Cholesterol Overload: Contact Sites to the Rescue!

Delivery of low-density lipoprotein-derived cholesterol to the endoplasmic reticulum (ER) is essential for cholesterol homeostasis, yet the mechanism of this transport has largely remained elusive. Two recent reports shed some light on this process, uncovering a role for Niemann Pick type-C1 protein (NPC1) in the formation of membrane contact sites (MCS) between late endosomes (LE)/lysosomes (Lys) and the ER. Both studies identified a loss of MCS in cells lacking functional NPC1, where cholesterol accumulates in late endocytic organelles. Remarkably, and taking different approaches, both studies have made a striking observation that expansion of LE/Lys-ER MCS can rescue the cholesterol accumulation phenotype in NPC1 mutant or deficient cells. In both cases, the cholesterol was shown to be transported to the ER, demonstrating the importance of ER-LE/Lys contact sites in the direct transport of low-density lipoprotein-derived cholesterol to the ER

Rotation set and Entropy

In 1991 Llibre and MacKay proved that if $f$ is a 2-torus homeomorphism isotopic to identity and the rotation set of $f$ has a non empty interior then $f$ has positive topological entropy. Here, we give a converselike theorem. We show that the interior of the rotation set of a 2-torus $C^{1+ \alpha}$ diffeomorphism isotopic to identity of positive topological entropy is not empty, under the additional hypotheses that $f$ is topologically transitive and irreducible. We also give examples that show that these hypotheses are necessary.Comment: 15 pages, 2 figures, references adde

670-GHz Down- and Up-Converting HEMT-Based Mixers

A large category of scientific investigation takes advantage of the interactions of signals in the frequency range from 300 to 1,000 GHz and higher. This includes astronomy and atmospheric science, where spectral observations in this frequency range give information about molecular abundances, pressures, and temperatures of small-sized molecules such as water. Additionally, there is a minimum in the atmospheric absorption at around 670 GHz that makes this frequency useful for terrestrial imaging, radar, and possibly communications purposes. This is because 670 GHz is a good compromise for imaging and radar applications between spatial resolution (for a given antenna size) that favors higher frequencies, and atmospheric losses that favor lower frequencies. A similar trade-off applies to communications link budgets: higher frequencies allow smaller antennas, but incur a higher loss. All of these applications usually require converting the RF (radio frequency) signal at 670 GHz to a lower IF (intermediate frequency) for processing. Further, transmitting for communication and radar generally requires up-conversion from IF to the RF. The current state-of-the-art device for performing the frequency conversion is based on Schottky diode mixers for both up and down conversion in this frequency range for room-temperature operation. Devices that can operate at room temperature are generally required for terrestrial, military, and planetary applications that cannot tolerate the mass, bulk, and power consumption of cryogenic cooling. The technology has recently advanced to the point that amplifiers in the region up to nearly 1,000 GHz are feasible. Almost all of these have been based on indium phosphide pseudomorphic high-electron mobility transistors (pHEMTs), in the form of monolithic microwave integrated circuits (MMICs). Since the processing of HEMT amplifiers is quite differ en t from that of Schottky diodes, use of Schottky mixers requires separate MMICs for the mixers and amplifiers. Fabrication of all the down-/up-conversion circuitry on single MMICs, using a ll-HEMT circuits, would constitute a major advance in circuit simplicity

Dietary Patterns Prior to Pregnancy and Associations with Pregnancy Complications

Few studies have explored pre-pregnancy diet and its relationship with pregnancy outcomes. The objectives of this study were to: (1) derive pre-pregnancy dietary patterns for women enrolled in a prospective cohort in the province of Alberta, Canada; (2) describe associations between dietary patterns and socio-demographic characteristics; and (3) describe associations between dietary patterns and pregnancy complications. Upon enrolment into the Alberta Pregnancy Outcomes and Nutrition (APrON) study (median age of gestation, 17 weeks), women (n = 1545) completed a validated 142-item food frequency questionnaire recording food and beverages consumed "in the 12 months prior to pregnancy". Other assessments included pre-pregnancy body mass index (BMI), gestational weight gain, gestational hypertension, gestational diabetes, and socio-demographic characteristics. Dietary patterns were derived using principal components analysis. Scores were calculated to represent adherence with each dietary pattern retained. Four dietary patterns were retained, accounting for 22.9% of the variation in the overall diet. Dietary patterns were named the "healthy", "meat and refined carbohydrate", "beans, cheese and salad" or "tea and coffee" patterns. Higher "healthy" pattern scores prior to pregnancy were associated with lower odds of developing gestational hypertension during pregnancy (adjusted Odds Ratio (OR): 0.6, 95% Confidence Intervals (CI): 0.4, 0.9). Diet prior to pregnancy is an important target for interventions and may reduce the likelihood of developing complications such as gestational hypertension during pregnancy

Aspirin in the 21st century-common mechanisms of disease and their modulation by aspirin: a report from the 2015 scientific conference of the international aspirin foundation, 28 August, London, UK.

Professor Peter Rothwell of Oxford University chaired the annual Scientific Conference of the International Aspirin Foundation in London on 28 August 2015. It took the form of four sessions. Aspirin has more than one action in its effects on disease. Its acetylation of cyclooxygenase 2 (COX-2) in platelets leads to the blockade of pro-inflammatory chemicals and generation of anti-inflammatory mediators and increase in nitrous oxide (NO) production, which helps to preserve arterial endothelium. But platelets are not its only target. There is now evidence that aspirin has a direct antitumour effect on intestinal mucosal cells that block their potential transformation into cancer cells. Randomised placebo-controlled trials (RCTs) in people with histories of colorectal neoplasia have shown that aspirin reduces the risk of recurrent adenomas and reduces long-term cancer incidence in patients with Lynch syndrome. Among women given aspirin for cardiovascular disease, there were fewer cancers than in those given placebo. Epidemiological evidence has suggested that aspirin treatment after cancer is diagnosed reduces the incidence of metastases and prolongs survival, and long-term studies of anticancer treatment with aspirin are under way to confirm this. Apart from cancer studies, aspirin use is now firmly established as treatment for antiphospholipid syndrome (Hughes syndrome) and is being used to prevent and treat the heightened risk of cardiovascular disease in diabetes mellitus and in patients with HIV

Latin America's Nitrogen Challenge

Latin America (LA) has many social indicators similar to those of highly developed economies but most frequently falls midway between least developed countries and industrialized regions. To move forward, LA must address uncontrolled urbanization, agricultural production, social inequity, and destruction of natural resources. We discuss these interrelated challenges in terms of human impact on the nitrogen (N) cycle. Human activity has caused unprecedented changes to the global N cycle; in the past century; total global fixation of reactive N (Nr) has at least doubled (1). Excess Nr leaked into the environment negatively affects soils, atmosphere, and water resources in temperate zones (1). In addition to N excess from human impact, mining of natural soil N creates N deficits in some regions (2, 3).Fil: Austin, Amy Theresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Bustamante, M. M. C.. Universidade Do Brasilia; BrasilFil: Nardoto, G. B.. Universidade Do Brasilia; BrasilFil: Mitre, S. K.. Universidade Do Brasilia; BrasilFil: Pérez, T.. Instituto Venezolano de Investigaciones Cientificas; VenezuelaFil: Ometto, J. P. H. B.. Centro de Previsao de Tempo e Estudos Climaticos. Instituto Nacional de Pesquisas Espaciais; BrasilFil: Ascarrunz, N. L.. Instituto Boliviano de Investigación Forestal; BoliviaFil: Forti, M. C.. Centro de Previsao de Tempo e Estudos Climaticos. Instituto Nacional de Pesquisas Espaciais; BrasilFil: Longo, K.. Centro de Previsao de Tempo e Estudos Climaticos. Instituto Nacional de Pesquisas Espaciais; BrasilFil: Gavito, M. E.. Universidad Nacional Autónoma de México; MéxicoFil: Enrich Prast, A.. Universidade Federal do Rio de Janeiro; BrasilFil: Martinelli, L. A.. Universidade de Sao Paulo; Brasi

Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice

Background and Aims: Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate‐limiting step in this pathway. Na+‐coupled neutral amino acid transporters (SNATs) 2 and 4 are believed to facilitate hepatic alanine uptake. In previous studies, we demonstrated that a member of the Ca2+‐dependent phospholipid binding annexins, Annexin A6 (AnxA6), regulates membrane trafficking along endo‐ and exocytic pathways. Yet, although AnxA6 is abundantly expressed in the liver, its function in hepatic physiology remains unknown. In this study, we investigated the potential contribution of AnxA6 in liver regeneration. Approach and Results: Utilizing AnxA6 knockout mice (AnxA6−/−), we challenged liver function after partial hepatectomy (PHx), inducing acute proliferative and metabolic stress. Biochemical and immunofluorescent approaches were used to dissect AnxA6−/− mice liver proliferation and energetic metabolism. Most strikingly, AnxA6−/− mice exhibited low survival after PHx. This was associated with an irreversible and progressive drop of blood glucose levels. Whereas exogenous glucose administration or restoration of hepatic AnxA6 expression rescued AnxA6−/− mice survival after PHx, the sustained hypoglycemia in partially hepatectomized AnxA6−/− mice was the consequence of an impaired alanine‐dependent GNG in AnxA6−/− hepatocytes. Mechanistically, cytoplasmic SNAT4 failed to recycle to the sinusoidal plasma membrane of AnxA6−/− hepatocytes 48 hours after PHx, impairing alanine uptake and, consequently, glucose production. Conclusions: We conclude that the lack of AnxA6 compromises alanine‐dependent GNG and liver regeneration in mice

Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation

Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4

Background: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective: This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods: We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1-4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results: Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions:Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition

Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense.

Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection