A Composite Chiral Pair of Rotational Bands in the odd-A Nucleus 135Nd

High-spin states in 135Nd were populated with the 110Pd(30Si,5n)135Nd reaction at a 30Si bombarding energy of 133 MeV. Two Delta(I)=1 bands with close excitation energies and the same parity were observed. These bands are directly linked by Delta(I)=1 and Delta(I)=2 transitions. The chiral nature of these two bands is confirmed by comparison with three-dimensional tilted axis cranking calculations. This is the first observation of a three-quasiparticle chiral structure and established the primarily geometric nature of this phenomenon.Comment: 10 pages, 5 figures (1 in color), 1 table, submitted to Physics Review Letters, written in REVTEX4 forma

Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability

The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state

Impact of germline and somatic missense variations on drug binding sites.

Advancements in next-generation sequencing (NGS) technologies are generating a vast amount of data. This exacerbates the current challenge of translating NGS data into actionable clinical interpretations. We have comprehensively combined germline and somatic nonsynonymous single-nucleotide variations (nsSNVs) that affect drug binding sites in order to investigate their prevalence. The integrated data thus generated in conjunction with exome or whole-genome sequencing can be used to identify patients who may not respond to a specific drug because of alterations in drug binding efficacy due to nsSNVs in the target protein\u27s gene. To identify the nsSNVs that may affect drug binding, protein-drug complex structures were retrieved from Protein Data Bank (PDB) followed by identification of amino acids in the protein-drug binding sites using an occluded surface method. Then, the germline and somatic mutations were mapped to these amino acids to identify which of these alter protein-drug binding sites. Using this method we identified 12 993 amino acid-drug binding sites across 253 unique proteins bound to 235 unique drugs. The integration of amino acid-drug binding sites data with both germline and somatic nsSNVs data sets revealed 3133 nsSNVs affecting amino acid-drug binding sites. In addition, a comprehensive drug target discovery was conducted based on protein structure similarity and conservation of amino acid-drug binding sites. Using this method, 81 paralogs were identified that could serve as alternative drug targets. In addition, non-human mammalian proteins bound to drugs were used to identify 142 homologs in humans that can potentially bind to drugs. In the current protein-drug pairs that contain somatic mutations within their binding site, we identified 85 proteins with significant differential gene expression changes associated with specific cancer types. Information on protein-drug binding predicted drug target proteins and prevalence of both somatic and germline nsSNVs that disrupt these binding sites can provide valuable knowledge for personalized medicine treatment. A web portal is available where nsSNVs from individual patient can be checked by scanning against DrugVar to determine whether any of the SNVs affect the binding of any drug in the database.The Pharmacogenomics Journal advance online publication, 26 January 2016; doi:10.1038/tpj.2015.97

An Intrinsically Disordered Region of the Acetyltransferase p300 with Similarity to Prion-Like Domains Plays a Role in Aggregation

Several human diseases including neurodegenerative disorders and cancer are associated with abnormal accumulation and aggregation of misfolded proteins. Proteins with high tendency to aggregate include the p53 gene product, TAU and alpha synuclein. The potential toxicity of aberrantly folded proteins is limited via their transport into intracellular sub-compartments, the aggresomes, where misfolded proteins are stored or cleared via autophagy. We have identified a region of the acetyltransferase p300 that is highly disordered and displays similarities with prion-like domains. We show that this region is encoded as an alternative spliced variant independently of the acetyltransferase domain, and provides an interaction interface for various misfolded proteins, promoting their aggregation. p300 enhances aggregation of TAU and of p53 and is a component of cellular aggregates in both tissue culture cells and in alpha-synuclein positive Lewy bodies of patients affected by Parkinson disease. Down-regulation of p300 impairs aggresome formation and enhances cytotoxicity induced by misfolded protein stress. These data unravel a novel activity of p300, offer new insights into the function of disordered domains and implicate p300 in pathological aggregation that occurs in neurodegeneration and cancer

Low Temperature Transport and Specific Heat Studies of Nd_{1-x}Pb_{x}MnO_{3} Single Crystals

Electrical transport and specific heat properties of Nd_{1-x}Pb_{x}MnO_{3} single crystals for 0.15 < x 0.5 have been studied in low temperature regime. The resistivity in the ferromagnetic insulating (FMI) phase for x < 0.3 has an activated character. The dependence of the activation gap Delta on doping x has been determined and the critical concentration for the zero-temperature metal-insulator transition was determined as x_{c} ~ 0.33. For a metallic sample with x=0.42, a conventional electron-electron (e-e) scattering term proportional T^{2} is found in the low-temperature electrical resistivity, although the Kadowaki-Woods ratio is found to be much larger for this manganite than for a normal metal. For a metallic sample with x=0.5, a resistivity minimum is observed for x= 0.5. The effect is attributed to weak localization and can be described by a negative T^{1/2} weak-localization contribution to resistivity for a disordered three-dimensional electron system. The specific heat data have been fitted to contributions from free electrons (gamma), spin excitations (beta_{3/2}), lattice and a Schottky-like anomaly related to the rare-earth magnetism of the Nd ions. The value of gamma is larger than for normal metals, which is ascribed to magnetic ordering effects involving Nd. Also, the Schottky-like anomaly appears broadened and weakened suggesting inhomogeneous molecular fields at the Nd-sites.Comment: 14 pages, 8 figure

Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic hepatitis B: re-modelling of antiviral and regulatory mediators

Background & Aims: GS‐9688 (selgantolimod) is a toll‐like receptor 8 (TLR8) agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS‐9688 has previously been evaluated in vitro in hepatitis B virus (HBV)‐infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS‐9688 to boost responses contributing to viral control and to modulate regulatory mediators. Approach & Results: We characterised the effect of GS‐9688 on immune cell subsets in vitro in PBMC of healthy controls and CHB patients. GS‐9688 activated dendritic cells and mononuclear phagocytes to produce IL‐12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and CHB patients. GS‐9688 increased the frequency of activated natural killer (NK) cells, mucosal‐associated invariant T‐cells (MAITs), CD4+ follicular helper T‐cells (TFH) and, in ~50% of patients, HBV‐specific CD8+T‐cells expressing interferon‐γ (IFNγ). Moreover, in vitro stimulation with GS‐9688 induced NK cell expression of IFNγ and TNFα and promoted hepatocyte lysis. We also assessed whether GS‐9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS‐9688 reduced the frequency of CD4+ regulatory T‐cells and monocytic myeloid‐derived suppressor cells (MDSC). Residual MDSC expressed higher levels of negative immune regulators, galectin‐9 and PD‐L1. Conversely, GS‐9688 induced an expansion of immunoregulatory TNF‐related apoptosis‐inducing ligand+ (TRAIL) regulatory NK cells and degranulation of arginase‐I+ polymorphonuclear‐MDSC (PMN‐MDSC). Conclusions: GS‐9688 induces cytokines in human PBMC that are able to activate antiviral effector function by multiple immune mediators (HBV‐specific CD8+T‐cells, TFH, NK cells and MAITs). Whilst reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimise the antiviral efficacy of GS‐9688

Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation

Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1

LIN-44/Wnt Directs Dendrite Outgrowth through LIN-17/Frizzled in C. elegans Neurons

Nervous system function requires proper development of two functional and morphological domains of neurons, axons and dendrites. Although both these domains are equally important for signal transmission, our understanding of dendrite development remains relatively poor. Here, we show that in C. elegans the Wnt ligand, LIN-44, and its Frizzled receptor, LIN-17, regulate dendrite development of the PQR oxygen sensory neuron. In lin-44 and lin-17 mutants, PQR dendrites fail to form, display stunted growth, or are misrouted. Manipulation of temporal and spatial expression of LIN-44, combined with cell-ablation experiments, indicates that this molecule is patterned during embryogenesis and acts as an attractive cue to define the site from which the dendrite emerges. Genetic interaction between lin-44 and lin-17 suggests that the LIN-44 signal is transmitted through the LIN-17 receptor, which acts cell autonomously in PQR. Furthermore, we provide evidence that LIN-17 interacts with another Wnt molecule, EGL-20, and functions in parallel to MIG-1/Frizzled in this process. Taken together, our results reveal a crucial role for Wnt and Frizzled molecules in regulating dendrite development in vivo