The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on timeof-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.
The biconcave disk shape and deformability of mammalian RBCs rely on the membrane skeleton, a viscoelastic network of short, membrane-associated actin filaments (F-actin) cross-linked by long, flexible spectrin tetramers. Nonmuscle myosin II (NMII) motors exert force on diverse F-actin networks to control cell shapes, but a function for NMII contractility in the 2D spectrin-F-actin network of RBCs has not been tested. Here, we show that RBCs contain membrane skeleton-associated NMIIA puncta, identified as bipolar filaments by superresolution fluorescence microscopy. MgATP disrupts NMIIA association with the membrane skeleton, consistent with NMIIA motor domains binding to membrane skeleton F-actin and contributing to membrane mechanical properties. In addition, the phosphorylation of the RBC NMIIA heavy and light chains in vivo indicates active regulation of NMIIA motor activity and filament assembly, while reduced heavy chain phosphorylation of membrane skeleton-associated NMIIA indicates assembly of stable filaments at the membrane. Treatment of RBCs with blebbistatin, an inhibitor of NMII motor activity, decreases the number of NMIIA filaments associated with the membrane and enhances local, nanoscale membrane oscillations, suggesting decreased membrane tension. Blebbistatin-treated RBCs also exhibit elongated shapes, loss of membrane curvature, and enhanced deformability, indicating a role for NMIIA contractility in promoting membrane stiffness and maintaining RBC biconcave disk cell shape. As structures similar to the RBC membrane skeleton exist in many metazoan cell types, these data demonstrate a general function for NMII in controlling specialized membrane morphology and mechanical properties through contractile interactions with short F-actin in spectrin-F-actin networks.
N2 fixation should be a critical process in the nitrogen-poor surface water of the eastern Mediterranean Sea. Despite favorable conditions, diazotroph abundance and N2 fixation rates remains low for reasons yet explained. The main goal of this study was to investigate the limiting nutrients for diazotrophy in this oligotrophic environment. Hence, we conducted dedicated bottle-microcosms with eastern Mediterranean Sea water that were supplemented with mono and polysaccharides as well as inorganic nitrogen and phosphorous. Our results indicate that the diazotrophic community expressing nifH was primarily represented by heterotrophic Proteobacteria. N2 fixation and heterotrophic bacterial activity increased up-to tenfold following two days of dark incubations, once seawater was supplemented with organic carbon substrate in the form of glucose (monosaccharides) or gum-xanthan (polysaccharide surrogate). Furthermore, our results point that carbon-rich polysaccharides, such as transparent exopolymer particles, enhance heterotrophic N2 fixation, by forming microenvironments of intense metabolic activity, high carbon: nitrogen ratio, and possibly low O2 levels. The conclusions of this study indicate that diazotrophs in the eastern Mediterranean coast are primarily limited by organic carbon substrates, as possibly in many other marine regions.
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