New Human Papilloma Virus E2 Transcription Factor Mimics: A Tripyrrole-Peptide Conjugate with Tight and Specific DNA-Recognition

BACKGROUND: Human papillomavirus (HPV) is the main causative agent of cervical cancer, particularly high risk strains such us HPV-16, -18 and -31. The viral encoded E2 protein acts as a transcriptional modulator and exerts a key role in viral DNA replication. Thus, E2 constitutes an attractive target for developing antiviral agents. E2 is a homodimeric protein that interacts with the DNA target through an α-helix of each monomer. However, a peptide corresponding to the DNA recognition helix of HPV-16 E2 binds DNA with lower affinity than its full-length DNA binding domain. Therefore, in an attempt to promote the DNA binding of the isolated peptide, we have designed a conjugate compound of the E2 α-helix peptide and a derivative of the antibiotic distamycin, which involves simultaneous minor- and major-groove interactions. METHODOLOGY/PRINCIPAL FINDINGS: An E2 α-helix peptide-distamycin conjugate was designed and synthesized. It was characterized by NMR and CD spectroscopy, and its DNA binding properties were investigated by CD, DNA melting and gel shift experiments. The coupling of E2 peptide with distamycin does not affect its structural properties. The conjugate improves significantly the affinity of the peptide for specific DNA. In addition, stoichiometric amounts of specific DNA increase meaningfully the helical population of the peptide. The conjugate enhances the DNA binding constant 50-fold, maintaining its specificity. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that peptide-distamycin conjugates are a promising tool to obtain compounds that bind the E2 target DNA-sequences with remarkable affinity and suggest that a bipartite major/minor groove binding scaffold can be a useful approach for therapeutic treatment of HPV infection

Low Doses of Ionizing Radiation Promote Tumor Growth and Metastasis by Enhancing Angiogenesis

Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk. The biological effects of these low doses of IR on the healthy tissue surrounding the tumor area, and in particular on the vasculature remain largely to be determined. We found that doses of IR lower or equal to 0.8 Gy enhance endothelial cell migration without impinging on cell proliferation or survival. Moreover, we show that low-dose IR induces a rapid phosphorylation of several endothelial cell proteins, including the Vascular Endothelial Growth Factor (VEGF) Receptor-2 and induces VEGF production in hypoxia mimicking conditions. By activating the VEGF Receptor-2, low-dose IR enhances endothelial cell migration and prevents endothelial cell death promoted by an anti-angiogenic drug, bevacizumab. In addition, we observed that low-dose IR accelerates embryonic angiogenic sprouting during zebrafish development and promotes adult angiogenesis during zebrafish fin regeneration and in the murine Matrigel assay. Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis and that these effects were prevented by the administration of a VEGF receptor-tyrosine kinase inhibitor immediately before IR exposure. These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR and may provide a new rationale basis to the improvement of current radiotherapy protocols

The 2024 Outline of Fungi and fungus-like taxa

With the simultaneous growth in interest from the mycological community to discover fungal species and classify them, there is also an important need to assemble all taxonomic information onto common platforms. Fungal classification is facing a rapidly evolving landscape and organizing genera into an appropriate taxonomic hierarchy is central to better structure a unified classification scheme and avoid incorrect taxonomic inferences. With this in mind, the Outlines of Fungi and fungus-like taxa (2020, 2022) were published as an open-source taxonomic scheme to assist mycologists to better understand the taxonomic position of species within the Fungal Kingdom as well as to improve the accuracy and consistency of our taxonomic language. In this paper, the third contribution to the series of Outline of Fungi and fungus-like taxa prepared by the Global Consortium for the Classification of Fungi and fungus-like taxa is published. The former is updated considering our previous reviews and the taxonomic changes based on recent taxonomic work. In addition, it is more comprehensive and derives more input and consensus from a larger number of mycologists worldwide. Apart from listing the position of a particular genus in a taxonomic level, nearly 1000 notes are provided for newly established genera and higher taxa introduced since 2022. The notes section emphasizes on recent findings with corresponding references, discusses background information to support the current taxonomic status and some controversial taxonomic issues are also highlighted. To elicit maximum taxonomic information, notes/taxa are linked to recognized databases such as Index Fungorum, Faces of Fungi, MycoBank and GenBank, Species Fungorum and others. A new feature includes links to Fungalpedia, offering notes in the Compendium of Fungi and fungus-like Organisms. When specific notes are not provided, links are available to webpages and relevant publications for genera or higher taxa to ease data accessibility. Following the recent synonymization of Caulochytriomycota under Chytridiomycota, with Caulochytriomycetes now classified as a class within the latter, based on formally described and currently accepted data, the Fungi comprises 19 Phyla, 83 classes, 1,220 families, 10,685 genera and ca 140,000 species. Of the genera, 39.5% are monotypic and this begs the question whether mycologists split genera unnecessarily or are we going to find other species in these genera as more parts of the world are surveyed? They are 433 speciose genera with more than 50 species. The document also highlights discussion of some important topics including number of genera categorized as incertae sedis status in higher level fungal classification. The number of species at the higher taxonomic level has always been a contentious issue especially when mycologists consider either a lumping or a splitting approach and herein we provide figures. Herein a summary of updates in the outline of Basidiomycota is provided with discussion on whether there are too many genera of Boletales, Ceratobasidiaceae, and speciose genera such as Colletotrichum. Specific case studies deal with Cortinarius, early diverging fungi, Glomeromycota, a diverse early divergent lineage of symbiotic fungi, Eurotiomycetes, marine fungi, Myxomycetes, Phyllosticta, Hymenochaetaceae and Polyporaceae and the longstanding practice of misapplying intercontinental conspecificity. The outline will aid to better stabilize fungal taxonomy and serves as a necessary tool for mycologists and other scientists interested in the classification of the Fungi

The power of monitoring: optimizing survey designs to detect occupancy changes in a rare amphibian population

Biodiversity conservation requires reliable species assessments and rigorously designed surveys. However, determining the survey effort required to reliably detect population change can be challenging for rare, cryptic and elusive species. We used a tropical bromeliad-dwelling frog as a model system to explore a cost-effective sampling design that optimizes the chances of detecting a population decline. Relatively few sampling visits were needed to estimate occupancy and detectability with good precision, and to detect a 30% change in occupancy with 80% power. Detectability was influenced by observer expertise, which therefore also had an effect on the sampling design – less experienced observers require more sampling visits to detect the species. Even when the sampling design provides precise parameter estimates, only moderate to large changes in occupancy will be detected with reliable power. Detecting a population change of 15% or less requires a large number of sites to be surveyed, which might be unachievable for range-restricted species occurring at relatively few sites. Unless there is high initial occupancy, rare and cryptic species will be particularly challenging when it comes to detecting small population changes. This may be a particular issue for long-term monitoring of amphibians which often display low detectability and wide natural fluctuations

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men &lt;= 50y, men &gt; 50y, women &lt;= 50y, women &gt; 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR&lt; 5%) age-specific effects, of which 11 had larger effects in younger (&lt; 50y) than in older adults (&gt;= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.</p

Optimal IL-7R-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on CK2 activity

Interleukin-7 and IL7R are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/IL7R-mediated signaling promotes leukemogenesis. Protein kinase CK2 is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Here, we show that while interleukin-7 had a minor but significant positive effect on CK2 activity in leukemia T-cells, CK2 activity was mandatory for optimal interleukin-7/IL7R-mediated signaling. CK2 pharmacological inhibition impaired STAT5 and PI3K/Akt pathway activation triggered by interleukin-7 or by mutational activation of IL7R. By contrast, forced expression of CK2 augmented interleukin-7 signaling in HEK293T cells reconstituted with the IL7R machinery. CK2 inactivation prevented interleukin-7-induced Bcl-2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. CK2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, CK2 was also required for the viability of mutant IL7R-expressing leukemia T-cells. Overall, our study identifies CK2 as a major player in the effects of interleukin-7 and IL7R in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting CK2 in this malignancy