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Papers of note in Science 356 (6343)

2017-06-20T11:38:01-07:00

This week’s articles describe a mechanism by which starvation primes a cellular nutrient-sensing system for activation upon refeeding; microRNAs that control pain sensitivity; and the lasting effects of early life stress on the likelihood of developing depression.




Papers of note in Nature 546 (7658)

2017-06-20T11:38:01-07:00

This week’s articles highlight a compound that may be useful for treating cryptosporidiosis and a kinase complex that links cell division to cellular metabolism.




Macrophages dont take more than they can eat

2017-06-20T11:38:01-07:00

Innate immune signaling feeds forward to control the rate at which macrophages phagocytose bacteria.




Papers of note in Science Translational Medicine 9 (394)

2017-06-20T11:38:01-07:00

This week’s articles describe how broccoli can combat type 2 diabetes, how monocytes contribute to the failure of organ transplant grafts, and how to more durably treat RET- or KRAS-driven lung cancer.




Dazed and confused from infection

2017-06-20T11:38:01-07:00

TNF-α produced by circulating CX3CR1high monocytes causes the problems that infected individuals have with learning and remembering.




Ligand- and voltage-gated Ca2+ channels differentially regulate the mode of vesicular neuropeptide release in mammalian sensory neurons

2017-06-20T11:38:01-07:00

Neuropeptides released from dorsal root ganglion (DRG) neurons play essential roles in the neurotransmission of sensory inputs, including those underlying nociception and pathological pain. Neuropeptides are released from intracellular vesicles through two modes: a partial release mode called "kiss-and-run" (KAR) and a full release mode called "full fusion–like" (FFL). Using total internal reflection fluorescence (TIRF) microscopy, we traced the release of pH-sensitive green fluorescent protein–tagged neuropeptide Y (pHluorin-NPY) from individual dense-core vesicles in the soma and axon of single DRG neurons after Ca2+ influx through either voltage-gated Ca2+ channels (VGCCs) or ligand-gated transient receptor potential vanilloid 1 (TRPV1) channels. We found that Ca2+ influx through VGCCs stimulated FFL and a greater single release of neuropeptides. In contrast, Ca2+ influx through TRPV1 channels stimulated KAR and a pulsed but prolonged release of neuropeptides that was partially mediated by Dynamin 1, which limits fusion pore expansion. Suppressing the Ca2+ gradient to an extent similar to that seen after TRPV1 activation abolished the VGCC preference for FFL. The findings suggest that by generating a steeper Ca2+ gradient, VGCCs promote a more robust fusion pore opening that facilitates FFL. Thus, KAR and FFL release modes are differentially regulated by the two principal types of Ca2+-permeable channels in DRG neurons.




Genetic evidence that {beta}-arrestins are dispensable for the initiation of {beta}2-adrenergic receptor signaling to ERK

2017-06-20T11:38:01-07:00

The β2-adrenergic receptor (β2AR) has provided a paradigm to elucidate how G protein–coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization. Unexpectedly, β-arr1 and β-arr2 and receptor internalization were dispensable for ERK activation. Instead, β2AR signaled through Gαs and Gβ subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for β2AR signaling through β-arrestin–independent pathways in key physiological functions and under pathological conditions.




The glycosylation pathway is required for the secretion of Slit and for the maintenance of the Slit receptor Robo on axons

2017-06-20T11:38:01-07:00

Slit proteins act as repulsive axon guidance cues by activating receptors of the Roundabout (Robo) family. During early neurogenesis in Drosophila melanogaster, Slit prevents the growth cones of longitudinal tract neurons from inappropriately crossing the midline, thus restricting these cells to trajectories parallel to the midline. Slit is expressed in midline glial cells, and Robo is present in longitudinal axon tracts and growth cones. We showed that the enzyme Mummy (Mmy) controlled Slit-Robo signaling through mechanisms that affected both the ligand and the receptor. Mmy was required for the glycosylation of Slit, which was essential for Slit secretion. Mmy was also required for maintaining the abundance and spatial distribution of Robo through an indirect mechanism that was independent of Slit secretion. Moreover, secretion of Slit was required to maintain the fasciculation and position of longitudinal axon tracts, thus maintaining the hardwiring of the nervous system. Thus, Mmy is required for Slit secretion and for maintaining Robo abundance and distribution in the developing nervous system in Drosophila.