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

Nat Med. 2012 Jan 29;

Authors: Liu PT, Wheelwright M, Teles R, Komisopoulou E, Edfeldt K, Ferguson B, Mehta MD, Vazirnia A, Rea TH, Sarno EN, Graeber TG, Modlin RL

Abstract

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.

PMID: 22286305 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 29;

Authors: Zhang G, Guo B, Wu H, Tang T, Zhang BT, 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

Abstract

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.

PMID: 22286306 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 29;

Authors: Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, Lambkin-Williams R, Gilbert A, Oxford J, Nicholas B, Staples KJ, Dong T, Douek DC, McMichael AJ, Xu XN

Abstract

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.

PMID: 22286307 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 29;

Authors: Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI

Abstract

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.

PMID: 22286308 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 26;

Authors: Choi C, Ganji SK, Deberardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, Yang XL, Mashimo T, Raisanen JM, Marin-Valencia I, Pascual JM, Madden CJ, Mickey BE, Malloy CM, Bachoo RM, Maher EA

Abstract

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.

PMID: 22281806 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 22;

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 HS, Rohbock K, Ruth P, Schlossmann J, Hütter J, Sandner P, Feil R, Engel J, Knipper M, Rüttiger L

Abstract

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.

PMID: 22270721 [PubMed - as supplied by publisher]

Magnetic resonance imaging of glutamate.

Nat Med. 2012 Jan 22;

Authors: Cai K, Haris M, Singh A, Kogan F, Greenberg JH, Hariharan H, Detre JA, Reddy R

Abstract

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 ∼3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an ∼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.

PMID: 22270722 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 22;

Authors: Xia D, Wang D, Kim SH, Katoh H, Dubois RN

Abstract

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.

PMID: 22270723 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 22;

Authors: Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Somasekar S, Serrano S, Himmelbauer H, Bellmunt J, Rovira A, Settleman J, Bosch F, Albanell J

Abstract

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.

PMID: 22270724 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 15;

Authors: Chen F, Liu Z, Wu W, Rozo C, Bowdridge S, Millman A, Van Rooijen N, Urban JF, Wynn TA, Gause WC

Abstract

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.

PMID: 22245779 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 15;

Authors: Wang W, Lv N, Zhang S, Shui G, Qian H, Zhang J, Chen Y, Ye J, Xie Y, Shen Y, Wenk MR, Li P

Abstract

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 β (C/EBPβ) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPβ 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/EBPβ to regulate expression of a subset of C/EBPβ downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPβ in mammary glands to control lipid secretion and pup survival.

PMID: 22245780 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 15;

Authors: Bird-Lieberman EL, Neves AA, Lao-Sirieix P, O’Donovan M, Novelli M, Lovat LB, Eng WS, Mahal LK, Brindle KM, Fitzgerald RC

Abstract

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.

PMID: 22245781 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 15;

Authors: Prysyazhna O, Rudyk O, Eaton P

Abstract

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 α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-α 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-α. 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.

PMID: 22245782 [PubMed - as supplied by publisher]

Three-dimensional imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury.

Nat Med. 2011;18(1):166-71

Authors: Ertürk A, Mauch CP, Hellal F, Förstner F, Keck T, Becker K, Jährling N, Steffens H, Richter M, Hübener M, Kramer E, Kirchhoff F, Dodt HU, Bradke F

Abstract

Studying regeneration in the central nervous system (CNS) is hampered by current histological and imaging techniques because they provide only partial information about axonal and glial reactions. Here we developed a tetrahydrofuran-based clearing procedure that renders fixed and unsectioned adult CNS tissue transparent and fully penetrable for optical imaging. In large spinal cord segments, we imaged fluorescently labeled cells by ‘ultramicroscopy’ and two-photon microscopy without the need for histological sectioning. We found that more than a year after injury growth-competent axons regenerated abundantly through the injury site. A few growth-incompetent axons could also regenerate when they bypassed the lesion. Moreover, we accurately determined quantitative changes of glial cells after spinal cord injury. Thus, clearing CNS tissue enables an unambiguous evaluation of axon regeneration and glial reactions. Our clearing procedure also renders other organs transparent, which makes this approach useful for a large number of preclinical paradigms.

PMID: 22198277 [PubMed - in process]

Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential.

Nat Med. 2011;18(1):143-7

Authors: Sela-Passwell N, Kikkeri R, Dym O, Rozenberg H, Margalit R, Arad-Yellin R, Eisenstein M, Brenner O, Shoham T, Danon T, Shanzer A, Sagi I

Abstract

Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes. Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy. TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues. We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease. Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs.

PMID: 22198278 [PubMed - in process]

Biotech entrepreneurs swoon over proposed fundraising changes.

Nat Med. 2012;18(1):3

Authors: Venkataramanan M

PMID: 22227645 [PubMed - in process]

Fighting science with politics.

Nat Med. 2012;18(1):1

Authors:

PMID: 22227644 [PubMed - in process]

EU court gets tough on patent extensions for combo products.

Nat Med. 2012;18(1):4

Authors: Waters H

PMID: 22227647 [PubMed - in process]

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

Nat Med. 2012;18(1):4

Authors: Venkataramanan M

PMID: 22227646 [PubMed - in process]

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

Nat Med. 2012;18(1):5

Authors: Williams SC

PMID: 22227648 [PubMed - in process]

Next-generation proteasome blockers promise safer cancer therapy.

Nat Med. 2012;18(1):7

Authors: Mullard A

PMID: 22227650 [PubMed - in process]

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

Nat Med. 2012;18(1):6

Authors: Hersher R

PMID: 22227649 [PubMed - in process]

HHS ruling on Plan B introduces new risk for drugmakers.

Nat Med. 2012;18(1):8

Authors: Willyard C

PMID: 22227652 [PubMed - in process]

Correction.

Nat Med. 2012;18(1):7

Authors:

PMID: 22227651 [PubMed - in process]

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

Nat Med. 2012;18(1):8

Authors: Waters H

PMID: 22227653 [PubMed - in process]

Straight talk with… Ronald DePinho.

Nat Med. 2012;18(1):9

Authors: Hersher R

Abstract

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.

PMID: 22227654 [PubMed - in process]

An act of tolerance.

Nat Med. 2012;18(1):12-6

Authors: Dolgin E

PMID: 22227656 [PubMed - in process]

News in brief: Biomedical briefing.

Nat Med. 2012;18(1):10-1

Authors:

PMID: 22227655 [PubMed - in process]

One way to help science: become Republican.

Nat Med. 2012;18(1):17

Authors: Otto SL

PMID: 22227657 [PubMed - in process]

Socially acceptable.

Nat Med. 2012;18(1):19

Authors: Sanders L

PMID: 22227658 [PubMed - in process]

Host defense against malaria favors Salmonella.

Nat Med. 2012;18(1):21-2

Authors: Maclennan CA

PMID: 22227659 [PubMed - in process]

PDGF-B exploits stromal EPO.

Nat Med. 2012;18(1):22-4

Authors: McGinnis LM, Kuo CJ

PMID: 22227660 [PubMed - in process]

Finding a sirtuin truth in Huntington’s disease.

Nat Med. 2012;18(1):24-6

Authors: La Spada AR

PMID: 22227661 [PubMed - in process]

Telomerase at the center of collapsing glomerulopathy.

Nat Med. 2012;18(1):26-7

Authors: Chugh SS, Clement LC

PMID: 22227662 [PubMed - in process]

The value of HPV vaccination.

Nat Med. 2012;18(1):28-9

Authors:

PMID: 22227663 [PubMed - in process]

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

Nat Med. 2012;18(1):30-1

Authors: Ohh M

PMID: 22227664 [PubMed - in process]

Tumor strengths and frailties: Aspiring to prevent colon cancer.

Nat Med. 2012;18(1):32-3

Authors: Maxwell PH

PMID: 22227665 [PubMed - in process]

Immunology: Dendritic cell demise.

Nat Med. 2012;18(1):34

Authors: Da Silva K

PMID: 22227667 [PubMed - in process]

Metabolism: Athero: all but Sirt-ain?

Nat Med. 2012;18(1):34

Authors: Levinson R

PMID: 22227666 [PubMed - in process]

Antimicrobials: An alternative strategy.

Nat Med. 2012;18(1):34

Authors: Swami M

PMID: 22227668 [PubMed - in process]

Psychiatric disorders: Partners in crime.

Nat Med. 2012;18(1):34

Authors: Chmielnicki E

PMID: 22227669 [PubMed - in process]

Unraveling the autoimmune translational research process layer by layer.

Nat Med. 2012;18(1):35-41

Authors: Blumberg RS, Dittel B, Hafler D, von Herrath M, Nestle FO

PMID: 22227670 [PubMed - in process]

Dysregulation of immune homeostasis in autoimmune diseases.

Nat Med. 2012;18(1):42-7

Authors: Kuchroo VK, Ohashi PS, Sartor RB, Vinuesa CG

PMID: 22227671 [PubMed - in process]

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

Nat Med. 2012;18(1):48-53

Authors: Roep BO, Buckner J, Sawcer S, Toes R, Zipp F

PMID: 22227672 [PubMed - in process]

Re-establishing immunological self-tolerance in autoimmune disease.

Nat Med. 2012;18(1):54-8

Authors: Sakaguchi S, Powrie F, Ransohoff RM

PMID: 22227673 [PubMed - in process]

Optimization of current and future therapy for autoimmune diseases.

Nat Med. 2012;18(1):59-65

Authors: Steinman L, Merrill JT, McInnes IB, Peakman M

PMID: 22227674 [PubMed - in process]

Autoimmunity’s next top models.

Nat Med. 2012;18(1):66-70

Authors: Wekerle H, Flügel A, Fugger L, Schett G, Serreze D

PMID: 22227675 [PubMed - in process]

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

Nat Med. 2012 Jan 8;

Authors: Lanner JT, Georgiou DK, Dagnino-Acosta A, Ainbinder A, Cheng Q, Joshi AD, Chen Z, Yarotskyy V, Oakes JM, Lee CS, Monroe TO, Santillan A, Dong K, Goodyear L, Ismailov II, Rodney GG, Dirksen RT, Hamilton SL

Abstract

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 °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.

PMID: 22231556 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 8;

Authors: Sainz B, Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S, Marsh KA, Yu X, Chayama K, Alrefai WA, Uprichard SL

Abstract

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼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.

PMID: 22231557 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 8;

Authors: Blank M, Tang Y, Yamashita M, Burkett SS, Cheng SY, Zhang YE

Abstract

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 γ-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.

PMID: 22231558 [PubMed - as supplied by publisher]

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

Nat Med. 2012 Jan 11;

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 JB, Paietta E, Racevskis J, Rowe JM, Rabadan R, Levine RL, Brown S, Pflumio F, Dominguez M, Ferrando A, Aifantis I

Abstract

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.

PMID: 22237151 [PubMed - as supplied by publisher]

Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway.

Nat Med. 2011 Dec 18;

Authors: Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, Yates JR, Bordone L, Guarente L, Krainc D

Abstract

Sirt1, a NAD-dependent protein deacetylase, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. Here we show that Sirt1 has a neuroprotective role in models of Huntington’s disease, an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein (HTT). Brain-specific knockout of Sirt1 results in exacerbation of brain pathology in a mouse model of Huntington’s disease, whereas overexpression of Sirt1 improves survival, neuropathology and the expression of brain-derived neurotrophic factor (BDNF) in Huntington’s disease mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant HTT. The neuroprotective effect of Sirt1 requires the presence of CREB-regulated transcription coactivator 1 (TORC1), a brain-specific modulator of CREB activity. We show that under normal conditions, Sirt1 deacetylates and activates TORC1 by promoting its dephosphorylation and its interaction with CREB. We identified BDNF as a key target of Sirt1 and TORC1 transcriptional activity in both normal and Huntington’s disease neurons. Mutant HTT interferes with the TORC1-CREB interaction to repress BDNF transcription, and Sirt1 rescues this defect in vitro and in vivo. These studies suggest a key role for Sirt1 in transcriptional networks in both the normal and Huntington’s disease brain and offer an opportunity for therapeutic development.

PMID: 22179316 [PubMed - as supplied by publisher]

ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.

Nat Med. 2011 Dec 18;

Authors: Hoetzenecker W, Echtenacher B, Guenova E, Hoetzenecker K, Woelbing F, Brück J, Teske A, Valtcheva N, Fuchs K, Kneilling M, Park JH, Kim KH, Kim KW, Hoffmann P, Krenn C, Hai T, Ghoreschi K, Biedermann T, Röcken M

Abstract

Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.

PMID: 22179317 [PubMed - as supplied by publisher]

Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization.

Nat Med. 2011 Dec 18;

Authors: Cunnington AJ, de Souza JB, Walther M, Riley EM

Abstract

In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plasmodium falciparum infection. Induction of heme oxygenase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis but might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We show that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Salmonella typhimurium) causes acute, fatal bacteremia with high bacterial load, features reproduced by phenylhydrazine-induced hemolysis or hemin administration. S. typhimurium localized predominantly in granulocytes. Py17XNL, phenylhydrazine and hemin caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. Inhibition of HO by tin protoporphyrin abrogated the impairment of resistance to S. typhimurium by hemolysis. Thus, a mechanism of tolerance to one infection, malaria, impairs resistance to another, NTS. Furthermore, HO inhibitors may be useful adjunctive therapy for NTS infection in the context of hemolysis.

PMID: 22179318 [PubMed - as supplied by publisher]

Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets.

Nat Med. 2011 Dec 18;

Authors: Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, Seredenina T, Arbez N, Zhu S, Sommers K, Qian J, Zhang J, Mori S, Yang XW, Tamashiro KL, Aja S, Moran TH, Luthi-Carter R, Martin B, Maudsley S, Mattson MP, Cichewicz RH, Ross CA, Holtzman DM, Krainc D, Duan W

Abstract

Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington’s disease pathogenesis and slowed disease progression in mice that model Huntington’s disease (Huntington’s disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington’s disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington’s disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington’s disease models and open new avenues for the development of neuroprotective strategies in Huntington’s disease.

PMID: 22179319 [PubMed - as supplied by publisher]

Reaction to retractions.

Nat Med. 2011;17(12):1523

Authors:

PMID: 22146429 [PubMed - in process]

Diseases in a dish: modeling human genetic disorders using induced pluripotent cells.

Nat Med. 2011 Dec 6;:1570-1576

Authors: Tiscornia G, Vivas EL, Belmonte JC

Abstract

The derivation of induced pluripotent cells (iPSCs) from individuals suffering from genetic syndromes offers new opportunities for basic research into these diseases and the development of therapeutic compounds. iPSCs can self renew and can be differentiated to many cell types, offering a potentially unlimited source of material for study. In this review we discuss the conceptual and practical issues to consider when attempting to model genetic diseases using iPSCs.

PMID: 22146428 [PubMed - as supplied by publisher]

Trial networks move beyond single-disease strategies.

Nat Med. 2011;17(12):1525

Authors: Dolgin E

PMID: 22146430 [PubMed - in process]

Institutes unite to put New York on the biopharma map.

Nat Med. 2011;17(12):1527

Authors: Waters H

PMID: 22146432 [PubMed - in process]

New HCV drugs trigger race for more tolerable therapies.

Nat Med. 2011;17(12):1526

Authors: Williams SC

PMID: 22146431 [PubMed - in process]

Genome center’s location stuck in transit.

Nat Med. 2011;17(12):1527

Authors: Waters H

PMID: 22146433 [PubMed - in process]

Class of once-weekly diabetes drugs poised for approval.

Nat Med. 2011;17(12):1528

Authors: Waters H

PMID: 22146435 [PubMed - in process]

Four-in-one HIV pill may be exception among combination drugs.

Nat Med. 2011;17(12):1528-9

Authors: Waters H

PMID: 22146434 [PubMed - in process]

Corrections.

Nat Med. 2011;17(12):1529

Authors:

PMID: 22146437 [PubMed - in process]

Patent-sharing scheme for neglected diseases may have catch.

Nat Med. 2011;17(12):1529

Authors: Waters H

PMID: 22146436 [PubMed - in process]

Biostatisticians call for more scientifically rigorous pilot studies.

Nat Med. 2011;17(12):1531

Authors: Willyard C

PMID: 22146439 [PubMed - in process]

International coding upgrade affects clinical research and reviews.

Nat Med. 2011;17(12):1530

Authors: Venkataramanan M

PMID: 22146438 [PubMed - in process]

News in brief: Biomedical briefing.

Nat Med. 2011;17(12):1532-3

Authors:

PMID: 22146441 [PubMed - in process]

Databases aim to bridge the East-West divide of drug discovery.

Nat Med. 2011;17(12):1531

Authors: Sanderson K

PMID: 22146440 [PubMed - in process]

Straight talk with… Amanda Glassman.

Nat Med. 2011;17(12):1534

Authors: Dolgin E

Abstract

Since its launch in 2001, the Center for Global Development (CGD) has been instrumental in convening working groups and issuing reports that shape the agenda for a range of topics that affect global poverty and people of the developing world. At the helm of its global health effort is Amanda Glassman. As the daughter of US Foreign Service diplomats, Glassman was exposed to disparities in public health in developing countries from a very young age. So it was a no-brainer for Glassman that she would devote her career to tackling those inequalities. She has spent the last two decades at places like the US Agency for International Development, the Inter-American Development Bank and the Brookings Institution. Last year, she joined CGD as the director of its global health policy division. One idea that the $10-million-a-year, Washington, DC-based think tank has championed with some success is what’s known as an advance market commitment (AMC), a financial instrument that incentivizes vaccine development for diseases primarily affecting low-income countries. It’s for this influence that the center, which is mainly funded by governments and philanthropic entities, was ranked the fifteenth most important US think tank the by Foreign Policy magazine in 2008. In recognition of CGD’s ten-year anniversary last month, Elie Dolgin spoke to Glassman about how the think tank turns its words into actions.

PMID: 22146442 [PubMed - in process]

Efficient drug approval and monitoring must rely on sound regulatory science.

Nat Med. 2011;17(12):1535

Authors: Meagher EA, Fitzgerald GA

PMID: 22146443 [PubMed - in process]

2011 in review.

Nat Med. 2011;17(12):1539

Authors:

PMID: 22146445 [PubMed - in process]

Breaking the silence.

Nat Med. 2011;17(12):1536-8

Authors: Katsnelson A

PMID: 22146444 [PubMed - in process]

The yearbook.

Nat Med. 2011;17(12):1539

Authors:

PMID: 22146446 [PubMed - in process]

Drugs in traffic: the road to approval.

Nat Med. 2011;17(12):1542-3

Authors:

PMID: 22146448 [PubMed - in process]

Notable advances 2011.

Nat Med. 2011;17(12):1540-1

Authors:

PMID: 22146447 [PubMed - in process]

A retrospective of retractions: the striking record in 2011.

Nat Med. 2011;17(12):1544

Authors:

PMID: 22146450 [PubMed - in process]

Timeline of events: A brief history of what made news this year.

Nat Med. 2011;17(12):1543

Authors:

PMID: 22146449 [PubMed - in process]

The history of hemophilia.

Nat Med. 2011;17(12):1545

Authors: High KA

PMID: 22146451 [PubMed - in process]

Mannose-binding lectin-the forgotten molecule?

Nat Med. 2011;17(12):1547-8

Authors: Osthoff M, Trendelenburg G, Eisen DP, Trendelenburg M

PMID: 22146452 [PubMed - in process]

Reply to: Mannose-binding lectin-the forgotten molecule?

Nat Med. 2011;17(12):1548

Authors: Iadecola C, Anrather J

PMID: 22146453 [PubMed - in process]

A gut triumvirate rules homeostasis.

Nat Med. 2011;17(12):1549-50

Authors: Chorny A, Cerutti A

PMID: 22146454 [PubMed - in process]

A sweet T cell response.

Nat Med. 2011;17(12):1551-2

Authors: Rappuoli R, De Gregorio E

PMID: 22146455 [PubMed - in process]

Stressed tumor cell, chemosensitized cancer.

Nat Med. 2011;17(12):1552-4

Authors: Wiemer EA

PMID: 22146456 [PubMed - in process]

NF-κB in DCs: it takes effort to be immature.

Nat Med. 2011;17(12):1554-6

Authors: Creusot RJ

PMID: 22146457 [PubMed - in process]

Nitrite-NO bailout for a NOS complex too big to fail.

Nat Med. 2011;17(12):1556-7

Authors: Gladwin MT, Tejero J

PMID: 22146458 [PubMed - in process]

Mixed results for a malaria vaccine.

Nat Med. 2011;17(12):1560-1

Authors:

PMID: 22146460 [PubMed - in process]

Diagnosis in a dish: your skin can help your brain.

Nat Med. 2011;17(12):1558-9

Authors: Huttner A, Rakic P

PMID: 22146459 [PubMed - in process]

Fruitful progress to fertility: Preserving oocytes from chemodestruction.

Nat Med. 2011;17(12):1562-3

Authors: Xu M, Pavone ME, Woodruff T

PMID: 22146461 [PubMed - in process]

Immunotherapy: A safety switch for immunotherapy.

Nat Med. 2011;17(12):1566

Authors: Farrell A

PMID: 22146463 [PubMed - in process]

Fruitful progress to fertility: Male fertility in the test tube.

Nat Med. 2011;17(12):1564-5

Authors: Clark AT, Phillips BT, Orwig KE

PMID: 22146462 [PubMed - in process]

Addiction: One thing leads to another.

Nat Med. 2011;17(12):1566

Authors: López JC

PMID: 22146464 [PubMed - in process]

Autoimmunity: Defects in DC tolerance.

Nat Med. 2011;17(12):1566

Authors: Swami M

PMID: 22146466 [PubMed - in process]

Neurological disorders: Serine to the rescue.

Nat Med. 2011;17(12):1566

Authors: Basson M

PMID: 22146465 [PubMed - in process]

Improving the efficacy of translational medicine by optimally integrating health care, academia and industry.

Nat Med. 2011;17(12):1567-9

Authors: Bornstein SR, Licinio J

PMID: 22146467 [PubMed - in process]

Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.

Nat Med. 2011;17(12):1692

Authors: Hansen SG, Vieville C, Whizin N, Coyne-Johnson L, Siess DC, Drummond DD, Legasse AW, Axthelm MK, Oswald K, Trubey CM, Piatak M, Lifson JD, Nelson JA, Jarvis MA, Picker LJ

PMID: 22146468 [PubMed - in process]

Targeting osteoclast-osteoblast communication.

Nat Med. 2011;17(12):1693

Authors: Cao X

PMID: 22146470 [PubMed - in process]

The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2.

Nat Med. 2011;17(12):1693

Authors: Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z

PMID: 22146469 [PubMed - in process]

Resolving controversies on the path to Alzheimer’s therapeutics.

Nat Med. 2011;17(12):1693

Authors: Selkoe DJ

PMID: 22146472 [PubMed - in process]

The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2.

Nat Med. 2011;17(12):1693

Authors: Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z

PMID: 22146471 [PubMed - in process]