Early brainstem [18F]THK5351 uptake is linked to cortical hyper-excitability in healthy aging

BACKGROUND: Neuronal hyper-excitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-beta (Aβ) protein accumulation, both central to AD neuropathology, promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau, and its associated neuroinflammation, and cortical Aβ aggregations remains unknown. METHODS: We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late middle-aged individuals (50-69 y; 45 women). We assessed whole-brain [18F]THK5351 positron emission tomography (PET) uptake as a proxy measure of tau/neuroinflammation, and whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers. RESULTS: We find that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment is associated with increased cortical excitability (r = .29, p = .02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (pFWE-corrected < .001), was not significantly associated with cortical excitability (r = .14, p = .25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = -.20, p = .11). CONCLUSION: These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans. TRIAL REGISTRATION: EudraCT 2016-001436-35. FUNDING: F.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund

Modeling [F-18]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection

peer reviewedThe selectivity of [F-18]MPPF (fluorine-18-labeled 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [F-18]MPPF, dynamic positron emission tomography (PET) data Were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: F-v (vascular fraction). K-1, k(2) (plasma/free compartment exchange rate). k(off). k(on)/V-r (association and dissociation rate), B-max (receptor concentration), and to deduce K-d (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential Were compared With indices generated by Logan-Patlak graphical analysis. The 5HT(1A) specificity for MPPF was evidenced. A B-max of 2.9 pmol/mL and a K-d of 2.8 nmol/L were found in hippocampal regions, K-d and distribution volume in the free compartment were regionally stable. and the Logan binding potential was linearly correlated to B-max. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols

Recent Advances in Graph Partitioning

We survey recent trends in practical algorithms for balanced graph partitioning together with applications and future research directions

New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.Eur-Intafa

Lung Epithelial Injury by B. Anthracis Lethal Toxin Is Caused by MKK-Dependent Loss of Cytoskeletal Integrity

Bacillus anthracis lethal toxin (LT) is a key virulence factor of anthrax and contributes significantly to the in vivo pathology. The enzymatically active component is a Zn2+-dependent metalloprotease that cleaves most isoforms of mitogen-activated protein kinase kinases (MKKs). Using ex vivo differentiated human lung epithelium we report that LT destroys lung epithelial barrier function and wound healing responses by immobilizing the actin and microtubule network. Long-term exposure to the toxin generated a unique cellular phenotype characterized by increased actin filament assembly, microtubule stabilization, and changes in junction complexes and focal adhesions. LT-exposed cells displayed randomly oriented, highly dynamic protrusions, polarization defects and impaired cell migration. Reconstitution of MAPK pathways revealed that this LT-induced phenotype was primarily dependent on the coordinated loss of MKK1 and MKK2 signaling. Thus, MKKs control fundamental aspects of cytoskeletal dynamics and cell motility. Even though LT disabled repair mechanisms, agents such as keratinocyte growth factor or dexamethasone improved epithelial barrier integrity by reducing cell death. These results suggest that co-administration of anti-cytotoxic drugs may be of benefit when treating inhalational anthrax

Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness.

BACKGROUND: Mechanisms of anesthesia-induced loss of consciousness remain poorly understood. Resting-state functional magnetic resonance imaging allows investigating whole-brain connectivity changes during pharmacological modulation of the level of consciousness. METHODS: Low-frequency spontaneous blood oxygen level-dependent fluctuations were measured in 19 healthy volunteers during wakefulness, mild sedation, deep sedation with clinical unconsciousness, and subsequent recovery of consciousness. RESULTS: Propofol-induced decrease in consciousness linearly correlates with decreased corticocortical and thalamocortical connectivity in frontoparietal networks (i.e., default- and executive-control networks). Furthermore, during propofol-induced unconsciousness, a negative correlation was identified between thalamic and cortical activity in these networks. Finally, negative correlations between default network and lateral frontoparietal cortices activity, present during wakefulness, decreased proportionally to propofol-induced loss of consciousness. In contrast, connectivity was globally preserved in low-level sensory cortices, (i.e., in auditory and visual networks across sedation stages). This was paired with preserved thalamocortical connectivity in these networks. Rather, waning of consciousness was associated with a loss of cross-modal interactions between visual and auditory networks. CONCLUSIONS: Our results shed light on the functional significance of spontaneous brain activity fluctuations observed in functional magnetic resonance imaging. They suggest that propofol-induced unconsciousness could be linked to a breakdown of cerebral temporal architecture that modifies both within- and between-network connectivity and thus prevents communication between low-level sensory and higher-order frontoparietal cortices, thought to be necessary for perception of external stimuli. They emphasize the importance of thalamocortical connectivity in higher-order cognitive brain networks in the genesis of conscious perception

Computational analysis of the evolutionarily conserved Missing In Metastasis/Metastasis Suppressor 1 gene predicts novel interactions, regulatory regions and transcriptional control

Missing in Metastasis (MIM), or Metastasis Suppressor 1 (MTSS1), is a highly conserved protein, which links the plasma membrane to the actin cytoskeleton. MIM has been implicated in various cancers, however, its modes of action remain largely enigmatic. Here, we performed an extensive in silico characterisation of MIM to gain better understanding of its function. We detected previously unappreciated functional motifs including adaptor protein (AP) complex interaction site and a C-helix, pointing to a role in endocytosis and regulation of actin dynamics, respectively. We also identified new functional regions, characterised with phosphorylation sites or distinct hydrophilic properties. Strong negative selection during evolution, yielding high conservation of MIM, has been combined with positive selection at key sites. Interestingly, our analysis of intra-molecular co-evolution revealed potential regulatory hotspots that coincided with reduced potentially\ua0pathogenic polymorphisms. We explored databases for the mutations and expression levels of MIM in cancer. Experimentally, we focused on chronic lymphocytic leukaemia (CLL), where MIM showed high overall expression, however, downregulation on poor prognosis samples. Finally, we propose strong conservation of MTSS1 also on the transcriptional level and predict novel transcriptional regulators. Our data highlight important targets for future studies on the role of MIM in different tissues and cancers

Brain Responses to Violet, Blue, and Green Monochromatic Light Exposures in Humans: Prominent Role of Blue Light and the Brainstem

BACKGROUND: Relatively long duration retinal light exposure elicits nonvisual responses in humans, including modulation of alertness and cognition. These responses are thought to be mediated in part by melanopsin-expressing retinal ganglion cells which are more sensitive to blue light than violet or green light. The contribution of the melanopsin system and the brain mechanisms involved in the establishment of such responses to light remain to be established. METHODOLOGY/PRINCIPAL FINDINGS: We exposed 15 participants to short duration (50 s) monochromatic violet (430 nm), blue (473 nm), and green (527 nm) light exposures of equal photon flux (10(13)ph/cm(2)/s) while they were performing a working memory task in fMRI. At light onset, blue light, as compared to green light, increased activity in the left hippocampus, left thalamus, and right amygdala. During the task, blue light, as compared to violet light, increased activity in the left middle frontal gyrus, left thalamus and a bilateral area of the brainstem consistent with activation of the locus coeruleus. CONCLUSION/SIGNIFICANCE: These results support a prominent contribution of melanopsin-expressing retinal ganglion cells to brain responses to light within the very first seconds of an exposure. The results also demonstrate the implication of the brainstem in mediating these responses in humans and speak for a broad involvement of light in the regulation of brain function