F.A.R.O.G. FORUM, Vol. 6 No. 4

https://digitalcommons.library.umaine.edu/francoamericain_forum/1065/thumbnail.jp

Alien Registration- Lajoie, Jeanne (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/28740/thumbnail.jp

Alien Registration- Lajoie, Jeanne (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/28740/thumbnail.jp

New Insights in Vanishing White Matter Disease: Isolated Bilateral Optic Neuropathy in Adult-Onset Disease: Response.

International audienc

NaCl-induced modulation of species distribution in a mixed P. aeruginosa / S. aureus /B. cepacia biofilm

Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia are notorious pathogens known for their ability to form resilient biofilms, particularly within the lung environment of cystic fibrosis (CF) patients. The heightened concentration of NaCl, prevalent in the airway liquid of CF patients' lungs, has been identified as a factor that promotes the growth of osmotolerant bacteria like S. aureus and dampens host antibacterial defenses, thereby fostering favorable conditions for infections.In this study, we aimed to investigate how increased NaCl concentrations impact the development of multi-species biofilms in vitro, using both laboratory strains and clinical isolates of P. aeruginosa, S. aureus, and B. cepacia co-cultures. Employing a low-nutrient culture medium that fosters biofilm growth of the selected species, we quantified biofilm formation through a combination of adherent CFU counts, qPCR analysis, and confocal microscopy observations.Our findings reaffirmed the challenges faced by S. aureus in establishing growth within 1:1 mixed biofilms with P. aeruginosa when cultivated in a minimal medium. Intriguingly, at an elevated NaCl concentration of 145 mM, a symbiotic relationship emerged between S. aureus and P. aeruginosa, enabling their co-existence. Notably, this hyperosmotic environment also exerted an influence on the interplay of these two bacteria with B. cepacia. We demonstrated that elevated NaCl concentrations play a pivotal role in orchestrating the distribution of these three species within the biofilm matrix.Furthermore, our study unveiled the beneficial impact of NaCl on the biofilm growth of clinically relevant mucoid P. aeruginosa strains, as well as two strains of methicillin-sensitive and methicillin-resistant S. aureus. This underscores the crucial role of the microenvironment during the colonization and infection processes. The results suggest that hyperosmotic conditions could hold the key to unlocking a deeper understanding of the genesis and behavior of CF multi-species biofilms

The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules

We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the \u3b1-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the \u3b1-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy. \ua9 2011 Nature America, Inc. All rights reserved

Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of Pseudomonas aeruginosa Quorum Sensing Signal as New Anti-Biofilm Agents

International audienceBiofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in particular, is a “critical priority” pathogen, responsible for severe infections, especially in cystic fibrosis patients because of its capacity to form resistant biofilms. Therefore, new therapeutic approaches are needed to complete the pipeline of molecules offering new targets and modes of action. Biofilm formation is mainly controlled by Quorum Sensing (QS), a communication system based on signaling molecules. In the present study, we employed a molecular docking approach (Autodock Vina) to assess two series of chromones-based compounds as possible ligands for PqsR, a LuxR-type receptor. Most compounds showed good predicted affinities for PqsR, higher than the PQS native ligand. Encouraged by these docking results, we synthesized a library of 34 direct and 25 retro chromone carboxamides using two optimized routes from 2-chromone carboxylic acid as starting material for both series. We evaluated the synthesized carboxamides for their ability to inhibit the biofilm formation of P. aeruginosa in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of P. aeruginosa biofilms (16/25 compound with % inhibition ≥ 50% at 50 μM), without cytotoxicity on Vero cells (IC50 > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (6n) was the most promising antibiofilm compound, with potential for hit to lead optimization

Application of calibrated fMRI in Alzheimer's disease

Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO2). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO2 values fell within the range from previous studies using positron emission tomography (PET) with 15O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO2 can be imaged with 15O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function. Keywords: Calibrated fMRI, Alzheimer's disease, Cerebral blood flow, Oxidative metabolism, Oxygen extraction fraction, BOLD calibration constant, Cerebrovascular reactivit

The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules

We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy