Cell-penetrating peptides-the Swiss Army knife of cancer vaccines.
Ontology highlight
ABSTRACT: Therapeutic cancer vaccination is an attractive treatment modality for cancer, but with limitations using existing whole-cell, peptide, or protein vaccines. We propose that a cell-penetrating peptide (CPP)-based vaccine delivering multi-epitopic antigens into antigen-presenting cells (APCs) offers great potential to induce an integrated antitumor immune response and robust, sustained therapeutic effect.
Project description:US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV.
Project description:In most species, the centromere is comprised of repetitive DNA sequences, which rapidly evolve. Paradoxically, centromeres fulfill an essential function during mitosis, as they are the chromosomal sites wherein, through the kinetochore, the mitotic spindles bind. It is now generally accepted that centromeres are transcribed, and that such transcription is associated with a broad range of functions. More than a decade of work on this topic has shown that centromeric transcripts are found across the eukaryotic tree and associate with heterochromatin formation, chromatin structure, kinetochore structure, centromeric protein loading, and inner centromere signaling. In this review, we discuss the conservation of small and long non-coding centromeric RNAs, their associations with various centromeric functions, and their potential roles in disease.
Project description:Homologous recombination (HR) is a ubiquitous cellular pathway that mediates transfer of genetic information between homologous or near homologous (homeologous) DNA sequences. During meiosis it ensures proper chromosome segregation in the first division. Moreover, HR is critical for the tolerance and repair of DNA damage, as well as in the recovery of stalled and broken replication forks. Together these functions preserve genomic stability and assure high fidelity transmission of the genetic material in the mitotic and meiotic cell divisions. This review will focus on the Rad54 protein, a member of the Snf2-family of SF2 helicases, which translocates on dsDNA but does not display strand displacement activity typical for a helicase. A wealth of genetic, cytological, biochemical and structural data suggests that Rad54 is a core factor of HR, possibly acting at multiple stages during HR in concert with the central homologous pairing protein Rad51.
Project description:The pdb-tools are a collection of Python scripts for working with molecular structure data in the Protein Data Bank (PDB) format. They allow users to edit, convert, and validate PDB files, from the command-line, in a simple but efficient manner. The pdb-tools are implemented in Python, without any external dependencies, and are freely available under the open-source Apache License at https://github.com/haddocking/pdb-tools/ and on PyPI.
Project description:UnlabelledMendel is one of the few statistical genetics packages that provide a full spectrum of gene mapping methods, ranging from parametric linkage in large pedigrees to genome-wide association with rare variants. Our latest additions to Mendel anticipate and respond to the needs of the genetics community. Compared with earlier versions, Mendel is faster and easier to use and has a wider range of applications. Supported platforms include Linux, MacOS and Windows.AvailabilityFree from www.genetics.ucla.edu/software/mendel.
Project description:The mammalian T cell receptor (TCR) orchestrates immunity by responding to many billions of different ligands that it has never encountered before and cannot adapt to at the protein sequence level. This remarkable receptor exists in two main heterodimeric isoforms: αβ TCR and γδ TCR. The αβ TCR is expressed on the majority of peripheral T cells. Most αβ T cells recognize peptides, derived from degraded proteins, presented at the cell surface in molecular cradles called major histocompatibility complex (MHC) molecules. Recent reports have described other αβ T cell subsets. These 'unconventional' T cells bear TCRs that are capable of recognizing lipid ligands presented in the context of the MHC-like CD1 protein family or bacterial metabolites bound to the MHC-related protein 1 (MR1). γδ T cells constitute a minority of the T cell pool in human blood, but can represent up to half of total T cells in tissues such as the gut and skin. The identity of the preferred ligands for γδ T cells remains obscure, but it is now known that this receptor can also functionally engage CD1-lipid, or immunoglobulin (Ig) superfamily proteins called butyrophilins in the presence of pyrophosphate intermediates of bacterial lipid biosynthesis. Interactions between TCRs and these ligands allow the host to discriminate between self and non-self and co-ordinate an attack on the latter. Here, we describe how cells of the T lymphocyte lineage and their antigen receptors are generated and discuss the various modes of antigen recognition by these extraordinarily versatile receptors.
Project description:Beyond its well-admitted role in development and organogenesis, it is now clear that the transcription factor c-Maf has owned its place in the realm of immune-related transcription factors. Formerly introduced solely as a Th2 transcription factor, the role attributed to c-Maf has gradually broadened over the years and has extended to most, if not all, known immune cell types. The influence of c-Maf is particularly prominent among T cell subsets, where c-Maf regulates the differentiation as well as the function of multiple subsets of CD4 and CD8 T cells, lending it a crucial position in adaptive immunity and anti-tumoral responsiveness. Recent research has also revealed the role of c-Maf in controlling Th17 responses in the intestine, positioning it as an essential factor in intestinal homeostasis. This review aims to present and discuss the recent advances highlighting the particular role played by c-Maf in T lymphocyte differentiation, function, and homeostasis.
Project description:Background and purposeWe recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).Experimental approachWe used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-β peptides on neuronal survival and neurite formation determined in vitro.Key resultsIn vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.Conclusions and implicationsDonecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.
Project description:Systems biology requires not only genome-scale data but also methods to integrate these data into interpretable models. Previously, we developed approaches that organize omics data into a structured hierarchy of cellular components and pathways, called a "data-driven ontology." Such hierarchies recapitulate known cellular subsystems and discover new ones. To broadly facilitate this type of modeling, we report the development of a software library called the Data-Driven Ontology Toolkit (DDOT), consisting of a Python package (https://github.com/idekerlab/ddot) to assemble and analyze ontologies and a web application (http://hiview.ucsd.edu) to visualize them. Using DDOT, we programmatically assemble a compendium of ontologies for 652 diseases by integrating gene-disease mappings with a gene similarity network derived from omics data. For example, the ontology for Fanconi anemia describes known and novel disease mechanisms in its hierarchy of 194 genes and 74 subsystems. DDOT provides an easy interface to share ontologies online at the Network Data Exchange.
Project description:Significant improvements have been made in the efficiency and accuracy of RNA 3D structure prediction methods in recent years; however, many tools developed in the field stay exclusive to only a few bioinformatic groups. To perform a complete RNA 3D structure modeling analysis as proposed by the RNA-Puzzles community, researchers must familiarize themselves with a quite complex set of tools. In order to facilitate the processing of RNA sequences and structures, we previously developed the rna-tools package. However, using rna-tools requires the installation of a mixture of libraries and tools, basic knowledge of the command line and the Python programming language. To provide an opportunity for the broader community of biologists to take advantage of the new developments in RNA structural biology, we developed rna-tools.online. The web server provides a user-friendly platform to perform many standard analyses required for the typical modeling workflow: 3D structure manipulation and editing, structure minimization, structure analysis, quality assessment, and comparison. rna-tools.online supports biologists to start benefiting from the maturing field of RNA 3D structural bioinformatics and can be used for educational purposes. The web server is available at https://rna-tools.online.