AMPK in Pathogens

During host–pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host–pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.CIHR -Canadian Institutes of Health Researc

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Presidential Signing Statements and Executive Power

A recent debate about the Bush administration\u27s use of presidential signing statements has raised questions about their function, legality, and value. We argue that presidential signing statements are legal and that they provide a useful way for the president to disclose his views about the meaning and constitutionality of legislation. In addition, basic tenets of positive political theory suggest that signing statements do not undermine the separation of powers or the legislative process and that, under certain circumstances, they can provide relevant evidence of statutory meaning. Although President Bush has raised many more constitutional challenges within his signing statements than prior presidents have, at least on their face these challenges are similar to challenges made by other recent presidents, such as President Clinton. Whether Bush\u27s views of executive power are significantly different from Clinton\u27s, and if so, whether they are inferior, remain open questions, but these issues are independent of whether signing statements are lawful

BODIPY–Bacteriochlorin Energy Transfer Arrays: Toward Near-IR Emitters with Broadly Tunable, Multiple Absorption Bands

A series of energy transfer arrays, comprising a near-IR absorbing and emitting bacteriochlorin, and BODIPY derivatives with different absorption bands in the visible region (503–668 nm) have been synthesized. Absorption band of BODIPY was tuned by installation of 0, 1, or 2 styryl substituents [2-(2,4,6-trimethoxyphenyl)­ethenyl], which leads to derivatives with absorption maxima at 503, 587, and 668 nm, respectively. Efficient energy transfer (>0.90) is observed for each dyad, which is manifested by nearly exclusive emission from bacteriochlorin moiety upon BODIPY excitation. Fluorescence quantum yield of each dyad in nonpolar solvent (toluene) is comparable with that observed for corresponding bacteriochlorin monomer, and is significantly reduced in solvent of high dielectric constants (DMF), most likely by photoinduced electron transfer. Given the availability of diverse BODIPY derivatives, with absorption between 500–700 nm, BODIPY–bacteriochlorin arrays should allow for construction of near-IR emitting agents with multiple and broadly tunable absorption bands. Solvent-dielectric constant dependence of Φ_f in dyads gives an opportunity to construct environmentally sensitive fluorophores and probes

Deep-Red Emissive BODIPY–Chlorin Arrays Excitable with Green and Red Wavelengths

We report here the synthesis and characterization of BODIPY–chlorin arrays containing a chlorin subunit, with tunable deep-red (641–685 nm) emission, and one or two BODIPY moieties, absorbing at 504 nm. Two types of arrays were examined: one where BODIPY moieties are attached through a phenylacetylene linker at the 13- or 3,13-positions of chlorin, and a second type where BODIPY is attached at the 10-position of chlorin through an amide linker. Each of the examined arrays exhibits an efficient (≥0.80) energy transfer from BODIPY to the chlorin moiety in both toluene and DMF and exhibits intense fluorescence of chlorin upon excitation of BODIPY at ∼500 nm. Therefore, the effective Stokes shift in such arrays is in the range of 140–180 nm. Dyads with BODIPY attached at the 10-position of chlorin exhibit a bright fluorescence in a range of solvents with different polarities (i.e., toluene, MeOH, DMF, and DMSO). In contrast to this, some of the arrays in which BODIPY is attached at the 3- or at both 3,13-positons of chlorin exhibit significant reduction of fluorescence in polar solvents. Overall, dyads where BODIPY is attached at the 10-position of chlorin exhibit ∼5-fold brighter fluorescence than corresponding chlorin monomers, upon excitation at 500 nm

Amphiphilic BODIPY-Hydroporphyrin Energy Transfer Arrays with Broadly Tunable Absorption and Deep Red/Near-Infrared Emission in Aqueous Micelles

BODIPY-hydroporphyrin energy transfer arrays allow for development of a family of fluorophores featuring a common excitation band at 500 nm, tunable excitation band in the deep red/near-infrared window, and tunable emission. Their biomedical applications are contingent upon retaining their optical properties in an aqueous environment. Amphiphilic arrays containing PEG-substituted BODIPY and chlorins or bacteriochlorins were prepared and their optical and fluorescence properties were determined in organic solvents and aqueous surfactants. The first series of arrays contains BODIPYs with PEG substituents attached to the boron, whereas in the second series, PEG substituents are attached to the aryl at the <i>meso</i> positions of BODIPY. For both series of arrays, excitation of BODIPY at 500 nm results in efficient energy transfer to and bright emission of hydroporphyrin in the deep-red (640–660 nm) or near-infrared (740–760 nm) spectral windows. In aqueous solution of nonionic surfactants (Triton X-100 and Tween 20) arrays from the second series exhibit significant quenching of fluorescence, whereas properties of arrays from the first series are comparable to those observed in polar organic solvents. Reported arrays possess large effective Stokes shift (115–260 nm), multiple excitation wavelengths, and narrow, tunable deep-red/near-IR fluorescence in aqueous surfactants, and are promising candidates for a variety of biomedical-related applications