microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease

Analysis of microRNA (miR) expression in the central nervous system white matter of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) revealed a significant reduction of miR-219, a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic before disease onset ameliorates clinical disease, reduces neurogliosis, and partially recovers motor and sensorimotor function by negatively regulating proinflammatory cytokines and virus RNA replication. Moreover, RNA sequencing of host lesions showed that miR-219 significantly downregulated two genes essential for the biosynthetic cholesterol pathway, Cyp51 (lanosterol 14-α-demethylase) and Srebf1 (sterol regulatory element-binding protein-1), and reduced cholesterol biosynthesis in infected mice and rat CG-4 glial precursor cells in culture. The change in cholesterol biosynthesis had both anti-inflammatory and anti-viral effects. Because RNA viruses hijack endoplasmic reticulum double-layered membranes to provide a platform for RNA virus replication and are dependent on endogenous pools of cholesterol, miR-219 interference with cholesterol biosynthesis interfered virus RNA replication. These findings demonstrate that miR-219 inhibits TMEV-induced demyelinating disease through its anti-inflammatory and anti-viral properties. MicroRNAs (miRs) are small noncoding RNAs that regulate a myriad of biological processes by controlling gene expression. In the latest issue of Molecular Therapy, Moyano et al. show that intranasal delivery of miR-219 in a mouse model of viral demyelination reduces neurological burden and improves life quality through anti-inflammatory and anti-viral mechanisms.Fil: Moyano, Ana Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina. University of Illinois; Estados UnidosFil: Steplowski, Jeffrey. University of Illinois; Estados UnidosFil: Wang, Haibo. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Son, Kyung No. University of Illinois; Estados UnidosFil: Rapolti, Diana I.. University of Illinois; Estados UnidosFil: Marshall, Jeffrey. University of Illinois; Estados UnidosFil: Elackattu, Vince. University of Illinois; Estados UnidosFil: Marshall, Michael S.. University of Illinois; Estados UnidosFil: Hebert, Amy K.. University of Illinois; Estados UnidosFil: Reiter, Cory R.. University of Illinois; Estados UnidosFil: Ulloa, Viviana. University of Illinois; Estados UnidosFil: Pituch, Katarzyna C.. University of Illinois; Estados UnidosFil: Givogri, Maria I.. University of Illinois; Estados UnidosFil: Lu, Q. Richard. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Lipton, Howard L.. University of Illinois; Estados UnidosFil: Bongarzone, Ernesto R.. University of Illinois; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentin

Modeling the Longitudinal Asymmetry in Sunspot Emergence -- the Role of the Wilson Depression

The distributions of sunspot longitude at first appearance and at disappearance display an east-west asymmetry that results from a reduction in visibility as one moves from disk centre to the limb. To first order, this is explicable in terms of simple geometrical foreshortening. However, the centre-to-limb visibility variation is much larger than that predicted by foreshortening. Sunspot visibility is also known to be affected by the Wilson effect: the apparent dish shape of the sunspot photosphere caused by the temperature-dependent variation of the geometrical position of the tau=1 layer. In this article we investigate the role of the Wilson effect on the sunspot appearance distributions, deducing a mean depth for the umbral tau=1 layer of 500 to 1500 km. This is based on the comparison of observations of sunspot longitude distribution and Monte Carlo simulations of sunspot appearance using different models for spot growth rate, growth time and depth of Wilson depression.Comment: 18 pages, 10 figures, in press (Solar Physics

Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects

Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations

Conversation therapy with people with aphasia and conversation partners using video feedback: a group and case series investigation of changes in interaction

Conversation therapies employing video for feedback and to facilitate outcome measurement are increasingly used with people with post-stroke aphasia and their conversation partners; however the evidence base for change in everyday interaction remains limited. We investigated the effect of Better Conversations with Aphasia (BCA), an intervention that is freely available online at https://extend.ucl.ac.uk/. Eight people with chronic agrammatic aphasia, and their regular conversation partners participated in the tailored 8 week program involving significant video feedback. We explored changes in: (i) conversation facilitators (such as multi-modal turns by people with aphasia); and (ii) conversation barriers (such as use of test questions by conversation partners). The outcome of intervention was evaluated directly by measuring change in video-recorded everyday conversations. The study employed a pre-post design with multiple 5 minute samples of conversation before and after intervention, scored by trained raters blind to the point of data collection. Group level analysis showed no significant increase in conversation facilitators. There was, however, a significant reduction in the number of conversation barriers. The case series data revealed variability in conversation behaviors across occasions for the same dyad and between different dyads. Specifically, post-intervention there was a significant increase in facilitator behaviors for two dyads, a decrease for one and no significant change for five dyads. There was a significant decrease in barrier behaviors for five dyads and no significant change for three dyads. The reduction in barrier behaviors was considerable; on average change from over eight to fewer than three barrier behaviors in 5 minutes of conversation. The pre-post design has the limitation of no comparison group. However, change occurs in targeted conversational behaviors and in people with chronic aphasia and their partners. The findings suggest change can occur after eight therapy sessions and have implications for clinical practice. A reduction in barrier behaviors may be easier to obtain, although the controlled case series results demonstrate a significant increase in conversation facilitators is also possible. The rehabilitation tool is available online and video technology was central to delivering intervention and evaluating change

KELT-12b: A P ~ 5 day, Highly Inflated Hot Jupiter Transiting A Mildly Evolved Hot Star

We announce the discovery of KELT-12b, a highly inflated Jupiter-mass planet transiting the mildly evolved, V = 10.64 host star TYC 2619-1057-1. We followed up the initial transit signal in the KELT-North survey data with precise ground-based photometry, high-resolution spectroscopy, precise radial velocity measurements, and high-resolution adaptive optics imaging. Our preferred best-fit model indicates that the host star has = 6279 ± 51 K, = 3.89 ± 0.05,[Fe/H] = , = , and = 2.37 ± 0.17 . The planetary companion has = 0.95 ± 0.14 , = , = , and density = g cm −3 , making it one of the most inflated giant planets known. Furthermore, for future follow-up, we report a high-precision time of inferior conjunction in of 2,457,083.660459 ± 0.000894 and period of days. Despite the relatively large separation of ∼0.07 au implied by its ∼5.03-day orbital period, KELT-12b receives significant flux of erg s −1 cm −2 from its host. We compare the radii and insolations of transiting gas giant planets around hot ( K) and cool stars, noting that the observed paucity of known transiting giants around hot stars with low insolation is likely due to selection effects. We underscore the significance of long-term ground-based monitoring of hot stars and space-based targeting of hot stars with the Transiting Exoplanet Survey Satellite to search for inflated gas giants in longer-period orbits

KELT-18b: Puffy Planet, Hot Host, Probably Perturbed

We report the discovery of KELT-18b, a transiting hot Jupiter in a 2.87-day orbit around the bright ( V = 10.1), hot, F4V star BD+60 1538 (TYC 3865-1173-1). We present follow-up photometry, spectroscopy, and adaptive optics imaging that allow a detailed characterization of the system. Our preferred model fits yield a host stellar temperature of K and a mass of , situating it as one of only a handful of known transiting planets with hosts that are as hot, massive, and bright. The planet has a mass of , a radius of , and a density of , making it one of the most inflated planets known around a hot star. We argue that KELT-18b’s high temperature and low surface gravity, which yield an estimated ∼600 km atmospheric scale height, combined with its hot, bright host, make it an excellent candidate for observations aimed at atmospheric characterization. We also present evidence for a bound stellar companion at a projected separation of ∼1100 au, and speculate that it may have contributed to the strong misalignment we suspect between KELT-18\u27s spin axis and its planet’s orbital axis. The inferior conjunction time is 2457542.524998 ± 0.000416 (BJD TDB ) and the orbital period is 2.8717510 ± 0.0000029 days. We encourage Rossiter–McLaughlin measurements in the near future to confirm the suspected spin–orbit misalignment of this system

A Giant Planet Undergoing Extreme-Ultraviolet Irradiation By Its Hot Massive-Star Host

The amount of ultraviolet irradiation and ablation experienced by a planet depends strongly on the temperature of its host star. Of the thousands of extrasolar planets now known, only six have been found that transit hot, A-type stars (with temperatures of 7,300–10,000 kelvin), and no planets are known to transit the even hotter B-type stars. For example, WASP-33 is an A-type star with a temperature of about 7,430 kelvin, which hosts the hottest known transiting planet, WASP-33b (ref. 1); the planet is itself as hot as a red dwarf star of type M (ref. 2). WASP-33b displays a large heat differential between its dayside and nightside2, and is highly inflated–traits that have been linked to high insolation3,4. However, even at the temperature of its dayside, its atmosphere probably resembles the molecule-dominated atmospheres of other planets and, given the level of ultraviolet irradiation it experiences, its atmosphere is unlikely to be substantially ablated over the lifetime of its star. Here we report observations of the bright star HD 195689 (also known as KELT-9), which reveal a close-in (orbital period of about 1.48 days) transiting giant planet, KELT-9b. At approximately 10,170 kelvin, the host star is at the dividing line between stars of type A and B, and we measure the dayside temperature of KELT-9b to be about 4,600 kelvin. This is as hot as stars of stellar type K4 (ref. 5). The molecules in K stars are entirely dissociated, and so the primary sources of opacity in the dayside atmosphere of KELT-9b are probably atomic metals. Furthermore, KELT-9b receives 700 times more extreme-ultraviolet radiation (that is, with wavelengths shorter than 91.2 nanometres) than WASP-33b, leading to a predicted range of mass-loss rates that could leave the planet largely stripped of its envelope during the main-sequence lifetime of the host star (ref. 6)

Measurement of the flavour composition of dijet events in pp collisions at root s=7 TeV with the ATLAS detector

This paper describes a measurement of the flavour composition of dijet events produced in pp collisions at √s=7 TeV using the ATLAS detector. The measurement uses the full 2010 data sample, corresponding to an integrated luminosity of 39 pb−1. Six possible combinations of light, charm and bottom jets are identified in the dijet events, where the jet flavour is defined by the presence of bottom, charm or solely light flavour hadrons in the jet. Kinematic variables, based on the properties of displaced decay vertices and optimised for jet flavour identification, are used in a multidimensional template fit to measure the fractions of these dijet flavour states as functions of the leading jet transverse momentum in the range 40 GeV to 500 GeV and jet rapidity |y|<2.1. The fit results agree with the predictions of leading- and next-to-leading-order calculations, with the exception of the dijet fraction composed of bottom and light flavour jets, which is underestimated by all models at large transverse jet momenta. The ability to identify jets containing two b-hadrons, originating from e.g. gluon splitting, is demonstrated. The difference between bottom jet production rates in leading and subleading jets is consistent with the next-to-leading-order predictions

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured