74 research outputs found
Formal Insertion of Alkenes Into C(sp3)−F Bonds Mediated by Fluorine-Hydrogen Bonding
C−F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C−F bonds and the low reactivity of the fluoride released upon C−F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C−F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C−F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides
Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols
A series of 2-(perfluoroalkylthio)benzothiazolium (BT-SRF) salts have been synthesized that serve as convenient sources of hitherto underexplored perfluoroalkylthiolate anions. An investigation of their reactivity in a deoxygenative nucleophilic substitution reaction led to the development of an unprecedented process that provides pentafluoroethyl and heptafluoropropyl thioethers directly from readily available alcohols
Integrating Signals from the T-Cell Receptor and the Interleukin-2 Receptor
T cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells
Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages
notes: PMCID: PMC4006850types: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov'tCandida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non-matured phagosomes is likely not triggered by initial recognition events via MAPK or NFκB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata.Deutsche ForschungsgemeinschaftNational Institutes for HealthWellcome TrustBBSR
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Grammatical aspect influences event duration estimations: Evidence from Dutch
Item does not contain fulltextThis study investigates the effect of grammatical aspect marking in Dutch sentences, on speakers’ estimations of the duration of highly familiar, everyday events. We first established the ‘inherent’ or natural duration of different events (Exp. 1). This was then used for the manipulation of aspect (Exp. 2). Participants dragged a slider across the computer screen to estimate the duration of progressive and non-progressive event descriptions. Findings show how the progressive form extends duration estimations for short events, whereas it shortens the perceived duration of inherently medium and long events. We interpret this as psycholinguistic evidence for the function of aspect in Dutch, i.e., giving an ‘inside’ view of the event and focusing a specific internal time span of the event
There is no prime for time: the missing link between form and concept of progressive aspect in L2 production
The acquisition of linguistic structures that require perspective-taking at the level of message generation is challenging. We investigate use of progressive aspect in L2 event encoding, using a sentence priming paradigm. We focus on Dutch, in which use of progressive aspect is optional. The progressive consists of a prepositional phrase (‘aan het,’ at-the), plus a verbal infinitive. We ask, to what extent L2 speakers, in comparison to native speakers, show priming effects in relation to form (prepositional phrase) or conceptual (progressive aspect) prime sentences. In native Dutch speakers we find a priming effect for the ‘progressive prime,’ compared to a ‘neutral prime’ (aspectually neutral event description). In L2 speakers this effect was absent. For the form prime, no priming effects were obtained in native speakers, rather, we find evidence for a partial blocking effect in L2 speakers. Results suggest that the strength of the link between concept and form of progressive aspect differs in native and L2 speakers. Specific factors contributed to the L2 findings, e.g., level of L2 proficiency and degree of L2 exposure. We conclude that (1) the conceptual basis of grammatical aspect can be primed in native speakers, and (2) in L2 speakers, access to conceptual information is less automatized
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First things first? Top-down influences on event apprehension
Not much is known about event apprehension, the earliest stage of information processing in elicited language production studies, using pictorial stimuli. A reason for our lack of knowledge on this process is that apprehension happens very rapidly (<350 ms after stimulus onset, Griffin & Bock 2000), making it difficult to measure the process directly. To broaden our understanding of apprehension, we analyzed landing positions and onset latencies of first fixations on visual stimuli (pictures of real-world events) given short stimulus presentation times, presupposing that the first fixation directly results from information processing during apprehensio
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