Novel antiplatelet agents in acute coronary syndrome

Nature Reviews Cardiology | Review   

Dual antiplatelet therapy (DAPT) with aspirin and the P2Y purinoceptor 12 (P2Y12)-receptor inhibitor clopidogrel has been considered the gold standard of care in patients with acute coronary syndrome (ACS). The FDA approval of the novel P2Y12-receptor antagonists prasugrel and ticagrelor, which are faster-acting and more potent than clopidogrel, in the past 5 years have improved clinical outcomes in patients with ACS. Even with these newer compounds, many patients continue to experience adverse ischaemic events. This Review will provide an overview of the antiplatelet agents currently used to treat patients with ACS. Furthermore, emerging antiplatelet therapies, including intravenous P2Y12 antagonists, oral PAR-1 antagonists and thromboxane-receptor inhibitors will be discussed.

Abstract

For more than 10 years, dual antiplatelet therapy with aspirin and clopidogrel has remained the cornerstone of treatment for patients with acute coronary syndrome (ACS). The novel oral P2Y purinoceptor 12 (P2Y₁₂)-receptor inhibitors prasugrel and ticagrelor were approved by the FDA for clinical use in 2009 and 2011, respectively. These agents have a faster-acting, more-potent, and more-predictable antiplatelet effect than clopidogrel, which translates into improved clinical outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, some patients continue to experience adverse ischaemic events despite treatment with aspirin and a P2Y₁₂-receptor antagonist, because platelets can remain activated via pathways not inhibited by these agents, such as the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin. Emerging antiplatelet therapies that might address these limitations include intravenous P2Y₁₂ antagonists, oral PAR-1 antagonists, and thromboxane-receptor inhibitors. In this Review, we provide an overview of these novel antiplatelet drugs, including newly approved agents and emerging compounds currently under clinical development, and also discuss evolving concepts and unmet needs related to antiplatelet therapy for the treatment of ACS.

At a glance

• Platelet adhesion, activation, and aggregation after plaque rupture or erosion are the major determinants of arterial thrombosis leading to acute coronary syndrome (ACS)
• Antiplatelet therapy, which targets pathways of platelet activation and aggregation, is pivotal in both the acute treatment and long-term secondary prevention of ischaemic events in patients with ACS
• Dual antiplatelet therapy with a combination of aspirin and either prasugrel or ticagrelor should be the treatment of choice in patients with ACS
• Drug selection should be based on contraindications and the individual patient's characteristics; clopidogrel should be used when both prasugrel and ticagrelor are contraindicated or not available
• Patients might continue to experience adverse events despite the use of prasugrel or ticagrelor
• New intravenous P2Y purinoceptor 12 inhibitors and agents that target other platelet-activation pathways have been developed

Figure 1: Mechanism of thrombus formation.

Plaque rupture exposes subendothelial components. Platelet adhesion during the rolling phase is mediated by interactions between vWF and GP Ib/V/IX receptor complexes located on the platelet surface, and between platelet collagen recep…

Figure 2: Platelet activation pathways targeted by current and novel antiplatelet agents.

Platelet adherence to injured vascular endothelium is mediated by binding of GP receptors to exposed extracellular matrix proteins (collagen and vWF). Complex intracellular signalling processes result in the local production and releas…

Figure 3: Mechanisms of action of P2Y₁₂ inhibitors.

Activation of P2Y₁₂ inhibits AC, causing a decrease in cAMP and VASP-P levels, and activation of P2Y₁ causes an increase in intracellular Ca²⁺ levels. These changes promote platelet aggregation by altering the ligand-binding properties…

Introduction

Arterial thrombosis after atherosclerotic plaque rupture or erosion is the major determinant of acute coronary syndrome (ACS).^{1, 2} Platelet adhesion, activation, and aggregation have important roles in the development of arterial thrombi; antiplatelet therapy is, therefore, pivotal in the treatment of ACS.^{2, 3, 4} Multiple platelet-signalling pathways are involved in thrombus formation and are potential targets for therapies.^{2, 3, 4} At present, three main classes of antiplatelet drugs are clinically approved for the treatment and secondary prevention of thrombotic complications in patients with ACS: oral cyclooxygenase-1 (COX-1; also known as prostaglandin G/H synthase 1) inhibitors, oral P2Y purinoceptor 12 (P2Y₁₂)-receptor inhibitors, and intravenous glycoprotein (GP) IIb/IIIa (also known as integrin α_IIbβ₃) inhibitors.^{5, 6, 7, 8}

The synergistic platelet-inhibitory effects exerted by dual antiplatelet therapy (DAPT) consisting of aspirin-induced blockade of COX-1 in conjunction with P2Y₁₂-receptor inhibition led to more than 10 years of clinical trials in patients with manifestations of ACS, including unstable angina, non-ST-segment elevation (NSTE) myocardial infarction (MI) and ST-segment elevation MI (STEMI).^{5, 6, 7, 8, 9, 10} Clopidogrel is the most broadly investigated P2Y₁₂-receptor inhibitor, owing to its favourable safety profile compared with ticlopidine.¹¹

Therefore, clopidogrel in combination with aspirin is still the cornerstone of treatment in patients with ACS.^{5, 6, 7, 8} However, despite the undisputable benefits of DAPT, a considerable number of patients continue to experience adverse thrombotic events.¹² These adverse events have been in part attributed to the nonuniform platelet inhibitory effects induced by clopidogrel, also known as interindividual clopidogrel response variability, where individuals who persist with high platelet reactivity despite clopidogrel therapy are at an increased risk of atherothrombotic recurrences.^{12, 13, 14, 15} Moreover, despite adequate COX-1 and P2Y₁₂-receptor blockade,^{3, 4} other platelet signalling pathways continue to be activated, and can contribute to thrombus formation. These observations have prompted the development of novel antithrombotic agents.

In this Review, we provide an overview of advances in antiplatelet therapy in the setting of ACS, focusing on novel drugs that have already been approved for clinical use, in addition to emerging agents at different phases of clinical development. However, a detailed description of the role of novel oral anticoagulants is beyond the scope of this Review, and the use of such agents is only briefly mentioned.

Mechanisms of atherothrombosis

Plaque rupture, fissure, or erosion exposes the subendothelial layer and leads to the recruitment and activation of platelets, as well as the generation of excessive levels of thrombin, which ultimately results in the formation of a fibrin-rich thrombus.^{1, 2, 3, 4} NSTE-ACS is frequently characterized by a nonocclusive or transiently occlusive thrombus, whereas a more stable and occlusive thrombus is typical in STEMI.¹ Platelet-activated thrombosis involves three principal steps: platelet adhesion, activation and recruitment of additional platelets, and platelet aggregation (Figure 1).^{3, 4, 16} Platelet adhesion during the initial rolling phase is mediated by interactions between the GP Ib/V/IX receptor complex, located on the surface of the platelet, and von Willebrand factor (vWF) bound to collagen exposed at the site of vascular injury.¹⁷ Rolling also brings the collagen receptors GP VI and GP Ia on platelets into contact with collagen.¹⁷ Binding of collagen to these receptors initiates platelet activation and triggers intracellular mechanisms that shifts platelet integrins to a high-affinity state, which induces the release of activating factors, in turn promoting aggregation, further recruitment, and further activation of circulating platelets.^{3, 4, 16, 17} These factors include ADP, epinephrine, serotonin, thrombin, and thromboxane A₂.^{3, 4} Platelet activation by these and other mediators (such as collagen) induces changes in platelet shape, expression of proinflammatory molecules (such as P-selectin and soluble CD40 ligand) and platelet procoagulant activity.^{3, 4, 16} The final step in platelet aggregation and thrombus formation involves the conversion of platelet GP IIb/IIIa (the main receptor mediating platelet aggregation) into its active form, which subsequently binds to the extracellular ligands fibrinogen and vWF, leading to platelet aggregation and thrombus formation mediated by platelet–platelet interaction.^{17, 18} In addition, vascular injury also exposes subendothelial tissue factor, which forms a complex with factor VIIa, activating the clotting cascade and leading to thrombin generation.¹⁹ However, only a modest amount of thrombin is produced as a result of the coagulation cascade; its main source within a platelet plug is the surface of activated platelets.^{16, 20} Thrombin converts fibrinogen to fibrin, generating a fibrin-rich clot, and further activates platelets by binding to protease-activated receptor (PAR)-1 and PAR-4.^{3, 4, 21, 22} Pathogenic thrombosis, therefore, involves a complex interplay between platelets and plasma components (coagulation factors) that interact in an auto-amplified process (Figure 1).

Francesco Franchi^1, & Dominick J. Angiolillo^1,

Nature Reviews Cardiology Year published: (2014) DOI: doi:10.1038/nrcardio.2014.156

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For diabetes, stem cell recipe offers new hope

Researchers coax stem cells into becoming long-sought insulin-producing β cells

news.sciencemag.org

 

This week, researchers reported a significant step towards finding a cure for diabetes. They've found a recipe that can turn human stem cells into functional pancreatic β cells—the same cells that are destroyed by the body’s own immune system in type 1 diabetes patients.

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 Douglas Melton

Two weeks after transplant into a diabetic mouse, human pancreatic β cells made in the lab produce enough insulin (green) to cure the animal.

Douglas Melton is as impatient as anyone for a cure for diabetes. His son developed the disease as an infant, and his daughter was diagnosed at age 14. For most of the past 2 decades, the developmental biologist at the Harvard Stem Cell Institute has focused his research on finding a cure. This week, he and his colleagues report a potentially significant step toward that goal: a recipe that can turn human stem cells into functional pancreatic β cells—the cells that are destroyed by the body’s own immune system in type 1 diabetes patients such as Melton’s son and daughter. The cells the researchers produced respond to glucose by producing insulin, just as normal β cells do. And when implanted into mice with a form of diabetes, the cells can cure the disorder.

 

“The diabetes research community has been waiting for ages for this type of breakthrough,” says Jorge Ferrer, who studies the genetics of β cells at Imperial College London. The lab-generated cells should be a valuable tool for studying diabetes and, Melton hopes, could eventually be used to treat patients.

 

Throughout the day, the pancreas regulates the body’s blood sugar levels, responding to an increase in glucose after a meal by secreting insulin, which helps cells take up the sugar. In type 1 diabetes, the body’s immune system mistakenly kills the β cells for still-unknown reasons, and the body is left without insulin. People control their diabetes by injecting carefully calibrated doses of insulin. But matching the precise insulin control achieved by the healthy pancreas is almost impossible, so researchers have hoped for decades to find a way to replace the missing cells.

 

When scientists isolated human embryonic stem (ES) cells in 1998, hopes soared. ES cells are pluripotent, which means that in theory they can turn into any of the body’s cell types—including β cells. Indeed, one of the first things researchers tried to make from ES cells was pancreatic β cells. Later they tried with so-called induced pluripotent stem (iPS) cells, made by reprogramming adult cells into an embryolike state. Either way, “it’s proved to be an extraordinarily complicated undertaking,” says Mark Magnuson of Vanderbilt University in Nashville, who studies pancreatic development.

 

Several teams have turned stem cells into precursors of β cells, which mature when placed into experimental animals. But the cells take 6 weeks to become fully functional β cells, and they can’t be studied easily outside the body. Nevertheless, a clinical trial started last month to test their therapeutic use in patients.

 

In Cell this week, Melton and his colleagues report a complex recipe that can transform either human ES cells or iPS cells directly into functional β cells. The breakthrough is based on more than a decade of tenacious work in Melton’s lab. He and his colleagues have painstakingly studied the signals that guide pancreas development, applying what they and others have found to develop a method that turns stem cells into mature β cells. “There’s no magic to this,” Melton says. “It’s not a discovery so much as applied developmental biology.”

 

The protocol “is reproducible, but it is tedious,” Melton adds. The stem cells are grown in flasks and require five different growth media and 11 molecular factors, from proteins to sugars, added in precise combinations over 35 days to turn them into β cells. On the bright side, Melton says, the technique can produce 200 million β cells in a single 500 ml flask—enough, in theory, to treat a patient. Melton says the protocol seems to work equally well with ES and iPS cell lines.

 

Before the cells can be used to treat type 1 diabetes, researchers need to find a way to protect them from immunologic rejection. The same autoimmune response that triggered the disease would likely attack new β cells derived from the patient’s own iPS cells, and a normal immune response would destroy ES-derived β cells, which would appear foreign. (That has been a challenge for efforts to treat type 1 diabetes with received transplants of β cells from deceased organ donors.) Melton and colleagues are now exploring how to physically encapsulate their stem cell–derived β cells, as well as ways to modify the β cells to enable them to ward off immune attack.

 

In the meantime, the cells should help the study of the autoimmune disorder. The technique “potentially provides ways to create model systems for studying the genetic basis of diabetes, or to discover novel therapies to enhance existing β cells,” Ferrer says. Melton says his lab has iPS cell lines from people with diabetes—both type 1 and type 2, in which the β cells are not destroyed—and healthy controls. They are generating β cells from those cell lines to look for differences that might explain how the different forms of the disease develop. They will also screen for chemicals that can stop or even reverse the damage diabetes does to β cells.  

 

Melton says his son and daughter—now 23 and 27 years old—were pleased but unsurprised by his group’s progress. Reversing the parent-child role, they gently nagged him to “get going and solve the [immune-rejection] problem.”

 

By Gretchen Vogel 9 October 2014 1:00 pm

Email Gretchen

Posted in Biology, Health

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Dendritic cells and macrophages in the kidney: a spectrum of good and evil

Nature Reviews Nephrology | Review

 

Renal dendritic cells and macrophages are key factors in the initiation and propagation of renal disease and tissue regeneration. This Review discusses the common and distinct characteristics of dendritic cells and macrophages as well as current understanding of the renal-specific functions of these important phagocytic, antigen-presenting cell types in potentiating or mitigating intrinsic kidney disease.

 

Abstract | Renal dendritic cells (DCs) and macrophages represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune-intelligence activity; they induce and regulate inflammatory responses to freely filtered antigenic material and protect the kidney from infection. Tissue-resident or infiltrating DCs and macrophages are key factors in the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration, regardless of the aetiological and pathogenetic mechanisms. The identification, and functional and phenotypic distinction of these cell types is complex and incompletely understood, and the same is true of their interplay and relationships with effector and regulatory cells of the adaptive immune system. In this Review, we discuss the common and distinct characteristics of DCs and macrophages, as well as key advances that have identified the renal-specific functions of these important phagocytic, antigen-presenting cells, and their roles in potentiating or mitigating intrinsic kidney disease. We also identify remaining issues that are of priority for further investigation, and highlight the prospects for translational and therapeutic application of the knowledge acquired.

 

Rogers, N. M. et al. Nat. Rev. Nephrol. advance online publication 30 September 2014; doi:10.1038/nrneph.2014.170

Figure 1: The heterogeneous but overlapping phenotype and functions of renal DCs and macrophages.

DCs are traditionally described as mediators of immune surveillance and antigen presentation, and as the primary determinants of responses to antigens—through initiation of either immune effector-cell functions or the development of tolerance. Macrophages also function as innate immune cells, predominantly through phagocytosis and production of toxic metabolites. However, the classical paradigm of DC versus macrophage phenotypes and functions is increasingly indistinct within the kidney, as these cells exhibit overlapping surface markers, functional capabilities, and ontogenic pathways. This molecular and phenotypic overlap between cell types and subsets complicates their identification and evaluation. *Marker described only in humans. Abbreviations: B-ATF-3, basic leucine zipper transcription factor ATF-like 3; BDCA-1, blood dendritic cell antigen 1; CCR, CC chemokine receptor; CSF-1R, colony-stimulating factor 1 receptor; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; DC-SIGN, dendritic-cell-specific ICAM-3-grabbing non-integrin; ECM, extracellular matrix; EMR1, EGF-like module-containing mucin-like hormone receptor-like 1; FcγR(II/III), low affinity IgG Fc region receptor (II/III); FLT3, fms-like tyrosine kinase 3; Gr-1, granulocyte-differentiation antigen-1; ICAM-1, intercellular adhesion molecule 1; ID-2, inhibitor of DNA binding 2; IL-4R, IL-4 receptor; IL-10R, IL-10 receptor; IRF, interferon regulatory factor; Ly6(C/G), lymphocyte antigen 6(C/G); SIRPα, signal-regulatory protein α (also known as tyrosine-protein phosphatase nonreceptor type substrate 1); STAT3, signal transducer and activator of transcription 3; ZBTB46, zinc finger and BTB domain containing protein 46.

Figure 2: The ontogeny of kidney-resident DCs and macrophages.

Bone-marrow-resident MDPs differentiate into monocytes that are released to the peripheral circulation under homeostatic and inflammatory conditions. MDPs also develop into CDPs, which subsequently differentiate to pre-DCs that can migrate from bone marrow to the renal interstitial compartment via the blood, with regular turnover. Under the influence of different chemokines and growth factors, the pre-DCs differentiate to form distinct, tissue-based DC subsets (broadly characterized as CX3CR1⁺ DCs or CD103⁺ DCs) that are capable of exodus to the draining lymph nodes where they can present antigens to B cells and T cells. Monocytes can also localize to the kidney under the influence of chemokines such as CCR2, and subsequently differentiate into DCs. Pre-DCs also give rise to pDC, although the presence of pDCs in kidneys of mice is disputed (dashed arrow). Abbreviations: B-ATF-3, basic leucine zipper transcription factor ATF-like 3; BDCA-(1/2), blood dendritic cell antigen (1/2); CCL(19/21), CC chemokine ligand (19/21); CCR(2/7), CC chemokine receptor (2/7); CDP, common dendritic cell precursor; CLEC4K, C-type lectin domain family 4 member K; CLEC9A, C-type lectin domain family 9 member A; CSF-1, colony-stimulating factor 1; CSF-1R, CSF-1 receptor; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; DC-SIGN, dendritic-cell-specific ICAM-3-grabbing non-integrin; FLT3, fms-like tyrosine kinase 3; FLT3LG, FLT3 ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; Ly6(C/G), lymphocyte antigen 6(C/G); M-CSF, macrophage colony-stimulating factor; MDP, monocyte–DC precursor; pDC, plasmacytoid DC.

Figure 3: Renal DC function in health and disease.

DCs perform homeostatic functions, including induction of tolerance to peripheral antigens typically cleared by the glomerulus, such as albumin, and anti-infection immunosurveillance. Interaction of DCs with bacteria causes them to generate chemokines to attract effector cells, such as neutrophils. The kidney-resident DCs also operate to exacerbate (proinflammatory DCs) or mitigate (anti-inflammatory DCs) a wide range of parenchymal disease, and the role of these cells in disease might be determined by either tissue-resident cells or influxing cells and antigens. For example, the responsiveness and maturation state of DCs might be regulated by ongoing interactions with tubular epithelial cells. Abbreviations: AKI, acute kidney injury; DC, dendritic cell; IRI, ischaemia–reperfusion injury; LPS, lipopolysaccharide; NTN, nephrotoxic nephritis; SLE, systemic lupus erythematosus; T_H17, type 17 T-helper; UUO, unilateral ureteral obstruction.

Figure 4: Macrophages in renal disease.

Tissue-resident macrophages or infiltrating proinflammatory monocytes can become classically activated by exposure to danger-associated molecular patterns or proinflammatory cytokines to take on an M1 phenotype, associated with production of IL-12 and IL-23, engagement of T cells for antigen presentation, activation or exacerbation of profibrotic parenchymal changes, and direct and indirect tissue injury. M1 macrophages can be reprogrammed to become alternatively activated M2 macrophages by stimulation with anti-inflammatory cytokines, such as IL-10 or CSF-1, or ingestion of apoptotic cells. M2 macrophages might facilitate and coordinate restoration of tubular cell and, therefore, kidney tubule integrity following injury. M2 macrophages can also express anti-inflammatory mediators, such as HO-1 and IL-10, which act to limit tissue injury and promote resolution of inflammation, but might also drive pericyte and myofibroblast activation through production of TGF-β, galectin 3 and PDGF. Abbreviations: AKI, acute kidney injury; CSF-1, colony-stimulating factor 1; ECM, extracellular matrix; HO-1, haem oxygenase-1; ICAM-1, intercellular adhesion molecule 1; M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; Wnt7b, wingless-related MMTV integration site 7B.

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Nanoscopy Wins Nobel

The Scientist » News & Opinion » Daily News               

Nanoscopy Wins Nobel

Eric Betzig, Stefan Hell, and William Moerner have won the 2014 Nobel Prize in Chemistry "for the development of super-resolved fluorescence microscopy."

 

By Tracy Vence | October 8, 2014

 





Eric Betzig (left), Stefan Hell (middle), and William

Moerner take home this year's Nobel Prize in Chemistry

for their work on super-resolved fluorescence

microscopy.

ILL. N. ELMEHED. © NOBEL MEDIA 2014; WIKIMEDIA COMMONS;

WIKIMEDIA COMMONS, K. LOWDER

Eric Betzig, Stefan Hell, and William Moerner have won the 2014 Nobel Prize in Chemistry “for the development of super-resolved fluorescence microscopy.”

 

Betzig, of the Howard Hughes Medical Institute’s Janelia Farm Research Campus in Ashburn, Virginia; Hell, of the Max Planck Institute for Biophysical Chemistry and the German Cancer Research Center; and Stanford University’s Moerner will share this year’s prize equally. The three are being honored for bringing “optical microscopy into the nanodimension,” enabling scientists to “study living cells in the tiniest molecular detail,” the Nobel Foundation said in its press release announcing the award.

 

In 2000, Hell developed a technique called stimulated emission depletion (STED) microscopy, which uses laser beams to home in on fluorescently glowing molecules, scanning a sample nanometer by nanometer to produce a high-resolution image. For this and other achievements, Hell shared a 2014 Kavli Award.

 

Working separately, Betzig and Moerner paved the way for single-molecule microscopy, in which interspersed molecules are fluoresced on and off such that, when the same area is imaged multiple times, superimposition of the resulting images results in nanolevel resolution. Betzig first used this method in 2006.

 

Bernd Rieger of the Delft University of Technology in the Netherlands said the three men “opened up a huge field of research [during] the last 8 to 10 years that made it possible to study molecular interactions with a light microscope, which is the work of most cell biologists. . . . They really made a big impact.”

 

“It’s a great recognition of Stefan’s work and a lot of work that’s been done over many years,” Mark Bates, a postdoc in Hell’s lab, said of his advisor’s Nobel. “The field of super-resolution fluorescence nanoscopy [was] first conceived by Stefan and then pushed forward by a lot of different groups around the world.”

 

“This isn’t something that was done 20 years ago and has matured now. We’re all still really excited about further developing these methods and applying them to different problems in biology. . . .  These are tools that are going to push forward the fields of neurobiology, cell biology, structural biology,” said Bates. For now, though, the nanobiophotonics department is abuzz with “a lot of people, a lot of champagne, and a lot of celebratory mood.”

 

Update (October 9, 8:19 a.m.): “Over the past 10 to 15 years there has been increasing use of optical methods to look at single molecules at the nano level,” said Catherine Lewis, director of the Division of Cell Biology and Biophysics at the National Institute of General Medical Sciences. “The advantage of this [approach] is that you can see the dynamics—molecules moving around, interacting with others, and where they are in the cell.”

 

Along with advances in instrumentation and fluorescent probes, as well as in computational techniques, the work of Moerner and his co-Laureates “has allowed scientists to observe and see individual single molecules in living cells in real time,” added Lewis. “I’m thrilled about this prize.”

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Brain’s “Inner GPS” Wins Nobel

The Scientist » News & Opinion » Daily News               

Brain’s “Inner GPS” Wins Nobel

John O’Keefe, May-Britt Moser, and Edvard Moser have won the 2014 Nobel Prize in Physiology or Medicine “for their discoveries of cells that constitute a positioning system in the brain.”

 

By Molly Sharlach and Tracy Vence | October 6, 2014

 

Left to right: John O’Keefe; May-Britt Moser, Edvard Moser

UCL, DAVID BISHOP; WIKIMEDIA, THE KAVLI INSTITUTE/NTNU

John O’Keefe, May-Britt Moser, and Edvard Moser have won the 2014 Nobel Prize in Physiology or Medicine “for their discoveries of cells that constitute a positioning system in the brain.”

 

O’Keefe, a professor of cognitive neuroscience at University College London, will receive one half of this year’s prize. Husband-and-wife team May-Britt and Edvard Moser, both professors at the Norwegian University of Science and Technology (NTNU), will share the second half.

 

Together identifying an inner positioning system within the brain, O’Keefe is being honored for his discovery of so-called place cells, while the Mosers are recognized for their later work identifying grid cells.

 

“The discoveries of John O’Keefe, May-Britt Moser and Edvard Moser have solved a problem that has occupied philosophers and scientists for centuries,” the Nobel Foundation noted in its press release announcing the award: “How does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment?”

 

Menno Witter, the Mosers’ colleague at NTNU’s Kavli Institute for Systems Neuroscience/Centre for Neural Computation, first met the pair in the 1990s when they were students at the University of Oslo; Witter was an assistant professor at VU University Amsterdam. 

 

Their work “is a very important contribution in terms of understanding at least part of the neural code that is generated in the brain that allows species—probably including humans—to navigate,” Witter told The Scientist. “We’re all very, very pleased, because it to us shows that what we’re doing . . . as a whole community is considered to be really important and prestigious. It is also, I think, a fabulous sign to the world that Norwegian science is really at a top level.”

 

Francesca Sargolini, a cognitive neuroscientist at Aix-Marseille University in France, worked with the Mosers when she was a postdoc. The lab had a “wonderful, stimulating atmosphere,” Sargolini told The Scientist. Discoveries made by O’Keefe and the Mosers have helped researchers understand “how the brain computes . . . information to make a representation of spaces, so we can use that information to move around in the environment and do what we do every day,” she added.

 

“This is a very well-deserved prize for John [O’Keefe] and the Mosers,” said Colin Lever, a senior lecturer in the department of psychology at Durham University in the U.K., who earned a PhD and continued postdoctoral research in O’Keefe’s lab.

 

“This is a fascinating area of research,” Lever continued. “What we’re discovering about the brain through spatial mapping is likely of greater consequence than just for understanding about space. . . . Indeed, it seems to support autobiographical memory in humans.”

 

Update (October 6, 11:57 a.m.): O’Keefe and Lynn Nadel met as graduate students at McGill University in Montreal. In 1978, when Nadel was a lecturer at University College London, the two coauthored the seminal book The Hippocampus as a Cognitive Map. “We pursued the spatial map story for some years together, and we still do so separately,” Nadel, who is now a professor of psychology at the University of Arizona, told The Scientist. “From my point of view, this award really recognizes the whole enterprise of looking at cognition in terms of brain function,” he added. “It’s pretty cool.”

 

Correction (October 6, 9:58 a.m.): This article has been updated to correct Witter's previous affiliation; he was at VU University Amsterdam when he first met the Mosers.

 

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Total Lunar Eclipse On Wednesday Will Be a Rare 'Selenelion'

By Joe Rao, Space.com Skywatching Columnist   |   October 06, 2014 01:35pm ET





A photo of the first total lunar

eclipse of 2014 taken from

Arizona.

Credit: Ron Delvaux via The Virtual

Telescope Project

View full size image

Observers of Wednesday morning's total lunar eclipse might be able to catch sight of an extremely rare cosmic sight.

 

On Oct. 8, Interested skywatchers should attempt to see the total eclipse of the moon and the rising sun simultaneously. The little-used name for this effect is called a "selenelion," a phenomenon that celestial geometry says cannot happen.

 

And indeed, during a lunar eclipse, the sun and moon are exactly 180 degrees apart in the sky. In a perfect alignment like this (called a "syzygy"), such an observation would seem impossible. But thanks to Earth's atmosphere, the images of both the sun and moon are apparently lifted above the horizon by atmospheric refraction. This allows people on Earth to see the sun for several extra minutes before it actually has risen and the moon for several extra minutes after it has actually set. [How to See the Total Lunar Eclipse (Visibility Maps)]

As a consequence of this atmospheric trick, for many localities east of the Mississippi River, watchers will have a chance to observe this unusual sight firsthand. Weather permitting, you could have a short window of roughly 2 to 9 minutes (depending on your location) with the possibility of simultaneously seeing the sun rising in the east while the eclipsed full moon is setting in the west.

 

Regions of visibility

 

From Newfoundland, the start of the partial stages of the total eclipse begins about 30 to 45 minutes before moonset.

 

A growing scallop of darkness will appear on the upper left part of the moon when it sets as the sun is coming up. Across eastern Nova Scotia, only the lowermost portion of the moon will be in view as it drops below the western horizon. Farther to the west and south along the Atlantic seaboard, the moon will rise completely immersed in the Earth's shadow.

 

The map shows the visibility regions for the Oct. 8, 2014 total lunar eclipse, which is

the second of four consecutive total eclipses of the moon between 2014 and 2015.

Sky & Telescope Magazine released this viewing map.

Credit: Sky & Telescope Magazine

View full size image

Now you see it … now you don't?

Then again, sighting a selenelion might be problematic feat. Twenty-five years ago, in the August 1989 issue of Sky & Telescope, Bradley Schaefer, an astronomer who extensively studied the visibility of the moon when it was low in the sky, noted that the full moon only becomes visible when it is about 2 degrees up and the sun is about 2 degrees below the horizon.

So, depending on the clarity of your sky, you might have up to roughly 10 to 15 minutes before sunrise for the sky to still be dark enough, and the moon to be high enough above any horizon haze for it to be clearly visible. And keep in mind that this holds only for the uneclipsed portion of the moon. You might, however, be able to mitigate the effects of a brightening sky somewhat by using binoculars or a telescope.

If the moon is totally eclipsed prior to sunrise, you probably are going to have to scan the western horizon with binoculars as the twilight brightens in order to still detect some semblance of the Moon, which will somewhat resemble a very dim and eerily illuminated mottled softball.

This chart shows the times of the end-stages of a total lunar eclipse taking place on

Oct. 8, 2014.

Credit: Space.com/Joe Rao

View full size image

 

A peculiar moonset

A series of four total

lunar eclipses in a row

is called a tetrad. See

how four blood moons

of a total lunar eclipse

tetrad work in this

Space.com infographic.

Credit: By Karl Tate,

Infographics Artist

View full size image

 

People who live in those portions of the United States and Canada that are a few hundred miles inland from the Eastern Seaboard should have a good view of the Moon's emergence from the umbra somewhat later. The low, partially eclipsed Moon in deep-blue twilight should offer a wide variety of interesting scenic possibilities for both artists and astrophotographers. From Toronto and points south through the eastern Ohio Valley and into the Piedmont to the Florida Gulf Coast, a peculiar-looking, waxing crescent moon with its cusps pointing downward will appear to set beyond the western horizon.

 

Farther west, across the western Great Lakes and down through the Deep South to the Gulf of Mexico, the moon will appear to be notched on its lower right side by the shadow.

Going still farther west, the Moon will go down "full," but if the western horizon is haze-free, assiduous observers from much of Minnesota, western Iowa, eastern portions of Nebraska and Kansas as well as central sections of Oklahoma and Texas might still be able to detect a faint penumbral stain on the moon's lower right limb.

 

Editor's Note: If you snap an amazing picture of the Oct. 8 total lunar eclipse, you can send photos, comments and your name and location to managing editor Tariq Malik at spacephotos@space.com.

Joe Rao serves as an instructor and guest lecturer at New York's Hayden Planetarium. He writes about astronomy for Natural History magazine, the Farmer's Almanac and other publications, and he is also an on-camera meteorologist for News 12 Westchester, N.Y. Follow us @Spacedotcom, Facebook and Google+. Original article on Space.com.

 

Editor's Recommendations

• October's Lunar Eclipse Won't Be Unusually Dark | Video
• Moon Turns Red - Lunar Eclipse Time-Lapse Video
• The Moon: 10 Surprising Lunar Facts

Author Bio

                      

Joe Rao

 

Joe Rao is a television meteorologist in the Hudson Valley, appearing weeknights on News 12 Westchester. He has also been an assiduous amateur astronomer for over 45 years, with a particular interest in comets, meteor showers and eclipses. He has co-led two eclipse expeditions and has served as on-board meteorologist for three eclipse cruises. He is also a contributing editor for Sky & Telescope and writes a monthly astronomy column for Natural History magazine as well as supplying astronomical data to the Farmers' Almanac. Since 1986 he has served as an Associate and Guest Lecturer at New York's Hayden Planetarium. In 2009, the Northeast Region of the Astronomical League bestowed upon him the prestigious Walter Scott Houston Award for more than four decades of promoting astronomy to the general public.

Joe Rao on   

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How Do You Get Herpes?

A cold sore on this patient’s lip was caused by the herpes simplex virus type 1 (HSV-1).
Credit: cdc.gov
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Herpes, a very common viral infection, spreads by person-to-person contact.

 

The infection is caused by the herpes simplex virus (HSV), which comes in two forms: HSV-1, which usually results in oral herpes infections affecting the mouth and lips; and HSV-2, which usually causes genital herpes affecting the genitals and anus.

 

Both types of HSV spread primarily by physical contact with an infected person. Most people get HSV-2 during sexual intercourse (vaginal or anal). HSV-1 tends to spread to individuals in childhood, when an adult who carries the virus touches the child — for example, by pinching a baby's cheeks. Among adults, HSV-1 usually spreads by kissing.

 

However, HSV-1 can also spread to the genitals during oral sex, while HSV-2 infections in the genitals can spread to the mouth during oral sex.

 

About 50 to 80 percent of U.S. adults carry HSV-1 (oral herpes), while 20 percent of people age 12 and older have HSV-2. In many cases, however, individuals with the virus don't know they have it. In fact, an estimated 90 percent of people with HSV-2 don't know they're infected.

 

That's because many people carry herpes without showing any signs of it. One symptom of a herpes infection is the presence of sores around the mouth, genitals or anus. These sores appear during a so-called herpes "outbreak" but usually clear up on their own.

 

The virus, however, never goes away — once you've been infected with herpes, it sticks with you forever. Most of that time, it will be dormant, living in your nerve cells (instead of in the skin cells, where it can cause sores).

 

People with dormant herpes virus can still pass it to others, though outbreaks of herpes sores make transmission more likely. Using barriers like condoms and dental dams during sex can lower your risk of getting herpes, but they are not 100 percent effective.

 

By Michael Dhar, Live Science Contributor   |   February 25, 2014 02:10pm ET

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