ~ 22 + 6 weeks of gestation. According to the diagnostic criteria for PE and the time of diagnosis (34 weeks of gestation), a total of 143 early-, 580 late-onset PE samples and 2,004 healthy controls were included. The wilcoxon rank sum test was used to identify the cfDNA profile for PE prediction. The Fisher’s exact test and Mann–Whitney U-test were used to compare categorical and continuous variables of clinical risk factors between PE samples and healthy controls, respectively. Machine learning methods were performed to develop and validate PE classifiers based on the cfDNA profile and clinical risk factors.ResultsBy using NIPT data to analyze cfDNA coverages in promoter regions, we found the cfDNA profile, which was differential cfDNA coverages in gene promoter regions between PE and healthy controls, could be used to predict early- and late-onset PE. Maternal age, body mass index, parity, past medical histories and method of conception were significantly differential between PE and healthy pregnant women. With a false positive rate of 10%, the classifiers based on the combination of the cfDNA profile and clinical risk factors predicted early- and late-onset PE in four datasets with an average accuracy of 89 and 80% and an average sensitivity of 63 and 48%, respectively.ConclusionIncorporating cfDNA profiles in classifiers might reduce performance variations in PE models based only on clinical risk factors, potentially expanding the application of NIPT in PE screening in the future.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. The causes of ALS are not fully understood. About 10% of ALS cases were associated with genetic factors. Since the discovery of the first familial ALS pathogenic gene SOD1 in 1993 and with the technology advancement, now over 40 ALS genes have been found. Recent studies have identified ALS related genes including ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. These genetic discoveries contribute to a better understanding of ALS and show the potential to aid the development of better ALS treatments. Besides, several genes appear to be associated with other neurological disorders, such as CCNF and ANXA11 linked to FTD. With the deepening understanding of the classic ALS genes, rapid progress has been made in gene therapies. In this review, we summarize the latest progress on classical ALS genes and clinical trials for these gene therapies, as well as recent findings on newly discovered ALS genes.

Cotton is one of the major cash crops globally. It is characterized by determinate growth and multiple fruiting, which makes the source–sink contradiction more obvious. Coordination between source and sink is crucial for normal growth, yield, and quality of cotton. Numerous studies reported how the assimilate transport and distribution under varying environmental cues affected crop yields. However, less is known about the functional mechanism underlying the assimilate transport between source and sink, and how their distribution impacts cotton growth. Here, we provided an overview of the assimilate transport and distribution mechanisms , and discussed the regulatory mechanisms involved in source-sink balance in relation to cotton yield. Therefore, this review enriched our knowledge of the regulatory mechanism involved in source–sink relationship for improved cotton yield.

IntroductionThe gradual loss of motor neurons (MNs) in the brain and spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the mechanisms underlying neurodegeneration in ALS are still not fully understood.MethodsBased on 75 ALS-pathogenicity/susceptibility genes and large-scale single-cell transcriptomes of human/mouse brain/spinal cord/muscle tissues, we performed an expression enrichment analysis to identify cells involved in ALS pathogenesis. Subsequently, we created a strictness measure to estimate the dosage requirement of ALS-related genes in linked cell types.ResultsRemarkably, expression enrichment analysis showed that α- and γ-MNs, respectively, are associated with ALS-susceptibility genes and ALS-pathogenicity genes, revealing differences in biological processes between sporadic and familial ALS. In MNs, ALS-susceptibility genes exhibited high strictness, as well as the ALS-pathogenicity genes with known loss of function mechanism, indicating the main characteristic of ALS-susceptibility genes is dosage-sensitive and the loss of function mechanism of these genes may involve in sporadic ALS. In contrast, ALS-pathogenicity genes with gain of function mechanism exhibited low strictness. The significant difference of strictness between loss of function genes and gain of function genes provided a priori understanding for the pathogenesis of novel genes without an animal model. Besides MNs, we observed no statistical evidence for an association between muscle cells and ALS-related genes. This result may provide insight into the etiology that ALS is not within the domain of neuromuscular diseases. Moreover, we showed several cell types linked to other neurological diseases [i.e., spinocerebellar ataxia (SA), hereditary motor neuropathies (HMN)] and neuromuscular diseases [i.e. hereditary spastic paraplegia (SPG), spinal muscular atrophy (SMA)], including an association between Purkinje cells in brain and SA, an association between α-MNs in spinal cord and SA, an association between smooth muscle cells and SA, an association between oligodendrocyte and HMN, a suggestive association between γ-MNs and HMN, a suggestive association between mature skeletal muscle and HMN, an association between oligodendrocyte in brain and SPG, and no statistical evidence for an association between cell type and SMA.DiscussionThese cellular similarities and differences deepened our understanding of the heterogeneous cellular basis of ALS, SA, HMN, SPG, and SMA.

BackgroundCyclin-dependent kinases (CDKs) are cell cycle regulators, and abnormal activation can accelerate tumor cell proliferation. However, The relation between CDKs dysregulation to colorectal cancer incidence and progression have not been examined in detail. Methods:Differences in CDKs expression between colorectal cancer and normal tissues, associations between expression and clinical prognosis, incidence and frequencies of CDKs gene mutations, and the influences of CDKs on tumor infiltration by immune cells were examined by analyses of Oncomine, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter, cBioPortal, GeneMANIA, and TIMER databases.ResultsColorectal cancer tissues showed enhanced expression levels of CDKs 1/2/4/5/6/8/12/13/19 but reduced CDK3 expression. CDK7 was highly expressed in some colorectal cancer tissues but downregulated in others. Expression levels of CDK1/3/4/7/8/10/11b/13/18/19/20 were correlated with clinical stage, and CDK 5/10/12/16 expression levels predicted prognosis and survival. Differential CDKs expression correlated with cell cycle progression, amino acid polypeptide modifications, and activation of other protein kinases. Expression levels of all CDKs except CDK16 were correlated with infiltration of CD4+T, CD8+T, B and Tregs cells.ConclusionsCDK 1 and 4 could be used as diagnostic biomarkers for CRC. CDK 5/10/12/16 can be utilized as prognostic biomarkers.

Long non-coding RNAs (lncRNAs) play important roles in various biological processes and human diseases, including cancer. In this study, we demonstrated a regulatory relationship between lncRNA GRIK1-AS1 and miR-375/IFIT2 axis in gastric cancer. Our results show a decreased expression of GRIK1-AS1 in gastric cancer tissues compared to adjacent normal gastric tissues. Gastric cell lines also have reduced levels of GRIK1-AS1 compared to gastric epithelial cell line GES-1. Ectopic expression of GRIK1-AS1 in gastric cancer cell lines significantly inhibits cellular viability, migration, and invasion. RNA-pull down and the luciferase activity assays show that GRIK1-AS1 mainly interacts specifically with miR-375. We further demonstrate a negatively regulatory relationship between lncRNA GRIK1-AS1 and miR-375. We discovered that IFIT2 was one of the direct key downstream target genes of miR-375, and established the important role of the GRIK1-AS1/miR-375/IFIT2 axis in the progression of gastric cancer. Taken together, our results revealed a novel mechanism of GRIK1-AS1 as a sponge to miR-375 that impacts gastric cancer progression via modulating target mRNA IFIT2 translation, and as a result, opens a new strategy to future GRIK1-AS1 based therapeutic development.

Fruit shape is an important external characteristic that consumers use to select preferred fruit cultivars. In peach, the flat fruit cultivars have become more and more popular worldwide. Genetic markers closely linking to the flat fruit trait have been identified and are useful for marker-assisted breeding. However, the cellular and genetic mechanisms underpinning flat fruit formation are still poorly understood. In this study, we have revealed the differences in fruit cell number, cell size, and in gene expression pattern between the traditional round fruit and modern flat fruit cultivars. Flat peach cultivars possessed significantly lower number of cells in the vertical axis because cell division in the vertical direction stopped early in the flat fruit cultivars at 15 DAFB (day after full bloom) than in round fruit cultivars at 35 DAFB. This resulted in the reduction in vertical development in the flat fruit. Significant linear relationship was observed between fruit vertical diameter and cell number in vertical axis for the four examined peach cultivars (R2 = 0.9964) at maturation stage, and was also observed between fruit vertical diameter and fruit weight (R2 = 0.9605), which indicated that cell number in vertical direction contributed to the flat shape formation. Furthermore, in RNA-seq analysis, 4165 differentially expressed genes (DEGs) were detected by comparing RNA-seq data between flat and round peach cultivars at different fruit development stages. In contrast to previous studies, we discovered 28 candidate genes potentially responsible for the flat shape formation, including 19 located in the mapping site and 9 downstream genes. Our study indicates that flat and round fruit shape in peach is primarily determined by the regulation of cell production in the vertical direction during early fruit development.