The non-coding landscape of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease marked by frequent recurrence and metastasis and stagnant survival rates. To enhance molecular knowledge of HNSCC and define a non-coding RNA (ncRNA) landscape of the disease, we profiled the transcriptome-wide dysregulation of long non-coding RNA (lncRNA), microRNA (miRNA), and PIWI-interacting RNA (piRNA) using RNA-sequencing data from 422 HNSCC patients in The Cancer Genome Atlas (TCGA). 307 non-coding transcripts differentially expressed in HNSCC were significantly correlated with patient survival, and associated with mutations in TP53, CDKN2A, CASP8, PRDM9, and FBXW7 and copy number variations in chromosomes 3, 5, 7, and 18. We also observed widespread ncRNA correlation to concurrent TP53 and chromosome 3p loss, a compelling predictor of poor prognosis in HNSCCs. Three selected ncRNAs were additionally associated with tumor stage, HPV status, and other clinical characteristics, and modulation of their expression in vitro reveals differential regulation of genes involved in epithelial-mesenchymal transition and apoptotic response. This comprehensive characterization of the HNSCC non-coding transcriptome introduces new layers of understanding for the disease, and nominates a novel panel of transcripts with potential utility as prognostic markers or therapeutic targets

Promiscuity and preferences of metallothioneins: the cell rules

Metalloproteins are essential for many cellular functions, but it has not been clear how they distinguish between the different metals to bind the correct ones. A report in BMC Biology finds that preferences of two metallothionein isoforms for two different cations are due to inherent properties of these usually less discriminating proteins. Here these observations are discussed in the context of the cellular mechanisms that regulate metal binding to proteins

A four-helix bundle stores copper for methane oxidation

Methane-oxidising bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase (pMMO). Certain methanotrophs are also able to switch to using the iron-containing soluble MMO (sMMO) to catalyse methane oxidation, with this switchover regulated by copper. MMOs are Nature’s primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and MMOs have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. We have discovered and characterised a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for pMMO. Csp1 is a tetramer of 4-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realised. Cytosolic homologues of Csp1 are present in diverse bacteria thus challenging the dogma that such organisms do not use copper in this location

Spatial symmetry constraint of charge-ordered kagome superconductor CsV3_3Sb5_5

Elucidating the symmetry of intertwined orders in exotic superconductors is at the quantum frontier. Recent surface sensitive studies of the topological kagome superconductor CsV$_3$Sb$_5$ discovered a cascade 4a$_0$ superlattice below the charge density wave (CDW) ordering temperature, which can be related to the pair density modulations in the superconducting state. If the 4a$_0$ phase is a bulk and intrinsic property of the kagome lattice, this would form a striking analogy to the stripe order and pair density wave discovered in the cuprate high-temperature superconductors, and the cascade ordering found in twisted bilayer graphene. High-resolution X-ray diffraction has recently been established as an ultra-sensitive probe for bulk translational symmetry-breaking orders, even for short-range orders at the diffusive limit. Here, combining high-resolution X-ray diffraction, scanning tunneling microscopy and scanning transmission electron microscopy, we demonstrate that the 4a$_0$ superstructure emerges uniquely on the surface and hence exclude the 4a$_0$ phase as the origin of any bulk transport or spectroscopic anomaly. Crucially, we show that our detected 2$\times$2$\times$2 CDW order breaks the bulk rotational symmetry to C2, which can be the driver for the bulk nematic orders and nematic surface superlattices including the 4a$_0$ phase. Our high-resolution data impose decisive spatial symmetry constraints on emergent electronic orders in the kagome superconductor CsV$_3$Sb$_5$

Biophysical and electrochemical studies of protein-nucleic acid interactions

This review is devoted to biophysical and electrochemical methods used for studying protein-nucleic acid (NA) interactions. The importance of NA structure and protein-NA recognition for essential cellular processes, such as replication or transcription, is discussed to provide background for description of a range of biophysical chemistry methods that are applied to study a wide scope of protein-DNA and protein-RNA complexes. These techniques employ different detection principles with specific advantages and limitations and are often combined as mutually complementary approaches to provide a complete description of the interactions. Electrochemical methods have proven to be of great utility in such studies because they provide sensitive measurements and can be combined with other approaches that facilitate the protein-NA interactions. Recent applications of electrochemical methods in studies of protein-NA interactions are discussed in detail

MAGE I Transcription Factors Regulate KAP1 and KRAB Domain Zinc Finger Transcription Factor Mediated Gene Repression

Class I MAGE proteins (MAGE I) are normally expressed only in developing germ cells but are aberrantly expressed in many cancers. They have been shown to promote tumor survival, aggressive growth, and chemoresistance but the underlying mechanisms and MAGE I functions have not been fully elucidated. KRAB domain zinc finger transcription factors (KZNFs) are the largest group of vertebrate transcription factors and regulate neoplastic transformation, tumor suppression, cellular proliferation, and apoptosis. KZNFs bind the KAP1 protein and direct KAP1 to specific DNA sequences where it suppresses gene expression by inducing localized heterochromatin characterized by histone 3 lysine 9 trimethylation (H3me3K9). Discovery that MAGE I proteins also bind to KAP1 prompted us to investigate whether MAGE I can affect KZNF and KAP1 mediated gene regulation. We found that expression of MAGE I proteins, MAGE-A3 or MAGE-C2, relieved repression of a reporter gene by ZNF382, a KZNF with tumor suppressor activity. ChIP of MAGE I (-) HEK293T cells showed KAP1 and H3me3K9 are normally bound to the ID1 gene, a target of ZNF382, but that binding is greatly reduced in the presence of MAGE I proteins. MAGE I expression relieved KAP1 mediated ID1 repression, causing increased expression of ID1 mRNA and ID1 chromatin relaxation characterized by loss of H3me3K9. MAGE I binding to KAP1 also induced ZNF382 poly-ubiquitination and degradation, consistent with loss of ZNF382 leading to decreased KAP1 binding to ID1. In contrast, MAGE I expression caused increased KAP1 binding to Ki67, another KAP1 target gene, with increased H3me3K9 and decreased Ki67 mRNA expression. Since KZNFs are required to direct KAP1 to specific genes, these results show that MAGE I proteins can differentially regulate members of the KZNF family and KAP1 mediated gene repression

Understanding How Social Entrepreneurs Fit into the Tourism Discourse

This chapter discusses how social entrepreneurs fit into the existing tourism discourse. It examines four areas of literature in particular, tourism entrepreneurs, sustainability, destination development and intrapreneurship, and analyzes how introducing the concept of social entrepreneurs into these discussions is useful, and contributes to our understanding. Furthermore the paper illustrates that as social entrepreneurs are relevant to a broad range of issues in the tourism literature this should prevent the development of research silos where social entrepreneurship scholars seek out their own vein of research. The nexus of common ground and interests, as displayed in this chapter, should enhance the development of research, thought and understanding of social entrepreneurs within the field as a whole The key argument is that research on social entrepreneurs is not just relevant for those interested in entrepreneurs it also effects our thinking on issues such as destination development, relationships between stakeholders, tourism policy and sustainability. The chapter concludes with a wide range of questions for further research

Desarrollo, subjetividad y transgresiones identitarias en las costas del sur- austral chileno

This work is part of an investigation into the contemporary dynamics of development and modernization in the southern and far southern coastal areas of Chile, specifically the shoreline of the northern part of the Aysen Region. The objective is to propose a theoretical-conceptual reflection to enable ethnographic data to be framed as a problem and interpreted as a function of a political reading which - why not say so? - could transform the world of the southern and far southern coastal zone. The central argument of the text is hypothetical: the dilemmas of development, in the current circumstances of the coasts of the Aysen Region, are susceptible of resolution (at least up to a point) from a conscious, reflexive change of perspective on culture as the word is understood in anthropology. Este trabajo se enmarca en una investigación sobre las dinámicas contemporáneas del desarrollo y la modernización en las costas sur-australes de Chile, específicamente en el litoral norte de la región de Aisén. A partir de un conjunto de datos etnográficos se propone una reflexión teórico-conceptual que permita problematizar e interpretar esos datos en función de una lectura política y, por qué no decirlo, transformadora del mundo costero sur-austral. El argumento central del texto tiene carácter hipotético: las encrucijadas del desarrollo, en las actuales coyunturas de las costas aiseninas, son susceptibles de ser resueltas (al menos hasta cierto punto) a partir de un giro reflexivo y consciente sobre eso que en antropología llamamos cultura

Protein target highlights in CASP15: Analysis of models by structure providers

We present an in-depth analysis of selected CASP15 targets, focusing on their biological and functional significance. The authors of the structures identify and discuss key protein features and evaluate how effectively these aspects were captured in the submitted predictions. While the overall ability to predict three-dimensional protein structures continues to impress, reproducing uncommon features not previously observed in experimental structures is still a challenge. Furthermore, instances with conformational flexibility and large multimeric complexes highlight the need for novel scoring strategies to better emphasize biologically relevant structural regions. Looking ahead, closer integration of computational and experimental techniques will play a key role in determining the next challenges to be unraveled in the field of structural molecular biology

Recombinant HIV Envelope Proteins Fail to Engage Germline Versions of Anti-CD4bs bNAbs

Vaccine candidates for HIV-1 so far have not been able to elicit broadly neutralizing antibodies (bNAbs) although they express the epitopes recognized by bNAbs to the HIV envelope glycoprotein (Env). To understand whether and how Env immunogens interact with the predicted germline versions of known bNAbs, we screened a large panel (N:56) of recombinant Envs (from clades A, B and C) for binding to the germline predecessors of the broadly neutralizing anti-CD4 binding site antibodies b12, NIH45-46 and 3BNC60. Although the mature antibodies reacted with diverse Envs, the corresponding germline antibodies did not display Env-reactivity. Experiments conducted with engineered chimeric antibodies combining the mature and germline heavy and light chains, respectively and vice-versa, revealed that both antibody chains are important for the known cross-reactivity of these antibodies. Our results also indicate that in order for b12 to display its broad cross-reactivity, multiple somatic mutations within its VH region are required. A consequence of the failure of the germline b12 to bind recombinant soluble Env is that Env-induced B-cell activation through the germline b12 BCR does not take place. Our study provides a new explanation for the difficulties in eliciting bNAbs with recombinant soluble Env immunogens. Our study also highlights the need for intense efforts to identify rare naturally occurring or engineered Envs that may engage the germline BCR versions of bNAbs