SummarySmall RNAs play a crucial role in genome defense against transposable elements and guide Argonaute proteins to nascent RNA transcripts to induce co-transcriptional gene silencing. However, the molecular basis of this process remains unknown. Here, we identify the conserved RNA helicase Aquarius/EMB-4 as a direct and essential link between small RNA pathways and the transcriptional machinery in Caenorhabditis elegans. Aquarius physically interacts with the germline Argonaute HRDE-1. Aquarius is required to initiate small-RNA-induced heritable gene silencing. HRDE-1 and Aquarius silence overlapping sets of genes and transposable elements. Surprisingly, removal of introns from a target gene abolishes the requirement for Aquarius, but not HRDE-1, for small RNA-dependent gene silencing. We conclude that Aquarius allows small RNA pathways to compete for access to nascent transcripts undergoing co-transcriptional splicing in order to detect and silence transposable elements. Thus, Aquarius and HRDE-1 act as gatekeepers coordinating gene expression and genome defense.
Proper regulation of the germline transcriptome is essential for fertility. In C. elegans, germline homeostasis hinges on a complex repertoire of both silencing and activating small RNA pathways, along with RNA processing. However, our understanding of how fundamental RNA processing steps intersect with small RNA machineries in the germline remains limited. Here, we link the conserved intron binding protein, EMB-4/AQR/IBP160, to the CSR-1 and HRDE-1 nuclear 22G-RNA pathways in the C. elegans germline. Loss of emb-4 leads to distinct alterations in CSR-1- versus HRDE-1-associated small RNA and mRNA transcriptomes. Our transcriptome-wide analysis shows that EMB-4 is enriched along pre-mRNAs of nearly 8,000 transcripts. While EMB-4 complexes are enriched for both intronic and exonic sequences of HRDE-1 targets, CSR-1 pathway targets are enriched for intronic, but not exonic, sequences. These data suggest that EMB-4 could contribute to a molecular signature that distinguishes the targets of these two germline small RNA pathways.
Infection with multiple drug resistant (MDR) Escherichia coli poses a life threat to immunocompromised pediatric cancer patients. Our aim is to genotypically characterize the plasmids harbored in MDR E. coli isolates recovered from bacteremic patients of Children's Cancer Hospital in Egypt 57357 (CCHE 57357). In this study, 21 carbapenem-resistant E. coli (CRE) isolates were selected that exhibit Quinolones and Aminoglycosides resistance. Plasmid shotgun sequencing was performed using Illumina nextgeneration sequencing platform. Isolates demonstrated resistant to all beta-lactams, carbapenems, aminoglycosides and quinolones. Of the 32 antimicrobial resistant genes identified that exceeded the analysis cutoff coverage, the highest represented genes were aph(6)-Id, sul2, aph(3″)-Ib, aph(3′)-Ia, sul1, dfrA12, TEM-220, NDM-11. Isolates employed a wide array of resistance mechanisms including antibiotic efflux, antibiotic inactivation, antibiotic target replacements and antibiotic target alteration. Sequenced isolates displayed diverse insertion sequences, including IS26, suggesting dynamic reshuffling of the harbored plasmids. Most isolates carried plasmids originating from other bacterial species suggesting a possible horizontal gene transfer. Only two isolates showed virulence factors with iroA gene cluster which was found in only one of them. Outside the realms of nosocomial infections among patients in hospitals, our results indicate a transfer of resistant genes and plasmids across different organisms. Escherichia coli represents the most frequent sources of blood stream and urinary tract infections worldwide. A continual increase in E. coli antibiotic resistance burdens medical facilities throughout the world by causing difficult to treat infections among patients 1,2. There has been a particular concern regarding the increase in Extended-Spectrum Beta-Lactamase (ESBL)-producing and carbapenem-resistant E. coli. carbapenem-resistant E. coli (CRE) have become resistant to the majority of available antibiotics, including carbapenems which are a last-resort treatment for multidrug-resistant pathogens. This is often accompanied by resistance to fluoroquinolones and aminoglycosides 3,4. The increase in antimicrobial resistance (AMR) frequency presents a global healthcare challenge by limiting the choices of antimicrobials that can be used in the treatment of bacterial infections 5,6. Mobile elements like transposons, integrons and plasmids frequently carry Multiple Drug Resistance (MDR) genetic motifs. These elements can be transferred from foodborne pathogens to human pathogens, increasing their virulence 7. This method has enabled the rapid propagation of AMR among several pathogenic bacterial genera to humans, including E. coli 8. CRE-encoding plasmids are now regarded as the primary vector facilitating this transmission between bacteria 9 .
PurposeTo report the first simultaneous onset of bilateral acute depigmentation of the iris (BADI) in two siblings.ObservationsTwo sisters presented with bilateral ocular pain, redness and light sensitivity. Examination revealed bilateral circulating pigment in the anterior chamber with pigment dusting on backs of the corneas, patchy iris depigmentation and heavy pigment deposition in the angle. Both patients had recently suffered from upper respiratory tract infections. Bilateral visual acuities were preserved and no transillumination defects were observed. The patients were diagnosed with BADI. Both cases were successfully controlled with topical corticosteroids and anti-glaucoma drops as well as topical glanciclovir gel.Conclusions and ImportanceTo date, there had been no published reports of BADI in the Middle East and Africa. This is the first observation of this entity in these regions. Moreover it is the first occurrence of BADI in two immediate siblings simultaneously. We also report the rare asymmetrical presentation with BADI in one of our patients. These observations point to the possibility of genetic factors underlying BADI as well as an infectious cause behind the etiology.
MicroRNA (miRNA) loaded Argonaute (AGO) complexes regulate gene expression via direct base-pairing with their mRNA targets. Current prediction approaches identified that between 20 to 60% of mammalian transcriptomes are regulated by miRNAs, but it remains largely unknown which fraction of these interactions are functional in a specific cellular context. Here, we integrated transcriptome data from a set of miRNA-depleted mouse embryonic stem cell (mESC) lines with published miRNA interaction predictions and AGO-binding profiles. This integrative approach, combined with molecular validation data, identified that only 6% of expressed genes are functionally and directly regulated by miRNAs in mESCs. In addition, analyses of the stem cell-specific miR-290-295 cluster target genes identified TFAP4 as an important transcription factor for early development. The extensive datasets developed in this study will support the development of improved predictive models for miRNA-mRNA functional interactions.
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