A Universal Strategy of Anti-Tumor mRNA Vaccine by Harnessing "Off-the-Shelf" Immunity.

Personalized neoantigen cancer mRNA vaccines are promising candidates for precision medicine. However, the difficulty of identifying neoantigens heavily hinders their broad applicability. This study developed a universal strategy of anti-tumor mRNA vaccine by harnessing "off-the-shelf" immunity to known antigens.

RNA structure in alternative splicing regulation: from mechanism to therapy.

Alternative splicing is a highly intricate process that plays a crucial role in post-transcriptional regulation and significantly expands the functional proteome of a limited number of coding genes in eukaryotes. Its regulation is multifactorial, with RNA structure exerting a significant impact. Aberrant RNA conformations lead to dysregulation of splicing patterns, which directly affects the manifestation of disease symptoms.

A potential link between aromatics-induced oviposition repellency behaviors and specific odorant receptor of Aedes albopictus.

Background: The Asian tiger mosquito, Aedes albopictus, is a competent vector for the spread of several viral arboviruses including dengue, chikungunya, and Zika. Several vital mosquito behaviors linked to survival and reproduction are primarily dependent on a sophisticated olfactory system for semiochemical perception. However, a limited number of studies has hampered our understanding of the relationship between the A.

Confluence and convergence of Dscam and Pcdh cell-recognition codes.

The ability of neurites of the same neuron to avoid each other (self-avoidance) is a conserved feature in both invertebrates and vertebrates. The key to self-avoidance is the generation of a unique subset of cell-surface proteins in individual neurons engaging in isoform-specific homophilic interactions that drive neurite repulsion rather than adhesion. Among these cell-surface proteins are fly Dscam1 and vertebrate clustered protocadherins (cPcdhs), as well as the recently characterized shortened Dscam (sDscam) in the Chelicerata.

Emerging Progress of RNA-Based Antitumor Therapeutics.

RNA-based therapeutics (e.g., mRNAs, siRNAs, microRNAs, ASOs, and saRNAs) have considerable potential for tumor treatment.

Structural basis for the self-recognition of sDSCAM in Chelicerata.

To create a functional neural circuit, neurons develop a molecular identity to discriminate self from non-self. The invertebrate Dscam family and vertebrate Pcdh family are implicated in determining synaptic specificity. Recently identified in Chelicerata, a shortened Dscam (sDscam) has been shown to resemble the isoform-generating characters of both Dscam and Pcdh and represent an evolutionary transition.

Trans-splicing facilitated by RNA pairing greatly expands sDscam isoform diversity but not homophilic binding specificity.

The () gene can generate tens of thousands of isoforms via alternative splicing, which is essential for nervous and immune functions. Chelicerates generate approximately 50 to 100 shortened Dscam (sDscam) isoforms by alternative promoters, similar to mammalian protocadherins. Here, we reveal that trans-splicing markedly increases the repository of sDscamβ isoforms in .

Recent advances in RNA structurome.

RNA structures are essential to support RNA functions and regulation in various biological processes. Recently, a range of novel technologies have been developed to decode genome-wide RNA structures and novel modes of functionality across a wide range of species. In this review, we summarize key strategies for probing the RNA structurome and discuss the pros and cons of representative technologies.

Self-avoidance alone does not explain the function of Dscam1 in mushroom body axonal wiring.

Alternative splicing of Drosophila Dscam1 into 38,016 isoforms provides neurons with a unique molecular code for self-recognition and self-avoidance. A canonical model suggests that the homophilic binding of identical Dscam1 isoforms on the sister branches of mushroom body (MB) axons supports segregation with high fidelity, even when only a single isoform is expressed. Here, we generated a series of mutant flies with a single exon 4, 6, or 9 variant, encoding 1,584, 396, or 576 potential isoforms, respectively.

Hidden RNA pairings counteract the "first-come, first-served" splicing principle to drive stochastic choice in splice variants.

encodes 38,016 isoforms via mutually exclusive splicing; however, the regulatory mechanism behind this is not fully understood. Here, we found a set of hidden RNA secondary structures that balance the stochastic choice of splice variants (designated balancer RNA secondary structures). In vivo mutational analyses revealed the dual function of these balancer interactions in driving the stochastic choice of splice variants, through enhancement of the inclusion of distal exon 6s by cooperating with docking site-selector pairing to form a stronger multidomain pre-mRNA structure and through simultaneous repression of the inclusion of proximal exon 6s by antagonizing their docking site-selector pairings.

Intron-targeted mutagenesis reveals roles for Dscam1 RNA pairing architecture-driven splicing bias in neuronal wiring.

Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam1) can generate 38,016 different isoforms through largely stochastic, yet highly biased, alternative splicing. These isoforms are required for nervous functions. However, the functional significance of splicing bias remains unknown.

Complex RNA Secondary Structures Mediate Mutually Exclusive Splicing of Coleoptera .

Mutually exclusive splicing is an important mechanism for expanding protein diversity. An extreme example is the Down syndrome cell adhesion molecular () gene of insects, containing four clusters of variable exons (exons 4, 6, 9, and 17), which potentially generates tens of thousands of protein isoforms through mutually exclusive splicing, of which regulatory mechanisms are still elusive. Here, we systematically analyzed the variable exon 4, 6, and 9 clusters of in Coleoptera species.

Chelicerata sDscam isoforms combine homophilic specificities to define unique cell recognition.

Thousands of Down syndrome cell adhesion molecule (Dscam1) isoforms and ∼60 clustered protocadhrein (cPcdh) proteins are required for establishing neural circuits in insects and vertebrates, respectively. The strict homophilic specificity exhibited by these proteins has been extensively studied and is thought to be critical for their function in neuronal self-avoidance. In contrast, significantly less is known about the Dscam1-related family of ∼100 shortened (sDscam) proteins in Chelicerata.

RNA structures in alternative splicing and back-splicing.

Alternative splicing greatly expands the transcriptomic and proteomic diversities related to physiological and developmental processes in higher eukaryotes. Splicing of long noncoding RNAs, and back- and trans- splicing further expanded the regulatory repertoire of alternative splicing. RNA structures were shown to play an important role in regulating alternative splicing and back-splicing.

RNA secondary structures in mutually exclusive splicing: unique evolutionary signature from the midge.

The gene potentially generates 38,016 distinct isoforms via mutually exclusive splicing, which are required for both nervous and immune functions. However, the mechanism underlying splicing regulation remains obscure. Here we show apparent evolutionary signatures characteristic of competing RNA secondary structures in exon clusters 6 and 9 of in the two midge species ( and ).

Role of RNA secondary structures in regulating Dscam alternative splicing.

Alternative splicing of mRNA precursors is a versatile mechanism of expanding proteomic diversity. The most striking example of this is the Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam1) gene, which potentially encodes 38,016 distinct isoforms by mutually exclusive splicing. The genomic organization of Dscam1 is largely conserved across the pancrustaceans, although the number of splice isoforms varies from 2240 in the clam shrimp (Eulimnadia texana) to 121,104 in the whiteleg shrimp (Litopenaeus vannamei).

Effects of a 15-amino-acid isoform of amyloid- β expressed by silkworm pupae on B6C3-Tg Alzheimer's disease transgenic mice.

Silkworms are an economically important insect.Silkworm pupae are also a nutrient-rich food and can be used as a pharmaceutical intermediate.The N-terminus of Aβ includes 1-15 amino acid residues with a B cell surface antigen that is necessary to produce antibody and prevent the adverse reactions observed in response to the full Aβ42 peptide.

Study of the whole genome, methylome and transcriptome of Cordyceps militaris.

The complete genome of Cordyceps militaris was sequenced using single-molecule real-time (SMRT) sequencing technology at a coverage over 300×. The genome size was 32.57 Mb, and 14 contigs ranging from 0.

Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated With Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS.

Background & Aims: We aimed to identify long noncoding RNAs (lncRNAs) that are up-regulated in gastric cancer tissues from patients and study their function in gastric tumor metastasis.

Methods: We collected gastric tumor and nontumor tissues from patients in China and analyzed levels of lncRNAs by microarray analysis, proteins by immunohistochemistry, and RNAs by quantitative reverse-transcription polymerase chain reaction; we compared these with survival times of patients and tumor progression. RNA levels were knocked down or knocked out in BGC-823, SGC-7901, and MKN45 cell lines using small interfering or short hairpin RNAs or clustered regularly interspaced short palindromic repeats (ie, CRISPR)/CRISPR associated protein 9 (ie, Cas9) vectors.

Revisiting Dscam diversity: lessons from clustered protocadherins.

The complexity of neuronal wiring relies on the extraordinary recognition diversity of cell surface molecules. Drosophila Dscam1 and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the striking diversity from a complex genomic locus, wherein the former encodes more than 10,000 distinct isoforms via alternative splicing, while the latter employs alternative promoters to attain isoform diversity. These structurally unrelated families show remarkably striking molecular parallels and even similar functions.

Competing RNA pairings in complex alternative splicing of a 3' variable region.

Alternative pre-mRNA splicing remarkably expands protein diversity in eukaryotes. can generate three major 3' splice isoforms that exhibit distinct innate immune recognition and defenses against various microbial infections. However, the regulatory mechanisms underlying the uniquely biased splicing pattern at the 3' variable region remain unclear.

Mutually exclusive alternative splicing of pre-mRNAs.

Pre-mRNA alternative splicing is an important mechanism used to expand protein diversity in higher eukaryotes, and mutually exclusive splicing is a specific type of alternative splicing in which only one of the exons in a cluster is included in functional transcripts. The most extraordinary example of this is the Drosophila melanogaster Down's syndrome cell adhesion molecule gene (Dscam), which potentially encodes 38,016 different isoforms through mutually exclusive splicing. Mutually exclusive splicing is a unique and challenging model that can be used to elucidate the evolution, regulatory mechanism, and function of alternative splicing.