Most moths use either of two types of compounds, aliphatic or alkenyl compounds, as sex pheromones. As previous studies on the neuroanatomy of

moths have mostly been carried out using moths that use aliphatic compounds, information on the brain of moths that use alkenyl compounds is scarce. Here, we describe the brain anatomy of the male lichen-feeding moth Eilema japonica (Lepidoptera: Arctiidae), which uses a mixture of alkenyl compounds as a sex pheromone. We reconstructed Daporinad molecular weight the major neuropils in the midbrain of E. japonica and compared them with those of the silkmoth, which uses an aliphatic derivative as a sex pheromone. The brain organization of the two species was basically similar, except for the size of the macroglomerular complex, where pheromone information is processed. The macroglomerular complex in E. japonica consisted of four large glomeruli, which were positioned along dorsoventral and anterior-posterior axes. The

glomerulus at the site of entry of the antennal nerve was shown to have the largest volume. The number of glomeruli was equal to the number of pheromone components that are crucial for orientation behavior in E. japonica. NeuroReport 23:857-861 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“One of the most consistently reported brain regions of structural and functional difference in attention deficit hyperactivity disorder buy AZD3965 (ADHD) is the basal ganglia, Vorinostat supplier particularly the caudate nucleus. Examining the structural organization of the basal ganglia in ADHD is important because it is the center of wider fronto-striatal networks, reported to be dysfunctional in ADHD. Fifteen right-handed 8- to 18-year-old males with ADHD-combined type and 15 right-handed,

age- and performance IQ-matched healthy males underwent diffusion tensor imaging. Caudate, putamen and thalamus were manually identified as regions of interest (ROIs) and tested for differences in fractional anisotropy and mean diffusivity. Measures of fractional anisotropy (FA) showed the expected increase with age within the whole-brain volume and within putamen and thalamus ROIs for both ADHD and control groups. In the caudate nucleus, however, developmental changes in FA with age were significantly different between ADHD and control groups. This study shows that the developmental trajectory of micro-structural organization within the caudate nucleus is different in children with ADHD compared with controls over ages 8-18 years. We suggest that the difference in developmental trajectories arises predominantly during mid-late adolescence and may reflect a developmental delay that begins to normalise over this critical late adolescent age. (C) 2008 Elsevier Ireland Ltd. All rights reserved.”
“Using event-related potential measures, the present study investigated the affective responses to aesthetic experience.

Taken together, the indications are that the downregulation of p53-mediated cell growth control is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host’s immune surveillance program against viral infections.”
“The synthesis enzyme glutamic acid decarboxylase (GAD65 or GAD67) identifies neurons as GABAergic. Recent studies have characterized the physiological properties of spinal cord GABAergic interneurons using lines

of GAD67-green Tanespimycin research buy fluorescent protein (GFP) transgenic mice. A more complete characterization of their phenotype is required to better understand the role of this population of inhibitory neurons in spinal cord function. Here, we characterize the distribution of lumbar spinal cord GAD67-GFP neurons at postnatal days (P) 0, 7, and 14, and adult based on their co-expression with GABA and determine the molecular phenotype of GAD67-GFP neurons at P14 based on the expression of various neuropeptides, calcium binding proteins, and other markers. At all ages >67% of GFP(+) neurons were also GABA(+). With increasing age; (1) GFP(+) and GABA(+) cell numbers declined, (ii) ventral horn GFP(+) and GABA(+) neurons vanished, and (iii) somatic labeling was reduced

while terminal labeling increased. At P14, vasoactive intestinal peptide and bombesin were expressed in similar to 63% and similar to 35% of GFP(+) cells, respectively. Somatostatin was found in a small number of neurons, whereas calcitonin gene-related peptide never co-localized with GFP. Moderate co-expression was found learn more for all the Ca(2+) binding proteins examined. Notably, most laminae I-II parvalbumin

neurons were also GFP. Neurogranin, a protein kinase C substrate, was found in similar to 1/2 of GFP(+) cells. Lastly, while only 7% of GFP(+) cells contain nitric oxide synthase (NOS), these cells represent a large fraction of all NOS(+) cells. We conclude that GAD67-GFP neurons represent the majority of spinal GABAergic neurons and that mouse dorsal horn GAD67-GFP(+) neurons comprise a phenotypically diverse population. (c) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Repeated Cyclosporin A ic50 bottleneck passages of RNA viruses result in accumulation of mutations and fitness decrease. Here, we show that clones of foot-and-mouth disease virus (FMDV) subjected to bottleneck passages, in the form of plaque-to-plaque transfers in BHK-21 cells, increased the thermosensitivity of the viral clones. By constructing infectious FMDV clones, we have identified the amino acid substitution M54I in capsid protein VP1 as one of the lesions associated with thermosensitivity. M54I affects processing of precursor P1, as evidenced by decreased production of VP1 and accumulation of VP1 precursor proteins. The defect is enhanced at high temperatures. Residue M54 of VP1 is exposed on the virion surface, and it is close to the B-C loop where an antigenic site of FMDV is located.

Interestingly, on trials where extinction occurred, there was a bias reporting the ‘active’ object on the extinguished side a reversal of the standard pattern of extinction but only when objects were seen from a self-perspective. The data show that several factors contribute to the effects of action relations on attention, depending upon the familiarity of the object pairs and the reference frame that stimuli have

been seen in. (C) 2013 Elsevier NCT-501 cell line Ltd. All rights reserved.”
“Histone deacetylases (HDACs) play critical roles in silencing tumor suppressor genes. HDAC inhibitors reactivate tumor suppressor genes and inhibit tumor cell growth in vitro and in vivo, and several HDAC inhibitors are currently being evaluated in clinical trials for cancer therapy. A comprehensive

analysis of proteins regulated by HDAC inhibitors would enhance our ability to define and characterize their essential therapeutic targets. Here, we employed stable isotope labeling with amino acids in cell culture-based quantitative proteomics to identify acetylated proteins in human breast cancer cells. Treatment with the clinically relevant HDAC inhibitor, suberoylanilide hydroxamic acid (vorinostat), induces lysine acetylation of 61 proteins in MDA-MB-231 human Selleckchem LCL161 breast cancer cells. Suberoylanilide hydroxamic acid not only induces lysine acetylation in chromatin-associated proteins, but also acetylates previously unrecognized nonhistone proteins, including transcriptional factors and regulators, chaperones, cell structure proteins, and glycolytic enzymes in

a time-dependent Selleckchem GSK461364 manner. Knowledge of the full repertoire of acetylated proteins will provide a foundation for further defining the functions of HDACs in cancer cells.”
“Tobacco viruses including Tobacco mosaic virus (TMV), Cucumber mosaic virus (CMV), Tobacco etch virus (TEV), Potato virus Y (PVY) and Tobacco vein banding mosaic virus (TVBMV) are major viruses infecting tobacco and can cause serious crop losses. A multiplex reverse transcription polymerase chain reaction assay was developed to detect simultaneously and differentiate all five viruses. The system used specific primer sets for each virus producing five distinct fragments 237, 273, 347, 456 and 547 bp, representing TMV, CMV subgroup 1, TEV, PVY0 and TVBMV, respectively. These primers were used for detection of the different viruses by single PCR and multiplex PCR and the results were confirmed by DNA sequencing analysis. The protocol was used to detect viruses from different parts of China. The simultaneous and sensitive detection of different viruses using the multiplex PCR is more efficient and economical than other conventional methods for tobacco virus detection. This multiplex PCR provides a rapid and reliable method for the detection and identification of major tobacco viruses, and will be useful for epidemiological studies. (C) 2012 Elsevier B.V.

Each experiment tested the effects of the initial cell density OSI-744 chemical structure and the multiplicity of infection at two levels, in the four possible combinations of levels and conditions, plus a further combination with each condition set at the

middle of its extreme levels. The yield of occlusion bodies proved to be sensitive to the modification of infection conditions. Maximum yield as high as 3 x 10(8) OBs mL(-1) was attained provided that the maximum density of viable cells was in the range between 4 and 8 x 10(5) cells mL(-1). The optimum value of the maximum density of viable cells could be reached by the combination of several values of initial cell density and multiplicity of infection. A regression model was established and validated in order to optimize the infection selleckchem conditions. These results demonstrate the importance of an adequate selection of infection conditions,

and they could be useful in the development of a feasible in vitro process to produce the AgMNPV insecticide in a new serum-free medium. (c) 2009 Elsevier B.V. All rights reserved.”
“Chondroitin sulfate proteoglycan (NG2) expressing cells, ubiquitously distributed in the CNS respond to injured or diseased neurons; however, their behaviors toward injured neurons Endocrinology inhibitor have remained to be fully explored. In the present study,

along with astrocytic and microglial responses, NG2 expressing cells reacted swiftly and robustly in the facial motor nucleus (FMN) subjected to axotomy. With time, hypertrophic NG2 expressing cells gradually adhered to and enwrapped the axotomized motoneurons. Tight encapsulations around axotomized motoneurons were eventually formed at 7, 14, and 28 days after axotomy. NG2 positive processes appeared to interpose between synapsin-1 immunoreactive nerve terminals and surfaces of axotomized motoneurons. Double labeling results showed that NG2 expressing cells encapsulating axotomized facial motoneurons were mainly microglia marked by OX42 and lectin; only a few of them were positive to platelet-derived growth factor-a receptor and none of them positive to ED-1. No Rhodamine particle was detected in the FMN ipsilateral to axotomy after venous injection of the particles. The results suggest that activated microglia in lesioned FMN were induced to express NG2 molecules. It is concluded that axotomized FMN showed two types of NG2 expressing cells namely constitutive NG2 cells and induced-NG2 expressing microglia. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

45 (SE = 0.96) % and 17.45(1.05) % respectively among 1947 men and 2909

women. BTSA1 in vitro The odds ratios (ORs) were 1 (reference). 1.64(95% CI = 1.06, 2.54) and 2.34 (1.41, 3.87) respectively for men with lowest, middle and highest third of linoleic FA intake (p for trend = 0.001): the ORs were I (reference), 0.88 (0.56, 1.38) and 0.48 (0.25, 0.95) respectively for women with lowest, middle and highest third of oleic FA intake (p for trend = 0.0347). No association was observed from saturated FA. These estimates were adjusted for fish consumption at baseline and major physical diseases at follow-up. The authors concluded that increased intake of oleic FA was associated with reduced risk among women while increased intake of linoleic FA was associated with increased risk of SDM among men. (C) 2009 Published by Elsevier Inc.”
“Background Differences in systolic blood pressure (SBP) of 10 mm Hg or more or 15 mm Hg or more between arms have been associated with peripheral

vascular disease and attributed to subclavian stenosis. We investigated whether an association exists between this difference and central or peripheral vascular disease, and mortality.

Methods We searched Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane, and Medline In Process databases for studies published before July, 2011, showing differences in SBP between arms, with data for subclavian stenosis, peripheral vascular disease, cerebrovascular disease, cardiovascular disease, or survival. We Anlotinib cell line used random effects meta-analysis to combine estimates of the association between differences in SBP between arms and each outcome.

Findings We identified 28 eligible

studies for review, 20 of which were included in our meta-analyses. In five invasive studies using angiography, mean difference in SBP between arms was 36.9 mm Hg (95% CI 35.4-38.4) for proven subclavian stenosis (>50% occlusion), and a difference of 10 mm Hg or more was strongly associated with subclavian learn more stenosis (risk ratio [RR] 8.8, 95% CI 3.6-21.2). In non-invasive studies, pooled findings showed that a difference of 15 mm Hg or more was associated with peripheral vascular disease (nine cohorts; RR 2.5, 95% CI 1.6-3.8; sensitivity 15%, 9-23; specificity 96%, 94-98); pre-existing cerebrovascular disease (five cohorts; RR 1.6, 1.1-2.4; sensitivity 8%, 2-26; specificity 93%, 86-97); and increased cardio vascular mortality (four cohorts; hazard ratio [HR] 1.7, 95% CI 1.1-2.5) and all-cause mortality (HR 1.6, 1.1-2.3). A difference of 10 mm Hg or higher was associated with peripheral vascular disease (five studies; RR 2.4, 1.5-3.9; sensitivity 32%, 23-41; specificity 91%, 86-94).

Interpretation A difference in SBP of 10 mm Hg or more, or of 15 mm Hg or more, between arms might help to identify patients who need further vascular assessment. A difference of 15 mm Hg or more could be a useful indicator of risk of vascular disease and death.

METHODS:

Three patients who underwent computed tomographic angiography scanning for reasons not related to this study were examined by neuronavigated image-guided TCD. The Doppler probe was fitted with reflective markers and tracked by a commercially available Kolibri image guidance system.

RESULTS: Image-guided TCD allowed identification of all major intracranial vessels. Unilateral acquisition of reliable Doppler signals for the internal carotid artery, carotid T, middle cerebral artery, middle cerebral artery bifurcation, and anterior cerebral artery required 14 +/- 6 Tubastatin A minutes. Preregistration of these targets and detection by neuronavigation alone shortened examination times significantly to 8 +/- 2 minutes. Registering the optimal examination trajectories on the neuronavigational device and applying navigational pilot software shortened times for repetitive examination further to 4 +/- 1 minutes and ensured that the examination was done at the exact same spot under the same angle as in previous examinations.

CONCLUSION:

Image guidance can be applied easily and efficiently to TCD. It provides anatomic orientation and may help to standardize investigation protocols, define pathological vascular territories for repeat investigations, and thus reduce inter-investigator variations. Image guidance may also extend the use of TCD to situations of a pathological or variant vascular anatomy.”
“BACKGROUND: Central nervous system (CNS) hemangioblastomas are a benign condition, which can be permanently cured by complete surgical removal.

However, the vascular Repotrectinib mouse see more nature of these lesions and difficulties in localizing the tumors account for operative morbidity and recurrence. Power Doppler flow sonography has been proven useful during surgical removal of other vascular lesions.

OBJECTIVE: To evaluate the usefulness of Power Doppler flow sonography for hemangioblastoma.

METHODS: We used the SonoWand Invite (Sonowand AS, Trondheim, Norway) intraoperative navigation system in a consecutive series of hemangioblastomas operated on at our institution. Patients with von Hippel-Lindau (VHL) disease as well as sporadic hemangioblastomas were included.

RESULTS: The system was used on n = 64 consecutive hemangioblastomas operated on at our institution from 2007 to 2009. The tumors were localized in the cerebellum (n = 26), spinal cord (n = 27), brainstem (n = 10), and supratentorial (n = 1). In VHL disease was diagnosed 53 patients, and germline mutations of the VHL tumor suppressor gene were identified in 98%. Average tumor size was 1782 mm(3) and 45% of the tumors were cystic. Forty-two of 64 tumors could be localized by grayscale sonography. All tumors were visible on power Doppler flow sonography. However, in 40 cases, only the pathological vessels and not the solid tumor itself enhanced on power Doppler.

Plasma glucose decreased in a dose-dependent manner 60 min after intravenous injection of syringin into fasting Wistar rats. In parallel to the decrease of plasma glucose, increases of plasma insulin

level as well as the plasma C-peptide was also observed in rats receiving same treatment. Both the plasma glucose lowering action and the raised plasma levels of insulin and C-peptide induced by syringin were also inhibited by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP), the antagonist of the muscarinic M(3) receptors, but not affected by the ganglionic nicotinic antagonist, pentolinium or hexamethonium. Moreover, disruption of synaptic available acetylcholine (ACh) using an inhibitor of choline uptake, hemicholinium-3, or vesicular C188-9 acetylcholine transport, vesamicol, abolished these actions of syringin. Also, physostigmine at concentration sufficient to inhibit acetylcholinesterase enhanced the actions of syringin. Mediation of ACh release from the nerve terminals to enhance insulin secretion by syringin can thus be considered. The results suggest that syringin has an ability to raise the release of ACh from nerve terminals,

which in turn to stimulate muscarinic M3 receptors in pancreatic cells and augment the insulin release to result in plasma glucose lowering action. (C) 2008 Elsevier Ireland Ltd. All rights reserved.”
“Peptides based on heptad repeat (HR) domains of class I viral fusion proteins ABT-737 in vivo are considered promising antiviral drugs targeting virus cell entry. We have analyzed the evolution of the mouse hepatitis coronavirus during multiple passaging in the presence of an HR2-based fusion inhibitor. Drug-resistant variants emerged as a result of multiple substitutions in the spike fusion protein, notably within

a 19-residue segment of YM155 order the HR1 region. Strikingly, one mutation, an A1006V substitution, which consistently appeared first in four independently passaged viruses, was the main determinant of the resistance phenotype, suggesting that only limited options exist for escape from the inhibitory effect of the HR2 peptide.”
“In two experiments applying a memory updating task subjects are asked to perform several arithmetic operations on stored numbers. From a trial-to-trial perspective these operations could be either performed on a previously processed item or on a new item which requires an object switch in working memory. Object switching results in prolonged operation times; these operation time costs reflect the switch of the focus of attention to the relevant information. Event-related brain potentials obtained in object switch trials show an increased P3a around 300 ms and a late, central negative component between 400 ms and 500 ms.

(C) 2010 Elsevier Inc. All rights reserved.”
“Forward Collision Warning Systems (FCWS) are expected to assist drivers; however, it is not completely clear whether these systems are of benefit to distracted drivers as much as they are to undistracted drivers. This study aims at investigating further the analysis of the effectiveness of a surrogate FCWS according to the attentional state EPZ015666 of participants. In this experiment electrophysiological and behavioural data were recording while participants were required to drive in a simple car simulator and to react to the braking of the

lead vehicle which could be announced by a warning system. The effectiveness of this warning system was evaluated when drivers were distracted or not by a secondary cognitive task. In a previous study, the warning signal was not completely effective likely due to the presence of this website another predictor of the forthcoming braking which competes with the warning. By eliminating this secondary predictor in the present study, the results confirmed the negative effect of the secondary task and revealed the expected effectiveness

of the warning system at behavioural and electrophysiological levels. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Objective: The aim of the present study was to identify the modern surgical results of pathologic T3 lung cancer and to examine the heterogeneity of this group from the nationwide database.

Methods: The registered data of 11,663 cases from the Japanese Joint Committee of Lung Cancer Registry conducted in 2010 were analyzed, which included patients with resected lung cancer during 2004. Of these patients, 531 with invasive T3 lung cancer constituted the study population.

Results: Of the 531 patients, 466 were men and 65 women, with a mean age of 65.9 years. The 3- and 5-year survival rates

and median survival time was 54.0%, 44.9%, and 46 months, respectively. A multivariate analysis showed incomplete resection, N2 disease, and no adjuvant therapy were independent prognostic factors of a poor outcome. However, pneumonectomy and N1 disease were not significantly associated with the prognosis. In terms of each involved structure, we detected 407 patients with T3 tumors involving the chest wall, 56 involving the mediastinal Torin 1 pleura, 45 with involvement of the bronchus within 2 cm of the carina, 31 involving the diaphragm, and 20 involving the pericardium. The corresponding 5-year survival rates were 43.2%, 40.1%, 55.2%, 42.6%, and 54.2%.

Conclusions: The modern 5-year survival rates of patients with T3 lung cancer involving any neighboring structures have been 40% to 55%, and the current pT3 group was proved to have a relatively uniform prognosis. (J Thorac Cardiovasc Surg 2012;144:431-7)”
“An endochitinase was previously purified and the gene was cloned from the psychrophilic Antarctic bacterium, Sanguibacter antarcticus (KCTC 13143).

(C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“The 2009 H1N1 pandemic influenza virus represents the greatest incidence of human infection with an influenza virus of swine origin to date. Moreover, triple-reassortant swine (TRS) H1N1 viruses, which share similar host and lineage origins with 2009 H1N1 viruses, have been responsible for sporadic human cases since 2005. Similar to 2009 AZD1080 manufacturer H1N1 viruses, TRS viruses are capable of causing severe disease

in previously healthy individuals and frequently manifest with gastrointestinal symptoms; however, their ability to cause severe disease has not been extensively studied. Here, we evaluated the pathogenicity and transmissibility of two TRS viruses associated with disease in humans in the ferret model. TRS and 2009 H1N1 viruses exhibited comparable viral titers and histopathologies following virus infection and were similarly unable to transmit efficiently via respiratory droplets in the ferret model. Utilizing TRS and 2009 H1N1 viruses, we conducted extensive hematologic and blood serum analyses on infected ferrets to identify lymphohematopoietic parameters associated with mild to severe influenza virus infection. Following H1N1 or H5N1 influenza virus infection, ferrets were found to recapitulate several laboratory

abnormalities previously documented with human disease, furthering the utility of the ferret model for the assessment of influenza Ro-3306 in vivo virus pathogenicity.”
“The ventrolateral division of the periaqueductal gray (vIPAG) and the adjacent deep mesencephalic reticular check details nucleus have been implicated in the control of sleep. The preoptic hypothalamus, which contains populations of sleep-active neurons, is an important source of afferents to the vIPAG. The perifornical lateral

hypothalamus (LH) contains populations of wake-active neurons and also projects strongly to the vIPAG. We examined nonREM and REM sleep-dependent expression of c-Fos protein in preoptic-vIPAG and LH-vIPAG projection neurons identified by retrograde labeling with Fluorogold (FG). Separate groups of rats (n=5) were subjected to 3 h total sleep deprivation (TSD) followed by 1 h recovery sleep (RS), or to 3 h of selective REM sleep deprivation (RSD) followed by RS. A third group of rats (n=5) was subjected to TSD without opportunity for RS (awake group). In the median preoptic nucleus (MnPN), the percentage of FG+ neurons that were also Fos+ was higher in TSD-RS animals compared to both RSD-RS rats and awake rats. There were significant correlations between time spent in deep nonREM sleep during the 1 h prior to sacrifice across groups and the percentage of double-labeled cells in MnPN and ventrolateral preoptic area (VLPO). There were no significant correlations between percentage of double-labeled neurons and time spent in REM sleep for any of the preoptic nuclei examined.

Here we investigate this question by inserting the known fibril-forming segment NNQQNY into the globular enzyme, T7 endonuclease I. From earlier studies, we know that in its fibril form, NNQQNY is in an extended conformation.

We first found that the inserted NNQQNY stimulates fibril formation of T7 endonuclease I in solution. Thus NNQQNY within T7 endonuclease I can exist in an extended conformation, capable of forming the steric zipper in the core of a fibril. We also found that T7 endonuclease I folds into a decamer that does not form fibrils. We determined the structure of the decamer by X-ray crystallography, finding an unusual oligomer without point group symmetry, and finding that the NNQQNY segments within the decamer adopt two twisted conformations, neither is apparently Selleck Pritelivir able to fibrillize. We conclude that twisting of fibril forming sequences from the fully extended conformation, imposed by the context of their placement in proteins, can interfere with fibril formation.”
“The find more purpose of these studies was to identify human leukocyte antigen (HLA)-A2(+) immunogenic peptides derived from

XBP1 antigens to induce a multiple myeloma (MM)-specific immune response. Six native peptides from non-spliced XBP1 antigen and three native peptides from spliced XBP1 antigen were selected and evaluated for their HLA-A2 specificity. Among them, XBP1(184-192), XBP1 SP196-204 and XBP1 SP367-375 peptides showed the highest level of binding affinity, but not stability to HLA-A2 molecules. Novel heteroclitic XBP1 peptides, YISPWILAV or YLFPQLISV, demonstrated a significant improvement in HLA-A2 stability from their native XBP1(184-192) or XBP1 SP367-375 peptide, respectively. Cytotoxic T lymphocytes generated by repeated

stimulation of CD3(+) T cells with each HLA-A2-specific heteroclitic peptide showed an increased percentage of CD8(+) (cytotoxic) and CD69(+)/ CD45RO(+) (activated SC75741 ic50 memory) T cells and a lower percentage of CD4(+) (helper) and CD45RA(+)/CCR7(+) (naive) T cells, which were distinct from the control T cells. Functionally, the cytotoxic T lymphocytes (CTL) demonstrated MM-specific and HLA-A2-restricted proliferation, interferon-gamma secretion and cytotoxic activity in response to MM cell lines and importantly, cytotoxicity against primary MM cells. These data demonstrate the distinct immunogenic characteristics of unique heteroclitic XBP1 peptides, which induce MM-specific CTLs and highlights their potential application for immunotherapy to treat the patients with MM or its pre-malignant condition. Leukemia (2011) 25, 1610-1619; doi:10.1038/leu.2011.