Nature Medicine

Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export.

Publication Date: 2012 Jan 29 PMID: 22286308
Authors: Lei, P. - Ayton, S. - Finkelstein, D. I. - Spoerri, L. - Ciccotosto, G. D. - Wright, D. K. - Wong, B. X. - Adlard, P. A. - Cherny, R. A. - Lam, L. Q. - Roberts, B. R. - Volitakis, I. - Egan, G. F. - McLean, C. A. - Cappai, R. - Duce, J. A. - Bush, A. I.
Journal: Nat Med

The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.

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Preexisting influenza-specific CD4(+) T cells correlate with disease protection against influenza challenge in humans.

Publication Date: 2012 Jan 29 PMID: 22286307
Authors: Wilkinson, T. M. - Li, C. K. - Chui, C. S. - Huang, A. K. - Perkins, M. - Liebner, J. C. - Lambkin-Williams, R. - Gilbert, A. - Oxford, J. - Nicholas, B. - Staples, K. J. - Dong, T. - Douek, D. C. - McMichael, A. J. - Xu, X. N.
Journal: Nat Med

Protective immunity against influenza virus infection is mediated by neutralizing antibodies, but the precise role of T cells in human influenza immunity is uncertain. We conducted influenza infection studies in healthy volunteers with no detectable antibodies to the challenge viruses H3N2 or H1N1. We mapped T cell responses to influenza before and during infection. We found a large increase in influenza-specific T cell responses by day 7, when virus was completely cleared from nasal samples and serum antibodies were still undetectable. Preexisting CD4(+), but not CD8(+), T cells responding to influenza internal proteins were associated with lower virus shedding and less severe illness. These CD4(+) cells also responded to pandemic H1N1 (A/CA/07/2009) peptides and showed evidence of cytotoxic activity. These cells are an important statistical correlate of homotypic and heterotypic response and may limit severity of influenza infection by new strains in the absence of specific antibody responses. Our results provide information that may aid the design of future vaccines against emerging influenza strains.

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A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy.

Publication Date: 2012 Jan 29 PMID: 22286306
Authors: Zhang, G. - Guo, B. - Wu, H. - Tang, T. - Zhang, B. T. - Zheng, L. - He, Y. - Yang, Z. - Pan, X. - Chow, H. - To, K. - Li, Y. - Li, D. - Wang, X. - Wang, Y. - Lee, K. - Hou, Z. - Dong, N. - Li, G. - Leung, K. - Hung, L. - He, F. - Zhang, L. - Qin, L.
Journal: Nat Med

Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.

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MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy.

Publication Date: 2012 Jan 29 PMID: 22286305
Authors: Liu, P. T. - Wheelwright, M. - Teles, R. - Komisopoulou, E. - Edfeldt, K. - Ferguson, B. - Mehta, M. D. - Vazirnia, A. - Rea, T. H. - Sarno, E. N. - Graeber, T. G. - Modlin, R. L.
Journal: Nat Med

Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae-infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.

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2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas.

Publication Date: 2012 Jan 26 PMID: 22281806
Authors: Choi, C. - Ganji, S. K. - Deberardinis, R. J. - Hatanpaa, K. J. - Rakheja, D. - Kovacs, Z. - Yang, X. L. - Mashimo, T. - Raisanen, J. M. - Marin-Valencia, I. - Pascual, J. M. - Madden, C. J. - Mickey, B. E. - Malloy, C. M. - Bachoo, R. M. - Maher, E. A.
Journal: Nat Med

Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.

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Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer.

Publication Date: 2012 Jan 22 PMID: 22270724
Authors: Montagut, C. - Dalmases, A. - Bellosillo, B. - Crespo, M. - Pairet, S. - Iglesias, M. - Salido, M. - Gallen, M. - Marsters, S. - Tsai, S. P. - Minoche, A. - Somasekar, S. - Serrano, S. - Himmelbauer, H. - Bellmunt, J. - Rovira, A. - Settleman, J. - Bosch, F. - Albanell, J.
Journal: Nat Med

Antibodies against epidermal growth factor receptor (EGFR)-cetuximab and panitumumab-are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

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Prostaglandin E(2) promotes intestinal tumor growth via DNA methylation.

Publication Date: 2012 Jan 22 PMID: 22270723
Authors: Xia, D. - Wang, D. - Kim, S. H. - Katoh, H. - Dubois, R. N.
Journal: Nat Med

Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear. Here we show that prostaglandin E(2) (PGE(2)) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression.

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Magnetic resonance imaging of glutamate.

Publication Date: 2012 Jan 22 PMID: 22270722
Authors: Cai, K. - Haris, M. - Singh, A. - Kogan, F. - Greenberg, J. H. - Hariharan, H. - Detre, J. A. - Reddy, R.
Journal: Nat Med

Glutamate, a major neurotransmitter in the brain, shows a pH- and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging by nuclear magnetic resonance. GluCEST asymmetry is observed approximately 3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an approximately 100% elevation of GluCEST in the ipsilateral side compared with the contralateral side, predominantly owing to pH changes. In a rat brain tumor model with blood-brain barrier disruption, intravenous glutamate injection resulted in a clear elevation of GluCEST and a similar increase in the proton magnetic resonance spectroscopy signal of glutamate. GluCEST maps from healthy human brain were also obtained. These results demonstrate the feasibility of using GluCEST for mapping relative changes in glutamate concentration, as well as pH, in vivo. Contributions from other brain metabolites to the GluCEST effect are also discussed.

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cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.

Publication Date: 2012 Jan 22 PMID: 22270721
Authors: Jaumann, M. - Dettling, J. - Gubelt, M. - Zimmermann, U. - Gerling, A. - Paquet-Durand, F. - Feil, S. - Wolpert, S. - Franz, C. - Varakina, K. - Xiong, H. - Brandt, N. - Kuhn, S. - Geisler, H. S. - Rohbock, K. - Ruth, P. - Schlossmann, J. - Hutter, J. - Sandner, P. - Feil, R. - Engel, J. - Knipper, M. - Ruttiger, L.
Journal: Nat Med

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.

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Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension.

Publication Date: 2012 Jan 15 PMID: 22245782
Authors: Prysyazhna, O. - Rudyk, O. - Eaton, P.
Journal: Nat Med

Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control. Hydrogen peroxide (H(2)O(2)) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H(2)O(2) causes the formation of a disulfide bond between the two alpha subunits of protein kinase G I-alpha (PKGI-alpha), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-alpha oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S 'redox-dead' version of PKGI-alpha. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H(2)O(2) on resistance vessels and resulted in hypertension in vivo.

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Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus.

Publication Date: 2012 Jan 15 PMID: 22245781
Authors: Bird-Lieberman, E. L. - Neves, A. A. - Lao-Sirieix, P. - O'Donovan, M. - Novelli, M. - Lovat, L. B. - Eng, W. S. - Mahal, L. K. - Brindle, K. M. - Fitzgerald, R. C.
Journal: Nat Med

Barrett's esophagus is an example of a pre-invasive state, for which current endoscopic surveillance methods to detect dysplasia are time consuming and inadequate. The prognosis of cancer arising in Barrett's esophagus is improved by early detection at the stage of mucosal carcinoma or high-grade dysplasia. Molecular imaging methods could revolutionize the detection of dysplasia, provided they permit a wide field of view and highlight abnormalities in real time. We show here that cell-surface glycans are altered in the progression from Barrett's esophagus to adenocarcinoma and lead to specific changes in lectin binding patterns. We chose wheat germ agglutinin as a candidate lectin with clinical potential. The binding of wheat germ agglutinin to human tissue was determined to be specific, and we validated this specific binding by successful endoscopic visualization of high-grade dysplastic lesions, which were not detectable by conventional endoscopy, with a high signal-to-background ratio of over 5.

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Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids.

Publication Date: 2012 Jan 15 PMID: 22245780
Authors: Wang, W. - Lv, N. - Zhang, S. - Shui, G. - Qian, H. - Zhang, J. - Chen, Y. - Ye, J. - Xie, Y. - Shen, Y. - Wenk, M. R. - Li, P.
Journal: Nat Med

Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPbeta onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBPbeta to regulate expression of a subset of C/EBPbeta downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPbeta in mammary glands to control lipid secretion and pup survival.

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An essential role for T(H)2-type responses in limiting acute tissue damage during experimental helminth infection.

Publication Date: 2012 Jan 15 PMID: 22245779
Authors: Chen, F. - Liu, Z. - Wu, W. - Rozo, C. - Bowdridge, S. - Millman, A. - Van Rooijen, N. - Urban, J. F. Jr - Wynn, T. A. - Gause, W. C.
Journal: Nat Med

Helminths induce potent T helper 2 (T(H)2)-type immune responses that can mediate worm expulsion, but the role of this response in controlling the acute tissue damage caused by migrating multicellular parasites through vital tissues remains uncertain. We used a helminth infection model in which parasitic nematode larvae migrate transiently through the lung, resulting in hemorrhage and inflammation. We found that IL-17 initially contributed to inflammation and lung damage, whereas subsequent IL-4 receptor (IL-4R) signaling reduced elevations in IL-17 mRNA levels, enhanced the expression of insulin-like growth factor 1 (IGF-1) and IL-10 and stimulated the development of M2 macrophages, all of which contributed to the rapid resolution of tissue damage. These studies indicate an essential role for T(H)2-type immune responses in mediating acute wound healing during helminth infection.

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Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia.

Publication Date: 2012 Jan 11 PMID: 22237151
Authors: Ntziachristos, P. - Tsirigos, A. - Van Vlierberghe, P. - Nedjic, J. - Trimarchi, T. - Sol Flaherty, M. - Ferres-Marco, D. - da Ros, V. - Tang, Z. - Siegle, J. - Asp, P. - Hadler, M. - Rigo, I. - De Keersmaecker, K. - Patel, J. - Huynh, T. - Utro, F. - Poglio, S. - Samon, J. B. - Paietta, E. - Racevskis, J. - Rowe, J. M. - Rabadan, R. - Levine, R. L. - Brown, S. - Pflumio, F. - Dominguez, M. - Ferrando, A. - Aifantis, I.
Journal: Nat Med

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

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A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20.

Publication Date: 2012 Jan 8 PMID: 22231558
Authors: Blank, M. - Tang, Y. - Yamashita, M. - Burkett, S. S. - Cheng, S. Y. - Zhang, Y. E.
Journal: Nat Med

In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here we show that genomic ablation of Smad ubiquitin regulatory factor 2 (Smurf2), a HECT-domain E3 ubiquitin ligase, results in dysregulation of both the DNA damage response and genomic stability, culminating in increased susceptibility to various types of cancers in aged mice. We show that Smurf2 regulates the monoubiquitination of histone H2B as well as the trimethylation of histone H3 at Lys4 and Lys79 by targeting ring finger protein 20 (RNF20) for proteasomal degradation in both mouse and human cells. We also show that Smurf2 and RNF20 are colocalized at the gamma-H2AX foci of double-stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.

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Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor.

Publication Date: 2012 Jan 8 PMID: 22231557
Authors: Sainz, B. Jr - Barretto, N. - Martin, D. N. - Hiraga, N. - Imamura, M. - Hussain, S. - Marsh, K. A. - Yu, X. - Chayama, K. - Alrefai, W. A. - Uprichard, S. L.
Journal: Nat Med

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With approximately 170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.

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AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation.

Publication Date: 2012 Jan 8 PMID: 22231556
Authors: Lanner, J. T. - Georgiou, D. K. - Dagnino-Acosta, A. - Ainbinder, A. - Cheng, Q. - Joshi, A. D. - Chen, Z. - Yarotskyy, V. - Oakes, J. M. - Lee, C. S. - Monroe, T. O. - Santillan, A. - Dong, K. - Goodyear, L. - Ismailov, I. I. - Rodney, G. G. - Dirksen, R. T. - Hamilton, S. L.
Journal: Nat Med

Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that is associated with malignant hyperthermia in humans, die when exposed to short periods of temperature elevation (>/=37 degrees C). We show here that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents this heat-induced sudden death in this mouse model. The protection by AICAR is independent of AMP-activated protein kinase (AMPK) activation and results from a newly identified action of the compound on mutant Ryr1 to reduce Ca(2+) leak from the sarcoplasmic reticulum to the sarcoplasm. AICAR thus prevents Ca(2+)-dependent increases in the amount of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) that act to further increase resting Ca(2+) concentrations. If unchecked, the temperature-driven increases in resting Ca(2+) concentrations and the amounts of ROS and RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents heat-induced death in vivo. Our findings suggest that AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations.

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Autoimmunity's next top models.

Publication Date: 2012 PMID: 22227675
Authors: Wekerle, H. - Flugel, A. - Fugger, L. - Schett, G. - Serreze, D.
Journal: Nat Med

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Optimization of current and future therapy for autoimmune diseases.

Publication Date: 2012 PMID: 22227674
Authors: Steinman, L. - Merrill, J. T. - McInnes, I. B. - Peakman, M.
Journal: Nat Med

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Re-establishing immunological self-tolerance in autoimmune disease.

Publication Date: 2012 PMID: 22227673
Authors: Sakaguchi, S. - Powrie, F. - Ransohoff, R. M.
Journal: Nat Med

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The problems and promises of research into human immunology and autoimmune disease.

Publication Date: 2012 PMID: 22227672
Authors: Roep, B. O. - Buckner, J. - Sawcer, S. - Toes, R. - Zipp, F.
Journal: Nat Med

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Dysregulation of immune homeostasis in autoimmune diseases.

Publication Date: 2012 PMID: 22227671
Authors: Kuchroo, V. K. - Ohashi, P. S. - Sartor, R. B. - Vinuesa, C. G.
Journal: Nat Med

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Unraveling the autoimmune translational research process layer by layer.

Publication Date: 2012 PMID: 22227670
Authors: Blumberg, R. S. - Dittel, B. - Hafler, D. - von Herrath, M. - Nestle, F. O.
Journal: Nat Med

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Psychiatric disorders: Partners in crime.

Publication Date: 2012 PMID: 22227669
Authors: Chmielnicki, E.
Journal: Nat Med

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Antimicrobials: An alternative strategy.

Publication Date: 2012 PMID: 22227668
Authors: Swami, M.
Journal: Nat Med

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Immunology: Dendritic cell demise.

Publication Date: 2012 PMID: 22227667
Authors: Da Silva, K.
Journal: Nat Med

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Metabolism: Athero: all but Sirt-ain?

Publication Date: 2012 PMID: 22227666
Authors: Levinson, R.
Journal: Nat Med

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Tumor strengths and frailties: Aspiring to prevent colon cancer.

Publication Date: 2012 PMID: 22227665
Authors: Maxwell, P. H.
Journal: Nat Med

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Tumor strengths and frailties: Cancer SUMmOns Otto's metabolism.

Publication Date: 2012 PMID: 22227664
Authors: Ohh, M.
Journal: Nat Med

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The value of HPV vaccination.

Publication Date: 2012 PMID: 22227663
Authors:
Journal: Nat Med

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Telomerase at the center of collapsing glomerulopathy.

Publication Date: 2012 PMID: 22227662
Authors: Chugh, S. S. - Clement, L. C.
Journal: Nat Med

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Finding a sirtuin truth in Huntington's disease.

Publication Date: 2012 PMID: 22227661
Authors: La Spada, A. R.
Journal: Nat Med

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PDGF-B exploits stromal EPO.

Publication Date: 2012 PMID: 22227660
Authors: McGinnis, L. M. - Kuo, C. J.
Journal: Nat Med

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Host defense against malaria favors Salmonella.

Publication Date: 2012 PMID: 22227659
Authors: Maclennan, C. A.
Journal: Nat Med

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Socially acceptable.

Publication Date: 2012 PMID: 22227658
Authors: Sanders, L.
Journal: Nat Med

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One way to help science: become Republican.

Publication Date: 2012 PMID: 22227657
Authors: Otto, S. L.
Journal: Nat Med

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An act of tolerance.

Publication Date: 2012 PMID: 22227656
Authors: Dolgin, E.
Journal: Nat Med

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News in brief: Biomedical briefing.

Publication Date: 2012 PMID: 22227655
Authors:
Journal: Nat Med

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Straight talk with... Ronald DePinho.

Publication Date: 2012 PMID: 22227654
Authors: Hersher, R.
Journal: Nat Med

On 1 September, Ronald DePinho became the new president of the MD Anderson Cancer Center at the University of Texas in Houston. He arrives there after 14 years at the Dana-Farber Cancer Institute in Boston, where he was founding director of the renowned Belfer Center for Applied Cancer Research. DePinho is now in charge of remaking Houston as a hub for cancer drug development on par with Boston, and one of the first items on his agenda as president of MD Anderson is overseeing the creation of a new Institute for Applied Cancer Science. His wife, cancer geneticist Lynda Chin, is the scientific director for the institute, which is backed by a five-year $75 million base contribution from the University of Texas system promised in July. The power couple has already lured 22 principal investigators to the institute from their previous home in Boston. And DePinho has promised that by the second quarter of the 2012 fiscal year the new institute will be at or above the basic science capacity of the operation he left behind at the Belfer Center. Rebecca Hersher spoke with him about his decision to go to the Lone Star State and the current status of the cancer field.

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New NIH genetics center focuses its lens on exome, despite doubts.

Publication Date: 2012 PMID: 22227653
Authors: Waters, H.
Journal: Nat Med

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HHS ruling on Plan B introduces new risk for drugmakers.

Publication Date: 2012 PMID: 22227652
Authors: Willyard, C.
Journal: Nat Med

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Correction.

Publication Date: 2012 PMID: 22227651
Authors:
Journal: Nat Med

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Next-generation proteasome blockers promise safer cancer therapy.

Publication Date: 2012 PMID: 22227650
Authors: Mullard, A.
Journal: Nat Med

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Are drugmakers fishing for a market with prescription omega-3s?

Publication Date: 2012 PMID: 22227649
Authors: Hersher, R.
Journal: Nat Med

post to: CiteULike

Drugmaker reaps what it sows with first plant-made biologic.

Publication Date: 2012 PMID: 22227648
Authors: Williams, S. C.
Journal: Nat Med

post to: CiteULike

EU court gets tough on patent extensions for combo products.

Publication Date: 2012 PMID: 22227647
Authors: Waters, H.
Journal: Nat Med

post to: CiteULike

More trials are cut short, but not the debate over their trajectory.

Publication Date: 2012 PMID: 22227646
Authors: Venkataramanan, M.
Journal: Nat Med

post to: CiteULike

Biotech entrepreneurs swoon over proposed fundraising changes.

Publication Date: 2012 PMID: 22227645
Authors: Venkataramanan, M.
Journal: Nat Med

post to: CiteULike

Fighting science with politics.

Publication Date: 2012 PMID: 22227644
Authors:
Journal: Nat Med

post to: CiteULike