Reviewing Atrial Fibrillation Pathophysiology from a Network Medicine Perspective: The Relevance of Structural Remodeling, Inflammation, and the Immune System.

Atrial fibrillation (AF) is the most common type of sustained arrhythmia. The numerous gaps concerning the knowledge of its mechanism make improving clinical management difficult. As omics technologies allow more comprehensive insight into biology and disease at a molecular level, bioinformatics encompasses valuable tools for studying systems biology, as well as combining and modeling multi-omics data and networks. Network medicine is a subarea of network biology where disease traits are considered perturbations within the interactome. With this approach, potential disease drivers can be revealed, and the effect of drugs, novel or repurposed, used alone or in combination, may be studied. Thus, this work aims to review AF pathology from a network medicine perspective, helping researchers to comprehend the disease more deeply. Essential concepts involved in network medicine are highlighted, and specific research applying network medicine to study AF is discussed. Additionally, data integration through literature mining and bioinformatics tools, with network building, is exemplified. Together, all of the data show the substantial role of structural remodeling, the immune system, and inflammation in this disease etiology. Despite this, there are still gaps to be filled about AF.

Circadian Structural Plasticity Drives Remodeling of E Cell Output.

Behavioral outputs arise as a result of highly regulated yet flexible communication among neurons. The Drosophila circadian network includes 150 neurons that dictate the temporal organization of locomotor activity; under light-dark (LD) conditions, flies display a robust bimodal pattern. The pigment-dispersing factor (PDF)-positive small ventral lateral neurons (sLNv) have been linked to the generation of the morning activity peak (the "M cells"), whereas the Cryptochrome (CRY)-positive dorsal lateral neurons (LNds) and the PDF-negative sLNv are necessary for the evening activity peak (the "E cells") [1, 2]. While each group directly controls locomotor output pathways [3], an interplay between them along with a third dorsal cluster (the DN1ps) is necessary for the correct timing of each peak and for adjusting behavior to changes in the environment [4-7]. M cells set the phase of roughly half of the circadian neurons (including the E cells) through PDF [5, 8-10]. Here, we show the existence of synaptic input provided by the evening oscillator onto the M cells. Both structural and functional approaches revealed that E-to-M cell connectivity changes across the day, with higher excitatory input taking place before the day-to-night transition. We identified two different neurotransmitters, acetylcholine and glutamate, released by E cells that are relevant for robust circadian output. Indeed, we show that acetylcholine is responsible for the excitatory input from E cells to M cells, which show preferential responsiveness to acetylcholine during the evening. Our findings provide evidence of an excitatory feedback between circadian clusters and unveil an important plastic remodeling of the E cells' synaptic connections.