siRNA-mediated off-target gene silencing triggered by a 7 nt complementation

A growing body of evidence suggests that siRNA could generate off-target effects through different mechanisms. However, the full impact of off-target gene regulation on phenotypic induction and accordingly on data interpretation in the context of large-scale siRNA library screen has not been reported. Here we report on off-target gene silencing effects observed in a large-scale knockdown experiment designed to identify novel regulators of the HIF-1 pathway. All of the three ‘top hits’ from our screen have been demonstrated to result from off-target gene silencing. Two of the three ‘siRNA hits’ were found to directly trigger down-regulation of hif-1α mRNA through a 7 nt motif, AGGCAGT, that is present in both the hif-1α mRNA and the siRNAs. Further analysis revealed that the generation of off-target gene silencing via this 7 nt motif depends on the characteristics of the target mRNA, including the sequence context surrounding the complementary region, the position of the complementary region in the mRNA and the copy number of the complementary region. Interestingly, the off-target siRNA against hif-1α was also shown to trigger mRNA degradation with high probability of other genes that possess multiple copies of the AGGCAGT motif in the 3′-untranslated region. Lessons learned from this study will be a valuable asset to aid in designing siRNAs with more stringent target selectivity and improving ‘hits-follow-up’ strategies for future large-scale knockdown experiments

Drivers and mechanisms of tree mortality in moist tropical forests

Tree mortality rates appear to be increasing in moist tropical forests (MTFs) with significant carbon cycle consequences. Here, we review the state of knowledge regarding MTF tree mortality, create a conceptual framework with testable hypotheses regarding the drivers, mechanisms and interactions that may underlie increasing MTF mortality rates, and identify the next steps for improved understanding and reduced prediction. Increasing mortality rates are associated with rising temperature and vapor pressure deficit, liana abundance, drought, wind events, fire and, possibly, CO2 fertilization-induced increases in stand thinning or acceleration of trees reaching larger, more vulnerable heights. The majority of these mortality drivers may kill trees in part through carbon starvation and hydraulic failure. The relative importance of each driver is unknown. High species diversity may buffer MTFs against large-scale mortality events, but recent and expected trends in mortality drivers give reason for concern regarding increasing mortality within MTFs. Models of tropical tree mortality are advancing the representation of hydraulics, carbon and demography, but require more empirical knowledge regarding the most common drivers and their subsequent mechanisms. We outline critical datasets and model developments required to test hypotheses regarding the underlying causes of increasing MTF mortality rates, and improve prediction of future mortality under climate change

Clinical Guidelines for the Use of Unattended Portable Monitors in the Diagnosis of Obstructive Sleep Apnea in Adult Patients

Based on a review of literature and consensus, the Portable Monitoring Task Force of the American Academy of Sleep Medicine (AASM) makes the following recommendations: unattended portable monitoring (PM) for the diagnosis of obstructive sleep apnea (OSA) should be performed only in conjunction with a comprehensive sleep evaluation. Clinical sleep evaluations using PM must be supervised by a practitioner with board certification in sleep medicine or an individual who fulfills the eligibility criteria for the sleep medicine certification examination. PM may be used as an alternative to polysomnography (PSG) for the diagnosis of OSA in patients with a high pretest probability of moderate to severe OSA. PM is not appropriate for the diagnosis of OSA in patients with significant comorbid medical conditions that may degrade the accuracy of PM. PM is not appropriate for the diagnostic evaluation of patients suspected of having comorbid sleep disorders. PM is not appropriate for general screening of asymptomatic populations. PM may be indicated for the diagnosis of OSA in patients for whom in-laboratory PSG is not possible by virtue of immobility, safety, or critical illness. PM may also be indicated to monitor the response to non-CPAP treatments for sleep apnea. At a minimum, PM must record airflow, respiratory effort, and blood oxygenation. The airflow, effort, and oximetric biosensors conventionally used for in-laboratory PSG should be used in PM. The Task Force recommends that PM testing be performed under the auspices of an AASM-accredited comprehensive sleep medicine pro- gram with written policies and procedures. An experienced sleep technologist/technician must apply the sensors or directly educate patients in sensor application. The PM device must allow for display of raw data with the capability of manual scoring or editing of automated scoring by a qualified sleep technician/technologist. A board certified sleep specialist, or an individual who fulfills the eligibility criteria for the sleep medicine certification examination, must review the raw data from PM using scoring criteria consistent with current published AASM standards. Under the conditions specified above, PM may be used for unattended studies in the patient’s home. A follow-up visit to review test results should be performed for all patients undergoing PM. Negative or technically in- adequate PM tests in patients with a high pretest probability of moderate to severe OSA should prompt in-laboratory polysomnography

The Chandra Source Catalog

The Chandra Source Catalog (CSC) is a general purpose virtual X-ray astrophysics facility that provides access to a carefully selected set of generally useful quantities for individual X-ray sources, and is designed to satisfy the needs of a broad-based group of scientists, including those who may be less familiar with astronomical data analysis in the X-ray regime. The first release of the CSC includes information about 94,676 distinct X-ray sources detected in a subset of public ACIS imaging observations from roughly the first eight years of the Chandra mission. This release of the catalog includes point and compact sources with observed spatial extents <~ 30''. The catalog (1) provides access to the best estimates of the X-ray source properties for detected sources, with good scientific fidelity, and directly supports scientific analysis using the individual source data; (2) facilitates analysis of a wide range of statistical properties for classes of X-ray sources; and (3) provides efficient access to calibrated observational data and ancillary data products for individual X-ray sources, so that users can perform detailed further analysis using existing tools. The catalog includes real X-ray sources detected with flux estimates that are at least 3 times their estimated 1 sigma uncertainties in at least one energy band, while maintaining the number of spurious sources at a level of <~ 1 false source per field for a 100 ks observation. For each detected source, the CSC provides commonly tabulated quantities, including source position, extent, multi-band fluxes, hardness ratios, and variability statistics, derived from the observations in which the source is detected. In addition to these traditional catalog elements, for each X-ray source the CSC includes an extensive set of file-based data products that can be manipulated interactively.Comment: To appear in The Astrophysical Journal Supplement Series, 53 pages, 27 figure

Cold Accretion Disks and Lineless Quasars

The optical-UV continuum of quasars is broadly consistent with the emission from a geometrically thin optically thick accretion disk (AD). The AD produces the ionizing continuum which powers the broad and narrow emission lines. The maximum AD effective temperature is given by Teff=fmax(Mdot/M^2)^1/4, where M is the black hole mass, Mdot the accretion rate, and fmax is set by the black hole spin a_*. For a low enough value of Mdot/M^2 the AD may become too cold to produce ionizing photons. Such an object will form a lineless quasar. This occurs for a local blackbody (BB) AD with a luminosity Lopt=10^46 erg/s for M>3.6E9 Msun, when a_*=0, and for M>1.4E10 Msun, when a_*=0.998. Using the AD based Mdot, derived from M and Lopt, and the reverberation based M, derived from Lopt and the Hbeta FWHM, v, gives Teff \propto Lopt^-0.13v^-1.45. Thus, Teff is mostly set by v. Quasars with a local BB AD become lineless for v> 8,000 km/s, when a_*=0, and for v> 16,000 km/s, when a_*=0.998. Higher values of v are required if the AD is hotter than a local BB. The AD becoming non-ionizing may explain why line emitting quasars with v>10,000 km/s are rare. Weak low ionization lines may still be present if the X-ray continuum is luminous enough, and such objects may form a population of weak emission line quasars (WLQ). If correct, such WLQ should show a steeply falling SED at lambda<1000A. Such an SED was observed by Hryniewicz et al. in SDSS J094533.99+100950.1, a WLQ observed down to 570A, which is well modeled by a rather cold AD SED. UV spectroscopy of z~1-2 quasars is required to eliminate potential intervening Lyman limit absorption by the intergalactic medium (IGM), and to explore if the SEDs of lineless quasars and some additional WLQ are also well fit by a cold AD SED.Comment: Accepted for publication in MNRA

Statistical Characterization of the Chandra Source Catalog

The first release of the Chandra Source Catalog (CSC) contains ~95,000 X-ray sources in a total area of ~0.75% of the entire sky, using data from ~3,900 separate ACIS observations of a multitude of different types of X-ray sources. In order to maximize the scientific benefit of such a large, heterogeneous data-set, careful characterization of the statistical properties of the catalog, i.e., completeness, sensitivity, false source rate, and accuracy of source properties, is required. Characterization efforts of other, large Chandra catalogs, such as the ChaMP Point Source Catalog (Kim et al. 2007) or the 2 Mega-second Deep Field Surveys (Alexander et al. 2003), while informative, cannot serve this purpose, since the CSC analysis procedures are significantly different and the range of allowable data is much less restrictive. We describe here the characterization process for the CSC. This process includes both a comparison of real CSC results with those of other, deeper Chandra catalogs of the same targets and extensive simulations of blank-sky and point source populations.Comment: To be published in the Astrophysical Journal Supplement Series (Fig. 52 replaced with a version which astro-ph can convert to PDF without issues.

Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Getting Acquainted with Kant

My question here concerns whether Kant claims that experience has nonconceptual content, or whether, on his view, experience is essentially conceptual. However there is a sense in which this debate concerning the content of intuition is ill-conceived. Part of this has to do with the terms in which the debate is set, and part to do with confusion over the connection between Kant’s own views and contemporary concerns in epistemology and the philosophy of mind. However, I think much of the substance of the debate concerning Kant’s views on the content of experience can be salvaged by reframing it in terms of a debate about the dependence relations, if any, that exist between different cognitive capacities. Below, in Section 2, I clarify the notion of ‘content’ I take to be at stake in the interpretive debate. Section 3 presents reasons for thinking that intuition cannot have content in the relevant sense. I then argue, in Section 4, that the debate be reframed in terms of dependence. We should distinguish between Intellectualism, according to which all objective representation (understood in a particular way) depends on acts of synthesis by the intellect, and Sensibilism, according to which at least some forms of objective representation are independent of any such acts (or the capacity for such acts). Finally, in Section 5, I further elucidate the cognitive role of intuition. I articulate a challenge which Kant understands alethic modal considerations to present for achieving cognition, and argue that a version of Sensibilism that construes intuition as a form of acquaintance is better positioned to answer this challenge than Intellectualism

Fermionization of a bosonic gas under highly-elongated confinement: A diffusion quantum Monte Carlo study

The diffusion quantum Monte Carlo technique is used to solve the many-body Schroedinger equation fully quantum mechanically and nonperturbatively for bosonic atomic gases in cigar-shaped confining potentials. By varying the aspect ratio of the confining potential from 1 (spherical trap) to 10000 (highly elongated trap), we characterize the transition from the three-dimensional regime to the (quasi-)one-dimensional regime. Our results confirm that the bosonic gas undergoes ``fermionization'' for large aspect ratios. Importantly, many-body correlations are included explicitly in our approach.Comment: 10 pages, 8 figure