2-(Biphenyl-4-yl)acetic acid (felbinac)

The structure of the title compound, C14H12O2, displays the expected inter­molecular hydrogen bonding of the carb­oxy­lic acid groups, forming dimers. The dihedral angle between the two aromatic rings is 27.01 (7)°

Doublet-Triplet Splitting and Fermion Masses with Extra Dimensions

The pseudo-Goldstone boson mechanism for the ``doublet-triplet splitting'' problem of the grand unified theory can be naturally implemented in the scenario with extra dimensions and branes. The two SU(6) global symmetries of the Higgs sector are located on two separate branes while the SU(6) gauge symmetry is in the bulk. After including several vector-like fields in the bulk, and allowing the most general interactions with their natural strength (including the higher dimensional ones which may be generated by gravity) which are consistent with the geometry, a realistic pattern of the Standard Model fermion masses and mixings can be naturally obtained without any flavor symmetry. Neutrino masses and mixings required for the solar and atmospheric neutrino problems can also be accommodated. The geometry of extra dimensions and branes provides another way to realize the absence of certain interactions (as required in the pseudo-Goldstone boson mechanism) or the smallness of some couplings (e.g., the Yukawa couplings between the fermions and the Higgs bosons), in addition to the usual symmetry arguments.Comment: 16 pages, 4 figures, LaTeX, references and some clarifying remarks added, to be published in Phys. Rev.

Multiple functions of CXCL12 in a syngeneic model of breast cancer

BACKGROUND: A growing body of work implicates chemokines, in particular CXCL12 and its receptors, in the progression and site-specific metastasis of various cancers, including breast cancer. Various agents have been used to block the CXCL12-CXCR4 interaction as a means of inhibiting cancer metastasis. However, as a potent chemotactic factor for leukocytes, CXCL12 also has the potential to enhance anti-cancer immunity. To further elucidate its role in breast cancer progression, CXCL12 and its antagonist CXCL12(P2G) were overexpressed in the syngeneic 4T1.2 mouse model of breast carcinoma. RESULTS: While expression of CXCL12(P2G) significantly inhibited metastasis, expression of wild-type CXCL12 potently inhibited both metastasis and primary tumor growth. The effects of wild-type CXCL12 were attributed to an immune response characterized by the induction of CD8+ T cell activity, enhanced cell-mediated cytotoxicity, increased numbers of CD11c+ cells in the tumor-draining lymph nodes and reduced accumulation of myeloid-derived suppressor cells in the spleen.CONCLUSIONS: This study highlights the need to consider carefully therapeutic strategies that block CXCL12 signaling. Therapies that boost CXCL12 levels at the primary tumor site may prove more effective in the treatment of metastatic breast cancer.Sharon A Williams, Yuka Harata-Lee, Iain Comerford, Robin L Anderson, Mark J Smyth and Shaun R McCol

Ultrastructural and functional fate of recycled vesicles in hippocampal synapses

Efficient recycling of synaptic vesicles is thought to be critical for sustained information transfer at central terminals. However, the specific contribution that retrieved vesicles make to future transmission events remains unclear. Here we exploit fluorescence and time-stamped electron microscopy to track the functional and positional fate of vesicles endocytosed after readily releasable pool (RRP) stimulation in rat hippocampal synapses. We show that most vesicles are recovered near the active zone but subsequently take up random positions in the cluster, without preferential bias for future use. These vesicles non-selectively queue, advancing towards the release site with further stimulation in an actin-dependent manner. Nonetheless, the small subset of vesicles retrieved recently in the stimulus train persist nearer the active zone and exhibit more privileged use in the next RRP. Our findings reveal heterogeneity in vesicle fate based on nanoscale position and timing rules, providing new insights into the origins of future pool constitution

Neutrino oscillation experiments and limits on lepton-number and lepton-flavor violating processes

Using a three neutrino framework we investigate bounds for the effective Majorana neutrino mass matrix. The mass measured in neutrinoless double beta decay is its (11) element. Lepton-number and -flavor violating processes sensitive to each element are considered and limits on branching ratios or cross sections are given. Those processes include $\mu^- e^+$ conversion, $K^+ \to \pi^- \mu^+ \mu^+$ or recently proposed high-energy scattering processes at HERA. Including all possible mass schemes, the three solar solutions and other allowed possibilities, there is a total of 80 mass matrices. The obtained indirect limits are up to 14 orders of magnitude more stringent than direct ones. It is investigated how neutrinoless double beta decay may judge between different mass and mixing schemes as well as solar solutions. Prospects for detecting processes depending on elements of the mass matrix are also discussed.Comment: 16 pages, 2 figure

Multivalent binding of PWWP2A to H2A.Z regulates mitosis and neural crest differentiation

Replacement of canonical histones with specialized histone variants promotes altering of chromatin structure and function. The essential histone variant H2A.Z affects various DNA-based processes via poorly understood mechanisms. Here, we determine the comprehensive interactome of H2A.Z and identify PWWP2A as a novel H2A.Z-nucleosome binder. PWWP2A is a functionally uncharacterized, vertebrate-specific protein that binds very tightly to chromatin through a concerted multivalent binding mode. Two internal protein regions mediate H2A.Z-specificity and nucleosome interaction, whereas the PWWP domain exhibits direct DNA binding. Genome-wide mapping reveals that PWWP2A binds selectively to H2A.Z-containing nucleosomes with strong preference for promoters of highly transcribed genes. In human cells, its depletion affects gene expression and impairs proliferation via a mitotic delay. While PWWP2A does not influence H2A.Z occupancy, the C-terminal tail of H2A.Z is one important mediator to recruit PWWP2A to chromatin. Knockdown of PWWP2A in Xenopus results in severe cranial facial defects, arising from neural crest cell differentiation and migration problems. Thus, PWWP2A is a novel H2A.Z-specific multivalent chromatin binder providing a surprising link between H2A.Z, chromosome segregation, and organ development

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Effect of compound kushen injection, a natural compound mixture, and its identified chemical components on migration and invasion of colon, brain, and breast cancer cell lines

Traditional Chinese Medicines are promising sources of new agents for controlling cancer metastasis. Compound Kushen Injection (CKI), prepared from medicinal plants Sophora flavescens and Heterosmilax chinensis, disrupts cell cycle and induces apoptosis in breast cancer; however, effects on migration and invasion remained unknown. CKI, fractionated mixtures, and isolated components were tested in migration assays with colon (HT-29, SW-480, DLD-1), brain (U87-MG, U251-MG), and breast (MDA-MB-231) cancer cell lines. Human embryonic kidney (HEK-293) and human foreskin fibroblast (HFF) served as non-cancerous controls. Wound closure, transwell invasion, and live cell imaging showed CKI reduced motility in all eight lines. Fractionation and reconstitution of CKI demonstrated combinations of compounds were required for activity. Live cell imaging confirmed CKI strongly reduced migration of HT-29 and MDA-MB-231 cells, moderately slowed brain cancer cells, and had a small effect on HEK-293. CKI uniformly blocked invasiveness through extracellular matrix. Apoptosis was increased by CKI in breast cancer but not in non-cancerous lines. Cell viability was unaffected by CKI in all cell lines. Transcriptomic analyses of MDA-MB-231indicated down-regulation of actin cytoskeletal and focal adhesion genes with CKI treatment, consistent with observed impairment of cell migration. The pharmacological complexity of CKI is important for effective blockade of cancer migration and invasion.Saeed Nourmohammadi, Thazin Nwe Aung, Jian Cui, Jinxin V. Pei, Michael Lucio De Ieso, Yuka Harata-Lee, Zhipeng Qu, David L. Adelson, and Andrea J. Yoo

Fractional deletion of Compound Kushen Injection indicates cytokine signaling pathways are critical for its perturbation of the cell cycle

Published online: 02 October 2019We used computational and experimental biology approaches to identify candidate mechanisms of action of aTraditional Chinese Medicine, Compound Kushen Injection (CKI), in a breast cancer cell line (MDA-MB-231). Because CKI is a complex mixture of plant secondary metabolites, we used a high-performance liquid chromatography (HPLC) fractionation and reconstitution approach to define chemical fractions required for CKI to induce apoptosis. The initial fractionation separated major from minor compounds, and it showed that major compounds accounted for little of the activity of CKI. Furthermore, removal of no single major compound altered the effect of CKI on cell viability and apoptosis. However, simultaneous removal of two major compounds identified oxymatrine and oxysophocarpine as critical with respect to CKI activity. Transcriptome analysis was used to correlate compound removal with gene expression and phenotype data. Many compounds in CKI are required to trigger apoptosis but significant modulation of its activity is conferred by a small number of compounds. In conclusion, CKI may be typical of many plant based extracts that contain many compounds in that no single compound is responsible for all of the bioactivity of the mixture and that many compounds interact in a complex fashion to influence a network containing many targets.T. N . Aung, S. Nourmohammadi, Z. Qu, Y. Harata-Lee, J. Cui, H. Y. Shen, A. J. Yool, T. Pukala, Hong Du, R. D. Kortschak, W. Wei, D. L. Adelso

ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot

Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots