Insig-1 and Insig-2 are endoplasmic reticulum (ER) proteins that inhibit lipid synthesis by blocking transport of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2) from ER to Golgi. In the Golgi, SREBPs are processed proteolytically to release their transcription-activating domains, which enhance the synthesis of fatty acids, triglycerides, and cholesterol. Heretofore, the two Insigs have redundant functions, and there is no rationale for two isoforms. The current data identify a specific function for Insig-2. We show that eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, inhibits fatty acid synthesis in human fibroblasts and rat hepatocytes by activating adenylate cyclase, which induces protein kinase A (PKA) to phosphorylate serine-106 in Insig-2. Phosphorylated Insig-2 inhibits the proteolytic processing of SREBP-1, thereby blocking fatty acid synthesis. Phosphorylated Insig-2 does not block the processing of SREBP-2, which activates cholesterol synthesis. Insig-1 lacks serine-106 and is not phosphorylated at this site. EPA inhibition of SREBP-1 processing was reduced by the replacement of serine-106 in Insig-2 with alanine or by treatment with KT5720, a PKA inhibitor. Inhibition did not occur in mutant human fibroblasts that possess Insig-1 but lack Insig-2. These data provide an Insig-2-specific mechanism for the long-known inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Field-aligned distributions of H+ with energy less than 100 eV in the magnetosphere originate from the ionosphere through ionospheric outflow. Recently, a statistical interhemispheric asymmetry in this ion outflow was reported. In this study, we investigate a case study of asymmetric field-aligned distributions (E < 100 eV) resulting from asymmetric outflow observed on 13 August 2019 by the Hot Plasma Composition Analyzer onboard the Magnetospheric Multiscale mission. During the reported event, the average phase space density in the parallel direction (pitch angle < 45 degrees) is about 4.7 times higher than in the anti-parallel direction (pitch angle > 135 degrees), indicating greater outflow from the southern hemisphere. In this event, electron precipitation fluxes are also asymmetric between hemispheres, with more electrons traveling to the southern hemisphere than to the northern hemisphere. Global MHD simulation results (SWMF/BAT-S-RUS available from the CCMC) confirm that several ionospheric parameters (joule heating, convection velocities, and energy fluxes of precipitating electrons) are more enhanced in the southern hemisphere. We suggest that these interhemispheric asymmetries might cause a stronger outflow from the southern hemisphere than from the northern hemisphere, to produce the observed asymmetric field-aligned distributions for the low-energy H+.

The surreal images of the Belgian artist Rene Magritte, characterized by juxtapositions and visual paradoxes, are widely used by advertisers, filmmakers, cartoonists, and graphic designers. If Magritte's images have the power to influence the visual vocabulary of the modern media, they may also have the power to influence young scientists by pointing the way to a successful career.

Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.

Significance Cholesterol constitutes 50% of lipids in the plasma membrane (PM) of animal cells. Sensors in the endoplasmic reticulum (ER) maintain this level by adjusting cholesterol uptake, synthesis, and storage. Uptake is mediated by LDL receptors, which deliver cholesterol-carrying LDL to lysosomes from which cholesterol moves to the PM and then to the ER. We report PM-to-ER transport of LDL cholesterol requires cholesterol-binding Aster proteins anchored to the ER and phosphatidylserine embedded in the PM. Asters are known to bind phosphatidylserine, and this accounts for part of the phosphatidylserine requirement. However, the current data suggest an additional requirement for phosphatidylserine independent of Asters. These data advance our knowledge of PM cholesterol homeostasis, a control mechanism essential for cell growth and survival.

This paper presents the first determination of the average global and regional response of ring current (RC) flux intensity versus four key solar wind (SW) and interplanetary magnetic field (IMF) parameters: SW electric field (ESW), IMF polarity (BZ,IMF), SW pressure (PSW), and SW speed (VSW). We analyze energetic neutral atom (ENA) images from Two Wide‐angle Imaging Neutral‐atom Spectrometers (TWINS) to measure the RC response, and use 5‐min downstream‐propagated data from the Advanced Composition Explorer (ACE) and Wind to measure SW driving. Our imaging data comprises 61 events, including 1,838 global 2D equatorial maps of line‐of‐sight (LOS) averaged ion flux derived from background‐subtracted, 15 min TWINS ENA images spanning 1–30 keV. Average spatial and spectral distributions were organized into four driver strength groups for each SW parameter. ESW has the strongest correlation with RC ion flux (coefficients are [0.95, 0.94, 0.88] at [1, 16, 30] keV, respectively), confirming that magnetospheric convection is a primary driver. In case studies, the global RC responds rapidly (≤15 min) to changes in ESW ranging from strong to weak. PSW is correlated with RC intensity, though not as strongly as ESW, indicating the secondary importance of PSW‐driven compression in RC injections. Strong ESW increases lower‐energy ions farther eastward and higher‐energy ions closer to midnight, consistent with an energy‐dependent interplay between magnetic drift and convection. The strongest SW driving preferentially increases the least energetic ions, suggesting that quasi‐steady convection can load the nightside RC with cooler ions.

The creative process in art and science involves two phases-generating and exploring new and wild ideas (building castles in the sky) and then narrowing down and focusing on the most tractable and useful ones (building houses of cards that don't topple over).

The B$^0_s$ and B$^+$ production yields are measured in PbPb collisions at a center-of-mass energy per nucleon pair of 5.02 TeV. The data sample, collected with the CMS detector at the LHC, corresponds to an integrated luminosity of 1.7 nb$^{-1}$. The mesons are reconstructed in the exclusive decay channels B$^0_s$ $\to$ J/$\psi(\mu^+\mu^-)\phi($K$^+$K$^-)$ and B$^+$ $\to$ J/$\psi(\mu^+\mu^-)$K$^+$, in the transverse momentum range 7-50 GeV/c and absolute rapidity 0-2.4. The B$^0_s$ meson is observed with a statistical significance in excess of five standard deviations for the first time in nucleus-nucleus collisions. The measurements are performed as functions of the transverse momentum of the B mesons and of the PbPb collision centrality. The ratio of production yields of B$^0_s$ and B$^+$ is measured and compared to theoretical models that include quark recombination effects.

Truly creative works of science and art produce unexpected and surprising results-just like the punch line of a good joke that generates an unfamiliar twist on a familiar idea. Surprise stimulates curiosity, which triggers a search to reveal the mystery of things unknown.

The cholesterol-sensing protein Scap induces cholesterol synthesis by transporting membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum (ER) to the Golgi apparatus for proteolytic activation. Transport requires interaction between Scap’s two ER luminal loops (L1 and L7), which flank an intramembrane sterol-sensing domain (SSD). Cholesterol inhibits Scap transport by binding to L1, which triggers Scap’s binding to Insig, an ER retention protein. Here we used cryoelectron microscopy (cryo-EM) to elucidate two structures of full-length chicken Scap: (1) a wild-type free of Insigs and (2) mutant Scap bound to chicken Insig without cholesterol. Strikingly, L1 and L7 intertwine tightly to form a globular domain that acts as a luminal platform connecting the SSD to the rest of Scap. In the presence of Insig, this platform undergoes a large rotation accompanied by rearrangement of Scap’s transmembrane helices. We postulate that this conformational change halts Scap transport of SREBPs and inhibits cholesterol synthesis.

Tragic events such as pandemics can be remembered as well as foreshadowed by works of art. Paintings by the artists Edvard Munch and John Singer Sargent (1918-19) tell us in real time what it was like to be stricken by the Spanish flu. Paintings by Edward Hopper (1940s and '50s) foretell the lockdown and social distancing of today's COVID-19 pandemic.

The 2020 Lasker Awards will not be given this year owing to the global coronavirus disease 2019 (COVID-19) pandemic.One way to help fill this void is to reflect and celebrate the major advances in infectious disease research that have been honored with Lasker Awards over the last 75 years.Since 1946, when the Lasker Awards were first presented, 29 awards have been bestowed on 5 organizations and 35 individuals who expanded scientific knowledge concerning how viruses and other infectious pathogens cause disease (7 awards), how infections can be treated with drugs (7 awards), and how infections can be prevented with vaccines (15 awards).

Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid-PS-controls the movement of another lipid-cholesterol-between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.