Exonuclease Xrn1 regulates TORC1 signaling in response to SAM availability.

Autophagy is a conserved process of cellular self-digestion that promotes survival during nutrient stress. In yeast, methionine starvation is sufficient to induce autophagy. One pathway of autophagy induction is governed by the SEACIT complex, which regulates TORC1 activity in response to amino acids through the Rag GTPases Gtr1 and Gtr2. However, the precise mechanism by which SEACIT senses amino acids and regulates TORC1 signaling remains incompletely understood. Here, we identify the conserved 5'-3' RNA exonuclease Xrn1 as a surprising and novel regulator of TORC1 activity in response to methionine starvation. This role of Xrn1 is dependent on its catalytic activity, but not on degradation of any specific class of mRNAs. Instead, Xrn1 modulates the nucleotide-binding state of the Gtr1/2 complex, which is critical for its interaction with and activation of TORC1. This work identifies a critical role for Xrn1 in nutrient sensing and growth control that extends beyond its canonical housekeeping function in RNA degradation and indicates an avenue for RNA metabolism to function in amino acid signaling into TORC1.

Pbp1 associates with Puf3 and promotes translation of its target mRNAs involved in mitochondrial biogenesis.

Pbp1 (poly(A)-binding protein-binding protein 1) is a cytoplasmic stress granule marker that is capable of forming condensates that function in the negative regulation of TORC1 signaling under respiratory conditions. Polyglutamine expansions in its mammalian ortholog ataxin-2 lead to spinocerebellar dysfunction due to toxic protein aggregation. Here, we show that loss of Pbp1 in S. cerevisiae leads to decreased amounts of mRNAs and mitochondrial proteins which are targets of Puf3, a member of the PUF (Pumilio and FBF) family of RNA-binding proteins. We found that Pbp1 supports the translation of Puf3-target mRNAs in respiratory conditions, such as those involved in the assembly of cytochrome c oxidase and subunits of mitochondrial ribosomes. We further show that Pbp1 and Puf3 interact through their respective low complexity domains, which is required for Puf3-target mRNA translation. Our findings reveal a key role for Pbp1-containing assemblies in enabling the translation of mRNAs critical for mitochondrial biogenesis and respiration. They may further explain prior associations of Pbp1/ataxin-2 with RNA, stress granule biology, mitochondrial function, and neuronal health.

Integration of population and functional genomics to understand mechanisms of artemisinin resistance in Plasmodium falciparum.

Resistance to antimalarial drugs, and in particular to the artemisinin derivatives and their partner drugs, threatens recent progress toward regional malaria elimination and eventual global malaria eradication. Population-level studies utilizing whole-genome sequencing approaches have facilitated the identification of regions of the parasite genome associated with both clinical and in vitro drug-resistance phenotypes. However, the biological relevance of genes identified in these analyses and the establishment of a causal relationship between genotype and phenotype requires functional characterization. Here we examined data from population genomic and transcriptomic studies in the context of data generated from recent functional studies, using a new population genetic approach designed to identify potential favored mutations within the region of a selective sweep (iSAFE). We identified several genes functioning in pathways now known to be associated with artemisinin resistance that were supported in early population genomic studies, as well as potential new drug targets/pathways for further validation and consideration for treatment of artemisinin-resistant Plasmodium falciparum. In addition, we establish the utility of iSAFE in identifying positively-selected mutations in population genomic studies, potentially accelerating the time to functional validation of candidate genes.

Strategies for enhancing intratumoral spread of oncolytic adenoviruses.

Oncolytic viruses, effectively replicate viruses within malignant cells to lyse them without affecting normal ones, have recently shown great promise in developing therapeutic options for cancer. Adenoviruses (Ads) are one of the candidates in oncolytic virotheraoy due to its easily manipulated genomic DNA and expression of wide rane of its receptors on the various cancers. Although systematic delivery of oncolytic adenoviruses can target both primary and metastatic tumors, there are some drawbacks in the effective systematic delivery of oncolytic adenoviruses, including pre-existing antibodies and liver tropism. To overcome these limitations, intratumural (IT) administration of oncolytic viruses have been proposed. However, IT injection of Ads leaves much of the tumor mass unaffected and Ads are not able to disperse more in the tumor microenvironment (TME). To this end, various strategies have been developed to enhance the IT spread of oncolytic adenoviruses, such as using extracellular matrix degradation enzymes, junction opening peptides, and fusogenic proteins. In the present paper, we reviewed different oncolytic adenoviruses, their application in the clinical trials, and strategies for enhancing their IT spread.

Immunopeptidome screening to design An immunogenic construct against PRAME positive breast cancer; An in silico study.

BACKGROUND: Metastasis is the main cause of breast cancer (BC) lethality, especially in early stages, led to improvements in therapeutic procedures. Lately, by improvements in our perception of biological processes and immune system new classes of vaccines are emerged that grant us the opportunity of designing resolute constructs against desired antigens. In the current study, we used a variety of immunoinformatics tools to design a novel cancer vaccine against Preferentially Expressed Antigen of Melanoma (PRAME), which counts as a cancer testis antigen for various human cancers including BC. The PRAME up-regulation leads to strengthen BC stem cells maintenance, drug resistance, cell survival, adaptation, and apoptosis evading in cancerous cells. METHODS AND RESULTS: The PRAME co-expressed genes were mined and validated through BC RNA-sequencing of TCGA data. The immunodominant T-cell predicted epitopes were fused and engineered to form the vaccine. The safety, allergenicity, and immunogenic capabilities of the vaccine were confirmed by promising immunoinformatics tools. The vaccine's structure was verified to be hydrophilic in most areas through Kyte and Doolittle hydrophobicity plotting. The interactions between the designed vaccine and immune receptors of TLR4 and IL1R were confirmed by protein-protein docking after modeling its tertiary structure. Finally, codon optimization and in silico cloning were performed to guarantee better in-vivo results. CONCLUSION: In conclusion, concerning in silico assessments' results in this study, the designed vaccine can potentially boost immune responses against PRAME, therefore may decrease BC development and metastasis. According to the mined PRAME co-expressed genes and their functional annotation, cell cycle regulation is the prime mechanism opted by this construct and its adjacent regulatory genes along boosting immune reactions.

Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches.

Cancer therapy using oncolytic viruses is an emerging area, in which viruses are engineered to selectively propagate in tumor tissues without affecting healthy cells. Because of the advantages that adenoviruses (Ads) have over other viruses, they are more considered. To achieve tumor selectivity, two main modifications on Ads genome have been applied: small deletions and insertion of tissue- or tumor-specific promoters. Despite oncolytic adenoviruses ability in tumor cell lysis and immune responses stimulation, to further increase their antitumor effects, genomic modifications have been carried out including insertion of checkpoint inhibitors and antigenic or immunostimulatory molecules into the adenovirus genome and combination with dendritic cells and chemotherapeutic agents. This study reviews oncolytic adenoviruses structures, their antitumor efficacy in combination with other therapeutic strategies, and finally challenges around this treatment approach.

Fusobacterium nucleatum and colorectal cancer: A mechanistic overview.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. There are many risk factors involved in CRC. According to recent findings, the tumor microenvironment and feces samples of patients with CRC are enriched by Fusobacterium nucleatum. Thus, F. nucleatum is proposed as one of the risk factors in the initiation and progression of CRC. The most important mechanisms of Fusobacterium nucleatum involved in CRC carcinogenesis are immune modulation (such as increasing myeloid-derived suppressor cells and inhibitory receptors of natural killer cells), virulence factors (such as FadA and Fap2), microRNAs (such as miR-21), and bacteria metabolism. The aim of this review was to evaluate the mechanisms underlying the action of F. nucleatum in CRC.

Molecular insights into the interactions of GF-17 with the gram-negative and gram-positive bacterial lipid bilayers.

The cationic antimicrobial peptide GF-17, a 17-mer-derived peptide from human cathelicidin LL-37, has a significant strength in the killing of the methicillin-resistant Staphylococcus aureus and Escherichia coli strains. Herein, we conducted a series of all-atom molecular dynamics simulations to investigate the ability of GF-17 in perturbing the model membranes of the gram-positive, S. aureus, and gram-negative, E. coli, bacteria. We also explored the contributions of the specific residues in the peptide activity. The molecular dynamics results indicated that the peptide is stabilized on the membrane surface and rapidly binds to the phosphate headgroups of the model membranes through the electrostatic interactions and hydrogen bonds. Furthermore, both polar and nonpolar interactions are energetically favored for the binding with the membrane surface. The research also revealed the important roles of the phenylalanine residues in the early insertion of the peptide into the bacterial model membranes. In addition, the results demonstrated that the central residues Arg23 and Lys25 played a critical role in the binding of GF-17 to both gram-negative and gram-positive model membranes, in excellent agreement with experimental studies. This study emphasizes on the pivotal role of basic residues in prompt association of the peptide on the model membrane surface and on the significance of residues Phe17, Ile24, Phe27, and Val32 in hydrophobic interactions. Therefore, our observations provide insights into the membrane-GF-17 interactions at atomic details that are useful to develop potent antimicrobial peptides targeting multidrug-resistant bacteria.

Nanoparticles as new tools for inhibition of cancer angiogenesis.

Angiogenesis is known as one of the hallmarks of cancer. Multiple lines evidence indicated that vascular endothelium growth factor (VEGF) is a key player in the progression of angiogenesis and exerts its functions via interaction with tyrosine kinase receptors (TKRs). These receptors could trigger a variety of cascades that lead to the supply of oxygen and nutrients to tumor cells and survival of these cells. With respect to pivotal role of angiogenesis in the tumor growth and survival, finding new therapeutic approaches via targeting angiogenesis could open a new horizon in cancer therapy. Among various types of therapeutic strategies, nanotechnology has emerged as new approach for the treatment of various cancers. Nanoparticles (NPs) could be used as effective tools for targeting a variety of therapeutic agents. According to in vitro and in vivo studies, NPs are efficient in depriving tumor cells from nutrients and oxygen by inhibiting angiogenesis. However, the utilization of NPs are associated with a variety of limitations. It seems that new approaches such as NPs conjugated with hydrogels could overcome to some limitations. In the present review, we summarize various mechanisms involved in angiogenesis, common anti-angiogenesis strategies, and application of NPs for targeting angiogenesis in various cancers.