KAP1 Recruitment of the 7SK snRNP Complex to Promoters Enables Transcription Elongation by RNA Polymerase II

SummaryThe transition from transcription initiation to elongation at promoters of primary response genes (PRGs) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoter-proximal regions in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP) complex. However, it remains unclear how and why the 7SK snRNP is assembled at these sites. Here we report that the transcriptional regulator KAP1 continuously tethers the 7SK snRNP to PRG promoters to facilitate P-TEFb recruitment and productive elongation in response to stimulation. Remarkably, besides PRGs, genome-wide studies revealed that KAP1 and 7SK snRNP co-occupy most promoter-proximal regions containing paused Pol II. Collectively, we provide evidence of an unprecedented mechanism controlling 7SK snRNP delivery to promoter-proximal regions to facilitate "on-site" P-TEFb activation and Pol II elongation

Electron-phonon interaction in ultrasmall-radius carbon nanotubes

We perform analysis of the band structure, phonon dispersion, and electron-phonon interactions in three types of small-radius carbon nanotubes. We find that the (5,5) can be described well by the zone-folding method and the electron-phonon interaction is too small to support either a charge-density wave or superconductivity at realistic temperatures. For ultra-small (5,0) and (6,0) nanotubes we find that the large curvature makes these tubes metallic with a large density of states at the Fermi energy and leads to unusual electron-phonon interactions, with the dominant coupling coming from the out-of-plane phonon modes. By combining the frozen-phonon approximation with the RPA analysis of the giant Kohn anomaly in 1d we find parameters of the effective Fr\"{o}lich Hamiltonian for the conduction electrons. Neglecting Coulomb interactions, we find that the (5,5) CNT remains stable to instabilities of the Fermi surface down to very low temperatures while for the (5,0) and (6,0) CNTs a CDW instability will occur. When we include a realistic model of Coulomb interaction we find that the charge-density wave remains dominant in the (6,0) CNT with $T_{\rm CDW}$ around 5 K while the charge-density wave instability is suppressed to very low temperatures in the (5,0) CNT, making superconductivity dominant with transition temperature around one Kelvin.Comment: 20 pages. Updated 7/23/0

Are CT-derived muscle measurements prognostic, independent of systemic inflammation in good performance status patients with advanced cancer?

The present study examined the relationships between CT-derived muscle measurements, systemic inflammation, and survival in advanced cancer patients with good performance status (ECOG-PS 0/1). Data was collected prospectively from patients with advanced cancer undergoing anti-cancer therapy with palliative intent. The CT Sarcopenia score (CT-SS) was calculated by combining the CT-derived skeletal muscle index (SMI) and density (SMD). The systemic inflammatory status was determined using the modified Glasgow Prognostic Score (mGPS). The primary outcome of interest was overall survival (OS). Univariate and multivariate Cox regressions were used for survival analysis. Three hundred and seven patients met the inclusion criteria, out of which 62% (n = 109) were male and 47% (n = 144) were ≥65 years of age, while 38% (n = 118) were CT-SS ≥ 1 and 47% (n = 112) of patients with pre-study blood were inflamed (mGPS ≥ 1). The median survival from entry to the study was 11.1 months (1–68.1). On univariate analysis, cancer type (p < 0.05) and mGPS (p < 0.001) were significantly associated with OS. On multivariate analysis, only mGPS (p < 0.001) remained significantly associated with OS. In patients who were ECOG-PS 0, mGPS was significantly associated with CT-SS (p < 0.05). mGPS may dominate the prognostic value of CT-derived sarcopenia in good-performance-status patients with advanced cancer

Lactate dehydrogenase: Relationship with the diagnostic GLIM criterion for cachexia in patients with advanced cancer

Background: Although suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined. Methods: Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011–2016, was retrospectively analysed. LDH values were grouped as <250/250–500/>500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis. Results: A total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p < 0.001), NLR (p < 0.05), mGPS (p < 0.05) and 3-month survival (p < 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p < 0.01), BMI (p < 0.05), skeletal muscle mass (p < 0.01), metastatic disease (p < 0.05), NLR (p < 0.05) and mGPS (p < 0.01). Discussion: LDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia

The Relationship between ECOG-PS, mGPS, BMI/WL Grade and Body Composition and Physical Function in Patients with Advanced Cancer

Cancer remains one of the leading causes of mortality worldwide and the associated reduction in physical function has a marked impact on both quality of life and survival. The aim of the present study was to examine the relationship between Eastern Cooperative Oncology Group-Performance status (ECOG-PS), modified Glasgow Prognostic Score (mGPS), Body Mass Index/Weight Loss grade (BMI/WL grade), and Computerised Tomography (CT)-derived body composition measurement and physical function in patients with advanced cancer. Nine sites contributed prospective data on patient demographics, ECOG-PS, mGPS, physical function tests, and CT-derived body composition. Categorical variables were analysed using χ2 test for linear-by-linear association, or χ2 test for 2-by-2 tables. Associations were analysed using binary logistic regression. A total of 523 cancer patients (266 males, 257 females) were included in the final analysis and most had metastatic disease (83.2%). The median overall survival was 5.6 months. On multivariate binary logistic regression analysis, a high ECOG-PS remained independently associated with a low skeletal muscle index (p < 0.001), low skeletal muscle density (p < 0.05), and timed up and go test failure (p < 0.001). A high mGPS remained independently associated with a low skeletal muscle density (p < 0.05) and hand grip strength test failure (p < 0.01). A high BMI/WL grade remained independently associated with a low subcutaneous fat index (p < 0.05), low visceral obesity (p < 0.01), and low skeletal muscle density (p < 0.05). In conclusion, a high ECOG-PS and a high mGPS as outlined in the ECOG-PS/mGPS framework were consistently associated with poorer body composition and physical function in patients with advanced cancer

WISE/NEOWISE Observations of the Jovian Trojans: Preliminary Results

We present the preliminary analysis of over 1739 known and 349 candidate Jovian Trojans observed by the NEOWISE component of the Wide-field Infrared Survey Explorer (WISE). With this survey the available diameters, albedos and beaming parameters for the Jovian Trojans have been increased by more than an order of magnitude compared to previous surveys. We find that the Jovian Trojan population is very homogenous for sizes larger than $\sim10$km (close to the detection limit of WISE for these objects). The observed sample consists almost exclusively of low albedo objects, having a mean albedo value of $0.07\pm0.03$. The beaming parameter was also derived for a large fraction of the observed sample, and it is also very homogenous with an observed mean value of $0.88\pm0.13$. Preliminary debiasing of the survey shows our observed sample is consistent with the leading cloud containing more objects than the trailing cloud. We estimate the fraction to be N(leading)/N(trailing) $\sim 1.4 \pm 0.2$, lower than the $1.6 \pm 0.1$ value derived by others.Comment: Accepted for publication in Astrophysical Journal. Electronic table will be available at the publishers websit

Main Belt Asteroids with WISE/NEOWISE I: Preliminary Albedos and Diameters

We present initial results from the Wide-field Infrared Survey Explorer (WISE), a four-band all-sky thermal infrared survey that produces data well suited to measuring the physical properties of asteroids, and the NEOWISE enhancement to the WISE mission allowing for detailed study of Solar system objects. Using a NEATM thermal model fitting routine we compute diameters for over 100,000 Main Belt asteroids from their IR thermal flux, with errors better than 10%. We then incorporate literature values of visible measurements (in the form of the H absolute magnitude) to determine albedos. Using these data we investigate the albedo and diameter distributions of the Main Belt. As observed previously, we find a change in the average albedo when comparing the inner, middle, and outer portions of the Main Belt. We also confirm that the albedo distribution of each region is strongly bimodal. We observe groupings of objects with similar albedos in regions of the Main Belt associated with dynamical breakup families. Asteroid families typically show a characteristic albedo for all members, but there are notable exceptions to this. This paper is the first look at the Main Belt asteroids in the WISE data, and only represents the preliminary, observed raw size and albedo distributions for the populations considered. These distributions are subject to survey biases inherent to the NEOWISE dataset and cannot yet be interpreted as describing the true populations; the debiased size and albedo distributions will be the subject of the next paper in this series.Comment: Accepted to ApJ. Online table to also appear on the publisher's websit

NEOWISE Observations of Near-Earth Objects: Preliminary Results

With the NEOWISE portion of the \emph{Wide-field Infrared Survey Explorer} (WISE) project, we have carried out a highly uniform survey of the near-Earth object (NEO) population at thermal infrared wavelengths ranging from 3 to 22 $\mu$m, allowing us to refine estimates of their numbers, sizes, and albedos. The NEOWISE survey detected NEOs the same way whether they were previously known or not, subject to the availability of ground-based follow-up observations, resulting in the discovery of more than 130 new NEOs. The survey's uniformity in sensitivity, observing cadence, and image quality have permitted extrapolation of the 428 near-Earth asteroids (NEAs) detected by NEOWISE during the fully cryogenic portion of the WISE mission to the larger population. We find that there are 981$\pm$19 NEAs larger than 1 km and 20,500$\pm$3000 NEAs larger than 100 m. We show that the Spaceguard goal of detecting 90% of all 1 km NEAs has been met, and that the cumulative size distribution is best represented by a broken power law with a slope of 1.32$\pm$0.14 below 1.5 km. This power law slope produces $\sim13,200\pm$1,900 NEAs with $D>$140 m. Although previous studies predict another break in the cumulative size distribution below $D\sim$50-100 m, resulting in an increase in the number of NEOs in this size range and smaller, we did not detect enough objects to comment on this increase. The overall number for the NEA population between 100-1000 m are lower than previous estimates. The numbers of near-Earth comets will be the subject of future work.Comment: Accepted to Ap

Demography and disorders of the French Bulldog population under primary veterinary care in the UK in 2013

Abstract Background Despite its Gallic name, the French Bulldog is a breed of both British and French origin that was first recognised by The Kennel Club in 1906. The French Bulldog has demonstrated recent rapid rises in Kennel Club registrations and is now (2017) the second most commonly registered pedigree breed in the UK. However, the breed has been reported to be predisposed to several disorders including ocular, respiratory, neurological and dermatological problems. The VetCompass™ Programme collates de-identified clinical data from primary-care veterinary practices in the UK for epidemiological research. Using VetCompass™ clinical data, this study aimed to characterise the demography and common disorders of the general population of French Bulldogs under veterinary care in the UK. Results French Bulldogs comprised 2228 (0.49%) of 445,557 study dogs under veterinary care during 2013. Annual proportional birth rates showed that the proportional ownership of French Bulldog puppies rose steeply from 0.02% of the annual birth cohort attending VetCompass™ practices in 2003 to 1.46% in 2013. The median age of the French Bulldogs overall was 1.3 years (IQR 0.6–2.5, range 0.0–13.0). The most common colours of French Bulldogs were brindle (solid or main) (32.36%) and fawn (solid or main) (29.9%). Of the 2228 French Bulldogs under veterinary care during 2013, 1612 (72.4%) had at least one disorder recorded. The most prevalent fine-level precision disorders recorded were otitis externa (14.0%, 95% CI: 12.6–15.5), diarrhoea (7.5%, 95% CI: 6.4–8.7), conjunctivitis (3.2%, 95% CI: 2.5–4.0), nails overlong (3.1%, 95% CI% 2.4–3.9) and skin fold dermatitis (3.0%, 95% CI% 2.3–3.8). The most prevalent disorder groups were cutaneous (17.9%, 95% CI: 16.3–19.6), enteropathy (16.7%, 95% CI: 15.2–18.3), aural (16.3%, 95% CI: 14.8–17.9), upper respiratory tract (12.7%, 95% CI: 11.3–14.1) and ophthalmological (10.5%, 95% CI: 9.3–11.9). Conclusions Ownership of French Bulldogs in the UK is rising steeply. This means that the disorder profiles reported in this study reflect a current young UK population and are likely to shift as this cohort ages. Otitis externa, diarrhoea and conjunctivitis were the most common disorders in French Bulldogs. Identification of health priorities based on VetCompass™ data can support evidence–based reforms to improve health and welfare within the breed

The Pan-STARRS Moving Object Processing System

We describe the Pan-STARRS Moving Object Processing System (MOPS), a modern software package that produces automatic asteroid discoveries and identifications from catalogs of transient detections from next-generation astronomical survey telescopes. MOPS achieves > 99.5% efficiency in producing orbits from a synthetic but realistic population of asteroids whose measurements were simulated for a Pan-STARRS4-class telescope. Additionally, using a non-physical grid population, we demonstrate that MOPS can detect populations of currently unknown objects such as interstellar asteroids. MOPS has been adapted successfully to the prototype Pan-STARRS1 telescope despite differences in expected false detection rates, fill-factor loss and relatively sparse observing cadence compared to a hypothetical Pan-STARRS4 telescope and survey. MOPS remains >99.5% efficient at detecting objects on a single night but drops to 80% efficiency at producing orbits for objects detected on multiple nights. This loss is primarily due to configurable MOPS processing limits that are not yet tuned for the Pan-STARRS1 mission. The core MOPS software package is the product of more than 15 person-years of software development and incorporates countless additional years of effort in third-party software to perform lower-level functions such as spatial searching or orbit determination. We describe the high-level design of MOPS and essential subcomponents, the suitability of MOPS for other survey programs, and suggest a road map for future MOPS development.Comment: 57 Pages, 26 Figures, 13 Table