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Porphyrinoids are robust heterocyclic dyes studied extensively for their applications in medicine and as photonic materials because of their tunable photophysical properties, diverse means of modifying the periphery, and the ability to chelate most transition metals. Commercial applications include their use as phthalocyanine dyes in optical discs, porphyrins in photodynamic therapy, and as oxygen sensors. Most applications of these dyes require exocyclic moieties to improve solubility, target diseases, modulate photophysical properties, or direct the self-organization into architectures with desired photonic properties. The synthesis of the porphyrinoid depends on the desired application, but the de novo synthesis often involves several steps, is time consuming, and results in low isolated yields. Thus, the application of core porphyrinoid platforms that can be rapidly and efficiently modified to evaluate new molecular architectures allows researchers to focus on the design concepts rather than the synthesis methods, and opens porphyrinoid chemistry to a broader scientific community. We have focused on several widely available, commercially viable porphyrinoids as platforms: meso-perfluorophenylporphyrin, perfluorophthalocyanine, and meso-perfluorophenylcorrole. The perfluorophenylporphyrin is readily converted to the chlorin, bacteriochlorin, and isobacteriochlorin. Derivatives of all six of these core platforms can be efficiently and controllably made via mild nucleophilic aromatic substitution reactions using primary S, N, and O nucleophiles bearing a wide variety of functional groups. The remaining fluoro groups enhance the photo and oxidative stability of the dyes and can serve as spectroscopic signatures to characterize the compounds or in imaging applications using F-19 NMR. This review provides an overview of the chemistry of fluorinated porphyrinoids that are being used as a platform to create libraries of photo-active compounds for applications in medicine and materials.

Epigenetic alterations are necessary for the establishment of functional and phenotypic diversity in the populations of immune cells of the monocytic lineage. The epigenetic status of individual genes at different time points defines their transcriptional responses throughout development and in response to environmental stimuli. Epigenetic states are defined at the level of DNA modifications, chromatin modifications, as well as at the level of RNA base changes through RNA editing. Drawing from lessons regarding the epigenome and epitranscriptome of cells of the monocytic lineage in the periphery, and from recently published RNAseq data deriving from brain resident monocytes, we discuss the impact of modulation of these epigenetic states and how they affect processes important for the development of a healthy brain, as well as mechanisms of neurodegenerative disease and aging. An understanding of the varied brain responses and pathologies in light of these novel gene regulatory systems in monocytes will lead to important new insights in the understanding of the aging process and the treatment and diagnosis of neurodegenerative disease.

A measurement is presented of differential cross sections for Higgs boson (H) production in pp collisions at root s = 8 TeV. The analysis exploits the H -> gamma gamma decay in data corresponding to an integrated luminosity of 19.7 fb(-1) collected by the CMS experiment at the LHC. The cross section is measured as a function of the kinematic properties of the diphoton system and of the associated jets. Results corrected for detector effects are compared with predictions at next-to-leading order and next-to-next-to-leading order in perturbative quantum chromodynamics, as well as with predictions beyond the standard model. For isolated photons with pseudorapidities vertical bar eta vertical bar < 2.5, and with the photon of largest and next-to-largest transverse momentum (p(T)(gamma)) divided by the diphoton mass m(gamma gamma) satisfying the respective conditions of p(T)(gamma)/m(gamma gamma) > 1/3 and > 1/4, the total fiducial cross section is 32 +/- 10 fb.

The exocyst is a hetero-octameric complex that has been proposed to serve as the tethering complex for exocytosis, although it remains poorly understood at the molecular level. Here, we purified endogenous exocyst complexes from Saccharomyces cerevisiae and showed that they are stable and consist of all eight subunits with equal stoichiometry. Using a combination of biochemical and auxin induced-degradation experiments in yeast, we mapped the subunit connectivity, identified two stable four-subunit modules within the octamer and demonstrated that several known exocyst-binding partners are not necessary for exocyst assembly and stability. Furthermore, we visualized the structure of the yeast complex by using negative-stain electron microscopy; our results indicate that the exocyst exists predominantly as a stable, octameric complex with an elongated architecture that suggests that the subunits are contiguous helical bundles packed together into a bundle of long rods.

In most chemokine receptors, one or multiple tyrosine residues have been identified within the receptor N-terminal domain that are, at least partially, modified by posttranslational tyrosine sulfation. For example, tyrosine sulfation has been demonstrated for Tyr-3, -10, -14, and -15 of CCR5, for Tyr-3, -14, and -15 of CCR8, and for Tyr-7, -12, and -21 of CXCR4. While there is evidence for several chemokine receptors that tyrosine sulfation is required for optimal interaction with the chemokine ligands, the precise role of tyrosine sulfation for chemokine receptor function remains unclear. Furthermore, the function of the chemokine receptor N-terminal domain in chemokine binding and receptor activation is also not well understood. Sulfotyrosine peptides corresponding to the chemokine receptor N-termini are valuable tools to address these important questions both in structural and functional studies. However, due to the lability of the sulfotyrosine modification, these peptides are difficult to obtain using standard peptide chemistry methods. In this chapter, we provide methods to prepare sulfotyrosine peptides by enzymatic in vitro sulfation of peptides using purified recombinant tyrosylprotein sulfotransferase (TPST) enzymes. In addition, we also discuss alternative approaches for the generation of sulfotyrosine peptides and methods for sulfopeptide analysis.

The classical theorem of M. Riesz about the conjugate harmonic functions is extended onto octonion-valued monogenic functions.

Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce A beta(42) production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for A beta(42) inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a beta- and gamma-secretases-dependent, 2-10 fold increase in the production of extracellular A beta(42) in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of A beta peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familialAD(FAD) patient (A beta PP K724N) produced more A beta(42) versus A beta(40) than neurons derived from healthy controls iPSCs (A beta PP WT). Triazines enhanced A beta(42) production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadein alpha, another gamma-secretase substrate, suggesting a direct effect of triazines on gamma-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone A beta(42)/A beta(43) amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

Non-fibrillar soluble oligomeric forms of amyloid-beta peptide (oA beta) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oA beta initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of A beta, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oA beta levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oA beta to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and A beta on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with A beta and tau pathology.

Plasmodium salivary sporozoites are the infectious form of the malaria parasite and are dormant inside salivary glands of Anopheles mosquitoes. During dormancy, protein translation is inhibited by the kinase UIS1 that phosphorylates serine 59 in the eukaryotic initiation factor 2 alpha (eIF2 alpha). De-phosphorylation of eIF2 alpha-P is required for the transformation of sporozoites into the liver stage. In mammalian cells, the de-phosphorylation of eIF2 alpha-P is mediated by the protein phosphatase 1 (PP1). Using a series of genetically knockout parasites we showed that in malaria sporozoites, contrary to mammalian cells, the eIF2 alpha-P phosphatase is a member of the PP2C/PPM phosphatase family termed UIS2. We found that eIF2 alpha was highly phosphorylated in uis2 conditional knockout sporozoites. These mutant sporozoites maintained the crescent shape after delivery into mammalian host and lost their infectivity. Both uis1 and uis2 were highly transcribed in the salivary gland sporozoites but uis2 expression was inhibited by the Pumilio protein Puf2. The repression of uis2 expression was alleviated when sporozoites developed into liver stage. While most eukaryotic phosphatases interact transiently with their substrates, UIS2 stably bound to phosphorylated eIF2 alpha, raising the possibility that high-throughput searches may identify chemicals that disrupt this interaction and prevent malaria infection.

We present a novel data analysis strategy which combined with subcellular fractionation and liquid chromatography-mass spectrometry (LC-MS) based proteomics provides a simple and effective workflow for global drug profiling. Five subcellular fractions were obtained by differential centrifugation followed by high resolution LC-MS and complete functional regulation analysis. The methodology combines functional regulation and enrichment analysis into a single visual summary. The workflow enables improved insight into perturbations caused by drugs. We provide a statistical argument to demonstrate that even crude subcellular fractions leads to improved functional characterization. We demonstrate this data analysis strategy on data obtained in a MS-based global drug profiling study. However, this strategy can also be performed on other types of large scale biological data.