Antagonists of the stress and opioid systems restore the functional connectivity of the prefrontal cortex during alcohol withdrawal through divergent mechanisms.

Chronic alcohol consumption leads to dependence and withdrawal symptoms upon cessation, contributing to persistent use. However, the brain network mechanisms by which the brain orchestrates alcohol withdrawal and how these networks are affected by pharmacological treatments remain elusive. Recent work revealed that alcohol withdrawal produces a widespread increase in coordinated brain activity and a decrease in modularity of the whole-brain functional network using single-cell whole-brain imaging of immediate early genes. This decreased modularity and functional hyperconnectivity are hypothesized to be novel biomarkers of alcohol withdrawal in alcohol dependence, which could potentially be used to evaluate the efficacy of new medications for alcohol use disorder. However, there is no evidence that current FDA-approved medications or experimental treatments known to reduce alcohol drinking in animal models can normalize the changes in whole-brain functional connectivity. In this report, we tested the effect of R121919, a CRF1 antagonist, and naltrexone, an FDA-approved treatment for alcohol use disorder, on whole-brain functional connectivity using the cellular marker FOS combined with graph theory and advanced network analyses. Results show that both R121919 and naltrexone restored the functional connectivity of the prefrontal cortex during alcohol withdrawal, but through divergent mechanisms. Specifically, R121919 increased FOS activation in the prefrontal cortex, partially restored modularity, and normalized connectivity, particularly in CRF1-rich regions, including the prefrontal, pallidum, and extended amygdala circuits. On the other hand, naltrexone decreased FOS activation throughout the brain, decreased modularity, and increased connectivity overall except for the Mu opioid receptor-rich regions, including the thalamus. These results identify the brain networks underlying the pharmacological effects of R121919 and naltrexone and demonstrate that these drugs restored different aspects of functional connectivity of the prefrontal cortex, pallidum, amygdala, and thalamus during alcohol withdrawal. Notably, these effects were particularly prominent in CRF1- and Mu opioid receptors-rich regions highlighting the potential of whole-brain functional connectivity using FOS as a tool for identifying neuronal network mechanisms underlying the pharmacological effects of existing and new medications for alcohol use disorder.

Furan oxidation based cross-linking: a new approach for the study and targeting of nucleic acid and protein interactions.

Furan mediated nucleic acid cross-linking, initially developed for DNA interstrand duplex cross-linking, has matured into a versatile tool for the study of protein and nucleic acid interactions, ready to face its applications. The methodology was initially developed for easy and clean chemical generation of DNA interstrand cross-linked duplexes, but has been further expanded for use with other probes, targets and triggers, now allowing mild biologically significant cross-linking with potential therapeutic benefit. It was shown that the methodology could be repurposed for RNA interstrand cross-linking, which is very relevant in today's antisense approaches or miRNA target identification endeavors. This further illustrates the furan oxidation method's generality and mildness, especially when using red light for oxidation. A complementary antigene approach has been explored through duplex targeting with furan modified triplex forming oligonucleotides (TFOs) and DNA binding proteins. Also targeting of peptides and proteins by furan-modified DNA and peptides has been explored. Thorough methodology examination exploring variable reaction conditions in combination with a series of different furan-modified building blocks and application of different activation signals resulted in a detailed understanding of the mechanisms involved and factors influencing the yield and selectivity of the reaction. In order to draw the bigger picture of the scope and limitations of furan-oxidation cross-linking, we here provide a unique side by side comparison and discussion of our published data, supplemented with unpublished results, providing a clear performance report of the currently established furan toolbox and its application potential in various biomacromolecular complexes.

A mildly inducible and selective cross-link methodology for RNA duplexes.

We here report on the furan oxidation methodology for interstrand cross-linking of RNA duplexes, which have a different structure and are more stiff, reactive and labile than their DNA counterparts. Through this mildly inducible approach, natural unmodified RNA can be selectively cross-linked in high yield. The method therefore has direct applications in the increasing number of RNA based technologies.

Fuel cells: principles, types, fuels, and applications.

During the last decade, fuel cells have received enormous attention from research institutions and companies as novel electrical energy conversion systems. In the near future, they will see application in automotive propulsion, distributed power generation, and in low power portable devices (battery replacement). This review gives an introduction into the fundamentals and applications of fuel cells: Firstly, the environmental and social factors promoting fuel cell development are discussed, with an emphasis on the advantages of fuel cells compared to the conventional techniques. Then, the main reactions, which are responsible for the conversion of chemical into electrical energy in fuel cells, are given and the thermodynamic and kinetic fundamentals are stated. The theoretical and real efficiencies of fuel cells are also compared to that of internal combustion engines. Next, the different types of fuel cells and their main components are explained and the related material issues are presented. A section is devoted to fuel generation and storage, which is of paramount importance for the practical aspects of fuel cell use. Finally, attention is given to the integration of the fuel cells into complete systems.