Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase

Nature Medicine 14, 723 (2008). doi:10.1038/nm1784

Authors: Mohammad Ali Faghihi, Farzaneh Modarresi, Ahmad M Khalil, Douglas E Wood, Barbara G Sahagan, Todd E Morgan, Caleb E Finch, Georges St. Laurent III, Paul J Kenny & Claes Wahlestedt

The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis

Nature Medicine 14, 748 (2008). doi:10.1038/nm1763

Authors: Kirsten Neubert, Silke Meister, Katrin Moser, Florian Weisel, Damian Maseda, Kerstin Amann, Carsten Wiethe, Thomas H Winkler, Joachim R Kalden, Rudolf A Manz & Reinhard E Voll

Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke

Nature Medicine 14, 731 (2008). doi:10.1038/nm1787

Authors: Enming J Su, Linda Fredriksson, Melissa Geyer, Erika Folestad, Jacqueline Cale, Johanna Andrae, Yamei Gao, Kristian Pietras, Kris Mann, Manuel Yepes, Dudley K Strickland, Christer Betsholtz, Ulf Eriksson & Daniel A Lawrence

TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

Nature Medicine 14, 738 (2008). doi:10.1038/nm1758

Authors: Shinichiro Yamamoto, Shunichi Shimizu, Shigeki Kiyonaka, Nobuaki Takahashi, Teruaki Wajima, Yuji Hara, Takaharu Negoro, Toshihito Hiroi, Yuji Kiuchi, Takaharu Okada, Shuji Kaneko, Ingo Lange, Andrea Fleig, Reinhold Penner, Miyuki Nishi, Hiroshi Takeshima & Yasuo Mori

Hepatic insulin resistance directly promotes formation of cholesterol gallstones

Nature Medicine 14, 778 (2008). doi:10.1038/nm1785

Authors: Sudha B Biddinger, Joel T Haas, Bian B Yu, Olivier Bezy, Enxuan Jing, Wenwei Zhang, Terry G Unterman, Martin C Carey & C Ronald Kahn

Despite the well-documented association between gallstones and the metabolic syndrome, the mechanistic links between these two disorders remain unknown. Here we show that mice solely with hepatic insulin resistance, created by liver-specific disruption of the insulin receptor (LIRKO mice) are markedly predisposed toward cholesterol gallstone formation due to at least two distinct mechanisms. Disinhibition of the forkhead transcription factor FoxO1, increases expression of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cholesterol secretion. Hepatic insulin resistance also decreases expression of the bile acid synthetic enzymes, particularly Cyp7b1, and produces partial resistance to the farnesoid X receptor, leading to a lithogenic bile salt profile. As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility.

SNO-hemoglobin is not essential for red blood cell–dependent hypoxic vasodilation

Nature Medicine 14, 773 (2008). doi:10.1038/nm1771

Authors: T Scott Isbell, Chiao-Wang Sun, Li-Chen Wu, Xinjun Teng, Dario A Vitturi, Billy G Branch, Christopher G Kevil, Ning Peng, J Michael Wyss, Namasivayam Ambalavanan, Lisa Schwiebert, Jinxiang Ren, Kevin M Pawlik, Matthew B Renfrow, Rakesh P Patel & Tim M Townes

The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing–NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin β-chain (βCys93) and, specifically, for S-nitrosation of βCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the βCys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell–mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of βCys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell–dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo.

Aggravation of viral hepatitis by platelet-derived serotonin

Nature Medicine 14, 756 (2008). doi:10.1038/nm1780

Authors: Philipp A Lang, Claudio Contaldo, Panco Georgiev, Ashraf Mohammad El-Badry, Mike Recher, Michael Kurrer, Luisa Cervantes-Barragan, Burkhard Ludewig, Thomas Calzascia, Beatrice Bolinger, Doron Merkler, Bernhard Odermatt, Michael Bader, Rolf Graf, Pierre-Alain Clavien, Ahmed N Hegazy, Max Löhning, Nicola L Harris, Pamela S Ohashi, Hans Hengartner, Rolf M Zinkernagel & Karl S Lang

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8+ T cell–dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8+ T cell–dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8+ T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.

Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs

Nature Medicine 14, 762 (2008). doi:10.1038/nm1777

Authors: Lin Shen, Susan Peterson, Ahmad R Sedaghat, Moira A McMahon, Marc Callender, Haili Zhang, Yan Zhou, Eleanor Pitt, Karen S Anderson, Edward P Acosta & Robert F Siliciano

Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC50 and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of ∼1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.

Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging

Nature Medicine 14, 767 (2008). doi:10.1038/nm1786

Authors: Ignacio Varela, Sandrine Pereira, Alejandro P Ugalde, Claire L Navarro, María F Suárez, Pierre Cau, Juan Cadiñanos, Fernando G Osorio, Nicolas Foray, Juan Cobo, Félix de Carlos, Nicolas Lévy, José M P Freije & Carlos López-Otín

Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LAΔ50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.

Molecular imaging of lymphoid organs and immune activation by positron emission tomography with a new [18F]-labeled 2′-deoxycytidine analog

Nature Medicine 14, 783 (2008). doi:10.1038/nm1724

Authors: Caius G Radu, Chengyi J Shu, Evan Nair-Gill, Stephanie M Shelly, Jorge R Barrio, Nagichettiar Satyamurthy, Michael E Phelps & Owen N Witte

Just spit it out

Nature Medicine 14, 706 (2008). doi:10.1038/nm0708-706

Author: Trisha Gura

The microbes that inhabit the human mouth have a lot to say about one's general health. That's part of the motivation behind a massive new push to catalog these oral bacteria. Trisha Gura finds out why researchers believe that the study of saliva deserves more than just lip service.

Chipping away at gallstones

Nature Medicine 14, 715 (2008). doi:10.1038/nm0708-715

Authors: Folkert Kuipers & Albert K Groen

Gallstone disease occurs more frequently in subjects with the metabolic syndrome and type 2 diabetes. Findings in a mouse model suggest that the forkhead transcription factor FoxO1 lies behind this association (pages 778–782).

Bench to Bedside: Soothing the seizures of children

Nature Medicine 14, 721 (2008). doi:10.1038/nm0708-721

Authors: Beat Lutz & Krisztina Monory

Endocannabinoids are versatile molecules, regulating a variety of functions in the body. Daniele Piomelli explores how recent clinical trials testing rimonabant, an inhibitor of endocannabinoid signaling, for weight loss emerged from studies of individuals with schizophrenia; such trials have spurred basic research into how endocannabinoids affect both energy use and mood. Beat Lutz and Krisztina Monory examine how rimonabant might prove useful for preventing the development of adult epilepsy in response to fever-induced seizures in infants and young children.

Rejuvenating premature aging

Nature Medicine 14, 713 (2008). doi:10.1038/nm0708-713

Authors: Eran Meshorer & Yosef Gruenbaum

Two commonly prescribed drugs, statins and aminobisphosphonates, may be helpful in combating the rare aging disorder, Hutchinson-Gilford progeria syndrome (pages 767–772).

Imatinib buys time for brain after stroke

Nature Medicine 14, 712 (2008). doi:10.1038/nm0708-712

Author: Peter Rieckmann

The most effective drug to treat acute ischemic stroke, tissue plasminogen activator (tPA), must be applied within three hours after symptom onset because of the risk of hemorrhage and other complications such as neurotoxicity. The anticancer drug imatinib (Gleevec) may help overcome these limitations by counteracting the ability of tPA to increase the permeability of the blood-brain barrier (pages 731–737).

Regulatory RNA goes awry in Alzheimer's disease

Nature Medicine 14, 711 (2008). doi:10.1038/nm0708-711

Authors: Peter St George-Hyslop & Christian Haass

An antisense RNA may contribute to Alzheimer's disease by upregulating β-secretase (pages 723–730).

The great pretenders

Nature Medicine 14, 695 (2008). doi:10.1038/nm0708-695

Some analysts believe that the economic hegemony of the US is on its last legs, but the same does not seem to be true of its scientific supremacy.

Straight talk with...Charles Rotimi

Nature Medicine 14, 704 (2008). doi:10.1038/nm0708-704

When Charles Rotimi moved from his native Nigeria in January 1982 to study public health at the University of Mississippi, he came face to face with a startling problem. In his coursework and daily life, he grappled with the question of why some US groups—in particular African-Americans—suffered overall poorer health than others, such as those of European ancestry. He's now poised to help answer that question as the head of the new Intramural Center for Genomics and Health Disparities, launched in March in Bethesda, Maryland, as part of the US National Institutes of Health (NIH). Charlotte Schubert talked with Rotimi about how perceptions of race influence research and medicine—and how genetics can be used to help break down stereotypes.