MicroRNAs in B cell development and malignancy

MicroRNAs are small RNA molecules that regulate gene expression and play critical roles in B cell development and malignancy. miRNA expression is important globally, as B cell specific knockouts of Dicer show profound defects in B cell development; and is also critical at the level of specific miRNAs. In this review, we discuss miRNAs that are involved in normal B cell development in the bone marrow and during B cell activation and terminal differentiation in the periphery. Next, we turn to miRNAs that are dysregulated during diseases of B cells, including malignant diseases and autoimmunity. Further study of miRNAs and their targets will lead to a better understanding of B cell development, and should also lead to the development of novel therapeutic strategies against B cell diseases

Editorial: mobile elements and plant genome evolution, comparative analyzes and computational tools

Multiple changes that occur constantly in the plant genome allow an organism to develop from a single-celled embryo to a multicellular organism. A significant part of these changes is associated with the recombination activity of numerous classes of interspersed repeats. These numerous families of interspersed repeats were often called "junk DNA" as they were not associated with vital protein-coding processes (1). Transposable elements (TEs), such as DNA transposons and retrotransposons, are the main part of these interspersed repeats (2). DNA transposons can rightfully be called true mobile elements, the activity of which can occur at any stage of cell development and manifest itself at any moment and stage of the organism's development. The diverse families of retrotransposons are highly abundant genetic elements that are related to retroviruses (3). Although retrotransposons are not true mobile elements like DNA transposons, retrotransposable elements (RTEs) form a variety of chromosomal structures, such as centromeric and telomeric regions (4), and are the main intergenic part of the genome (5). Retrotransposons move to new chromosomal locations via an RNA intermediate that is converted into extrachromosomal DNA by the encoded reverse transcriptase/RNaseH enzymes prior to reinsertion into the genome. This replicative mode of transposition can rapidly increase the copy number of elements and can thereby greatly increase plant genome size. RTEs can be clustered into distinct families each traceable to a single ancestral sequence or a closely related group of ancestral sequences. In contrast to multigene families, which are defined based on their biological role, repetitive families are usually defined based on their active ancestors (called master or source genes) and on their generation mechanisms. Over time, individual elements from repetitive families may acquire diverse biological roles. Some RTEs can provide evolutionary advantages to the host and increase their chances of survival (6). While the view that RTEs are beneficial to the host is not new, recent progress in the field has placed RTEs squarely in the center of the ongoing debate on eukaryotic evolution. To advance this important research field, in the Research Topic "Mobile Elements and Plant Genome Evolution, Comparative Analyses, and Computational Tools" we focus on the role of mobile elements with host genome evolution, discovery, and comparative and genome-wide profiling analysis of transposable elements. Different retrotransposon families, each with its own lineage and structure, may have been active at distinct phases in the evolution of a species. Retrotransposon sequences bear the promoters that bind the nuclear factors of transcription initialization and initiate RNA synthesis by polymerases II or III. In the article entitled "Additional ORFs in Plant LTR-Retrotransposons" by Vicient C.M. and Casacuberta J.M., LTR-retrotransposons that carry additional, not retrotransposon-specific open reading frames (aORF), were discovered and analyzed. This discovery expands on the unique potential of LTR-retrotransposons as evolutionary tools, as LTR-retrotransposons can be used to deliver new gene variants within a genome. The presence of a unique aORF in some characterized LTR-retrotransposon families like maize Grande, rice RIRE2, or Silene Retand, are just as typical as retrovirus gene transduction. As dispersed and ubiquitous mobile elements, the life cycle of replicative transposition leads to genome rearrangements that affect cellular function (7). Transposable elements are important drivers of species diversity and exhibit great variety in structure, size, and mechanisms of transposition, making them important putative actors in genome evolution. The research group led by Kashkush K., reported the potential impact of miniature transposable element insertions on the expression of wheat genes in different wheat species in the articles entitled "The Evolutionary Dynamics of a Novel Miniature Transposable Element in the Wheat Genome" and "Where the Wild Things Are: Transposable Elements as Drivers of Structural and Functional Variations in the Wheat Genome". The induced genetic rearrangements and insertions of mobile genetic elements in regions of active euchromatin contribute to genome alteration, which leads to "genomic stress" (8). TEmediated epigenetic modifications lead to phenotypic diversity, genetic variation, and environmental stress tolerance. TEs also contribute to genome plasticity and have a dramatic impact on the genetic diversity and evolution of the wheat genome. Using transposon display (9) and genome-wide profiling analysis of insertional polymorphisms of transposable elements (10), the authors discovered large genomic rearrangement events, such as deletions and introgressions in the wheat genome. High-throughput bioinformatics with next-generation sequencing (NGS) were key tools in these studies (11). Chromosomal rearrangements, gene duplications, and transposable element content may have a large impact on genomic structure, which could generate new phenotypic traits (7). In the article entitled "Genome Size Variation and Comparative Genomics Reveal Intraspecific Diversity in Brassica rapa", de Carvalho J.F. et al investigated structural variants and repetitive content between two accessions of Brassica rapa genomes and genome-size variation among a core collection using comparative genomics and cytogenetic approaches. Large genomic variants with a chromosome length difference of 17.6% between the A06 chromosomes of 'Z1' compared to 'Chiifu' belonging to different cultigroups of B. rapa highlighted the potential impact of differential insertion of repeat elements and inversions of large genomic regions in genome size intraspecific variability. Transposable elements are also the driving force in the evolution of epigenetic regulation and have a long-term impact on genomic instability and evolution. Remnants of RTEs appear to be overrepresented in transcription regulatory modules and other regions conserved among distantly related species, which may have implications for our understanding of their impact on speciation. RTEs are dynamic and play a role in chromosome crossing over recognition and in DNA recombination between homologous chromosomes. In the article entitled "Sequencing Multiple Cotton Genomes Reveals Complex Structures and Lays Foundation for Breeding", Wang X. et al revealed that post-polyploidization of cotton genome instability resulted in numerous genomic structural changes, DNA inversion and translocation, illegitimate recombinations, accumulation of repetitive sequences, and functional innovation accompanied by elevated evolutionary rates of genes. This genome study also revealed the evolutionary past of cotton plants, which were recursively affected by polyploidization, with a decaploidization contributing to the formation of the genus Gossypium, and a neo-tetraploidization contributing to the formation of the currently widely cultivated cotton plants. The centromere is a unique part of the chromosome that combines a conserved function with extreme variability in its DNA sequence. In the article entitled "Functional Allium fistulosum centromeres comprise arrays of a long satellite repeat, insertions of retrotransposons and chloroplast DNA" Kirov G.I., et al studied the largest plant genomic organization of the functional centromere in large-sized chromosomes in Allium fistulosum and A. cepa. Long, high-copy repeats are associated with insertions of retrotransposons and plastidial DNA, and the landscape of the centromeric regions of these species possess insertions of plastidial DNA. Among evolutionary factors, repetitive sequences play multiple roles in sex chromosome evolution. As such, the Spinacia genus serves as an ideal model to investigate the evolutionary mechanisms underlying the transition from homomorphic to heteromorphic sex chromosomes. This was studied in the article entitled "Genome-Wide Analysis of Transposable Elements and Satellite DNAs in Spinacia Species to Shed Light on Their Roles in Sex Chromosome Evolution" by Li N., et al. Major repetitive sequence classes in male and female genomes of Spinacia species and their ancestral relative, sugar beet, were elucidated in the evolutionary processes of sex chromosome evolution using NGS data. The differences of repetitive DNA sequences correlate with the formation of sex chromosomes and the transition from homomorphic sex chromosomes to heteromorphic sex chromosomes, as heteromorphic sex chromosomes existed exclusively in Spinacia tetrandra.Non peer reviewe

A rare variant of the superficial ulnar artery, and its clinical implications: a case report

The superficial ulnar artery is a rare variation of the upper limb arterial system that arises from the brachial or axillary artery and runs superficial to the muscles arising from the medial epicondyle [1-3]. The incidence is about 0.7 to 7% [1,4,5]. In our routine dissections we found a superficial ulnar artery, which crossed the cubital fossa superficial to the bicipital aponeurosis making it highly vulnerable to intra-arterial injection. This is a rare variation that every medical and nursing staff member should know about

Application of a lifestyle-based score to predict cardiovascular risk in African Americans: The Jackson heart study

Cardiovascular disease (CVD) primordial prevention tools applicable to diverse popula-tions are scarce. Our aim was to assess the performance of a lifestyle-based tool to estimate CVD risk in an African American population. The Jackson Heart Study is a prospective cohort including 5306 African American participants in Jackson, Mississippi (2000–2004), with a mean follow up of 12 years. The Healthy Heart Score is a lifestyle-based CVD risk prediction model based on nine components: body mass index (BMI), physical activity, smoking, and a 5-component diet score. Gender-specific beta coefficients from its derivation cohorts were used to assess the performance of the Healthy Heart Score. Model discrimination was assessed using Harrell’s C-Index for survival data and time dependent Area Under the Curve. Model calibration was evaluated through calibration plots. A total of 189 CVD events occurred. The Healthy Heart Score showed high-moderate discrimination for CVD events (C-statistic 0.75 [95% CI, 0.71–0.78]) but with little improvement over the age-only model. Both the age-only and Healthy Heart Score models had better performance in participants without diabetes at baseline and showed good calibration. In African Americans, the Healthy Heart Score does not improve prediction of mid-life CVD events beyond what is obtained by age alone.This research was funded by the National Heart, Lung, and Blood Institute, and the National Institute on Minority Health and Health Disparities, contract numbers HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C. M.S.-P. holds a Ramón y Cajal contract (RYC-2018-025069-I) from the Ministry of Science, Innovation and Universities and FEDER/FSE and a FIS grant PI20/00896 (Instituto de Salud Carlos III, State Secretary of R+D+I and FEDER/FSE). Preparation of this manuscript was supported by The Robert Wood Johnson Foundation (Harold Amos Medical Faculty Development Program ID# 76236, J.J.J.) and the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK117041, J.J.J.) of the National Institutes of Healt

Differential expression of porcine microRNAs in African swine fever virus infected pigs : a proof-of-concept study

African swine fever (ASF) is a re-expanding devastating viral disease currently threatening the pig industry worldwide. MicroRNAs are a class of 17-25 nucleotide non- coding RNAs that have been shown to have critical functions in a wide variety of biological processes, such as cell differentiation, cell cycle regulation, carcinogenesis, apoptosis, regulation of immunity as well as in viral infections by cleavage or translational repression of mRNAs. Nevertheless, there is no information about miRNA expression in an ASFV infection. In this proof-of-concept study, we have analyzed miRNAs expressed in spleen and submandibular lymph node of experimentally infected pigs with a virulent (E75) or its derived attenuated (E75CV1) ASFV strain, as well as, at different times post-infection with the virulent strain, by high throughput sequencing of small RNA libraries. Spleen presented a more differential expression pattern than lymph nodes in an ASFV infection. Of the most abundant miRNAs, 12 were differentially expressed in both tissues at two different times in infected animals with the virulent strain. Of these, miR-451, miR-145-5p, miR-181a and miR-122 presented up-regulation at late times post-infection while miR-92a, miR-23a, miR-92b-3p, miR-126-5p, miR-126-3p, miR-30d, miR-23b and miR-92c showed down-regulation. Of the 8 differentially expressed miRNAs identified at the same time post-infection in infected animals with the virulent strain compared with animals infected with its attenuated strain, miR-126-5p, miR-92c, miR-92a, miR-30e-5p and miR-500a-5p presented up-regulation whereas miR-125b, miR-451 and miR-125a were down-regulated. All these miRNAs have been shown to be associated with cellular genes involved in pathways related to the immune response, virus-host interactions as well as with several viral genes. The study of miRNA expression will contribute to a better understanding of African swine fever virus pathogenesis, essential in the development of any disease control strategy. The online version of this article (10.1186/s12985-017-0864-8) contains supplementary material, which is available to authorized users

Anti-IL-2 Treatment Impairs the Expansion of Treg Cell Population during Acute Malaria and Enhances the Th1 Cell Response at the Chronic Disease

Plasmodium chabaudi infection induces a rapid and intense splenic CD4+ T cell response that contributes to both disease pathogenesis and the control of acute parasitemia. The subsequent development of clinical immunity to disease occurs concomitantly with the persistence of low levels of chronic parasitemia. The suppressive activity of regulatory T (Treg) cells has been implicated in both development of clinical immunity and parasite persistence. To evaluate whether IL-2 is required to induce and to sustain the suppressive activity of Treg cells in malaria, we examined in detail the effects of anti-IL-2 treatment with JES6-1 monoclonal antibody (mAb) on the splenic CD4+ T cell response during acute and chronic P. chabaudi AS infection in C57BL/6 mice. JES6-1 treatment on days 0, 2 and 4 of infection partially inhibits the expansion of the CD4+CD25+Foxp3+ cell population during acute malaria. Despite the concomitant secretion of IL-2 and expression of high affinity IL-2 receptor by large CD4+ T cells, JES6-1 treatment does not impair effector CD4+ T cell activation and IFN-γ production. However, at the chronic phase of the disease, an enhancement of cellular and humoral responses occurs in JES6-1-treated mice, with increased production of TNF-α and parasite-specific IgG2a antibodies. Furthermore, JES6-1 mAb completely blocked the in vitro proliferation of CD4+ T cells from non-treated chronic mice, while it further increased the response of CD4+ T cells from JES6-1-treated chronic mice. We conclude that JES6-1 treatment impairs the expansion of Treg cell population during early P. chabaudi malaria and enhances the Th1 cell response in the late phase of the disease

A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88)

Functional insight into the reciprocal paracrine crosstalk of stromal fibroblasts in the head and neck cancer microenvironment

Trabajo presentado en el 18th ASEICA International Congress, celebrado en Santiago de Compostela (España) del 16 al 18 de noviembre de 2022