DNA crunching by a viral packaging motor: Compression of a procapsid-portal stalled Y-DNA substrate

AbstractMany large double-stranded DNA viruses employ high force-generating ATP-driven molecular motors to package to high density their genomes into empty procapsids. Bacteriophage T4 DNA translocation is driven by a two-component motor consisting of the procapsid portal docked with a packaging terminase-ATPase. Fluorescence resonance energy transfer and fluorescence correlation spectroscopic (FRET-FCS) studies of a branched (Y-junction) DNA substrate with a procapsid-anchoring leader segment and a single dye molecule situated at the junction point reveal that the “Y-DNA” stalls in proximity to the procapsid portal fused to GFP. Comparable structure Y-DNA substrates containing energy transfer dye pairs in the Y-stem separated by 10 or 14 base pairs reveal that B-form DNA is locally compressed 22–24% by the linear force of the packaging motor. Torsional compression of duplex DNA is thus implicated in the mechanism of DNA translocation

Cryptosporidium Parvum-Induced Inflammatory Bowel Disease of TCR-β- x TCR-δ-Deficient Mice

Experimental inoculation of neonatal immunocompetent strains of mice with Cryptosporidium parvum results in a transient, noninflammatory enteric infection. In the present study, we show that inoculation of mice deficient in a 3 and y8 T cells (TCR-3- X TCR-8-deficient mice) with C. parvum results in persistent infection and severe inflammatory bowel disease- like lesions. The most severe lesions in these mice were in the cecum with similar yet less severe lesions in the ileum and proximal colon. The most notable aspect of the histopathology was glandular hyperplasia with abscess formation, extensive fibrosis of the lamina propria with infiltrates of predominately polymorphonuclear cells and macrophages, and a few small aggregates of B cells. Persistently infected mice also developed extensive hepatic periportal fibrosis in association with C. parvum colonization of bile ducts. Lesions observed in TCR- 3- X TCR-8-deficient mice were markedly different than previously described lesions detected in C. parvum-infected TCR-o-deficient mice. Cryptosporidium parvum-infected TCR-o-deficient mice have extensive infiltrations of B cells, whereas TCR-P3- X TCR-8-deficient mice had only a few small aggregates of B cells. These findings indicate that although y8 T cells are not necessary for induction of intestinal inflammation in C. parvum-infected o(4 T- cell-deficient mice, their presence does alter the morphology of the ensuing lesion

LUCAS: A highly accurate yet simple risk calculator that predicts survival of COVID-19 patients using rapid routine tests

Background There is an urgent need to develop a simplified risk tool that enables rapid triaging of SARS CoV-2 positive patients during hospital admission, which complements current practice. Many predictive tools developed to date are complex, rely on multiple blood results and past medical history, do not include chest X ray results and rely on Artificial Intelligence rather than simplified algorithms. Our aim was to develop a simplified risk-tool based on five parameters and CXR image data that predicts the 60-day survival of adult SARS CoV-2 positive patients at hospital admission. Methods We analysed the NCCID database of patient blood variables and CXR images from 19 hospitals across the UK contributed clinical data on SARS CoV-2 positive patients using multivariable logistic regression. The initial dataset was non-randomly split between development and internal validation dataset with 1434 and 310 SARS CoV-2 positive patients, respectively. External validation of final model conducted on 741 Accident and Emergency admissions with suspected SARS CoV-2 infection from a separate NHS Trust which was not part of the initial NCCID data set. Findings The LUCAS mortality score included five strongest predictors (lymphocyte count, urea, CRP, age, sex), which are available at any point of care with rapid turnaround of results. Our simple multivariable logistic model showed high discrimination for fatal outcome with the AUC-ROC in development cohort 0.765 (95% confidence interval (CI): 0.738 - 0.790), in internal validation cohort 0.744 (CI: 0.673 - 0.808), and in external validation cohort 0.752 (CI: 0.713 - 0.787). The discriminatory power of LUCAS mortality score was increased slightly when including the CXR image data (for normal versus abnormal): internal validation AUC-ROC 0.770 (CI: 0.695 - 0.836) and external validation AUC-ROC 0.791 (CI: 0.746 - 0.833). The discriminatory power of LUCAS and LUCAS + CXR performed in the upper quartile of pre-existing risk stratification scores with the added advantage of using only 5 predictors. Interpretation This simplified prognostic tool derived from objective parameters can be used to obtain valid predictions of mortality in patients within 60 days SARS CoV-2 RT-PCR results. This free-to-use simplified tool can be used to assist the triage of patients into low, moderate, high or very high risk of fatality and is available at https://mdscore.net/. What is already known on this topic? Clinical prediction models such as NEWS2 is currently used in practice as mortality risk assessment. In a rapid response to support COVID-19 patient assessment and resource management, published risk tools and models have been found to have a high risk of bias and therefore cannot be translated into clinical practice. What this study adds? A newly developed and validated risk tool (LUCAS) based on rapid and routine blood tests predicts the mortality of patients infected with SARS-CoV-2 virus. This prediction model has both high and robust predictive power and has been tested on an external set of patients and therefore can be used to effectively triage patients when resources are limited. In addition, LUCAS can be used with chest imaging information and NEWS2 score

Measuring and Correcting Wind-Induced Pointing Errors of the Green Bank Telescope Using an Optical Quadrant Detector

Wind-induced pointing errors are a serious concern for large-aperture high-frequency radio telescopes. In this paper, we describe the implementation of an optical quadrant detector instrument that can detect and provide a correction signal for wind-induced pointing errors on the 100m diameter Green Bank Telescope (GBT). The instrument was calibrated using a combination of astronomical measurements and metrology. We find that the main wind-induced pointing errors on time scales of minutes are caused by the feedarm being blown along the direction of the wind vector. We also find that wind-induced structural excitation is virtually non-existent. We have implemented offline software to apply pointing corrections to the data from imaging instruments such as the MUSTANG 3.3 mm bolometer array, which can recover ~70% of sensitivity lost due to wind-induced pointing errors. We have also performed preliminary tests that show great promise for correcting these pointing errors in real-time using the telescope's subreflector servo system in combination with the quadrant detector signal.Comment: 17 pages, 11 figures; accepted for publication in PAS

bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice

bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice. HIV-associated nephropathy is characterized by extensive tubulointerstitial disease with epithelial cell injury, microcystic proliferation, and tubular regeneration with glomerulosclerosis. To explore the role of bFGF as a mediator of HIV-induced interstitial disease, we utilized an HIV transgenic mouse model that manifests clinical and histological features observed in patients. In transgenic mice, simultaneous renal epithelial cell proliferation and injury were detected in vivo. In areas of microcystic proliferation, immunoreactive bFGF colocalized with extracellular matrix. Kidneys from transgenic mice had increased bFGF low affinity binding sites, particularly in the renal interstitium. In vitro, transgenic renal tubular epithelial cells proliferated more rapidly and generated tubular structures spontaneously, in marked contrast to nontransgenic renal cells where these pathologic features could be mimicked by exogenous bFGF. These studies suggest that renal bFGF and its receptors play an important role in the pathogenesis of HIV-associated nephropathy

Surveying the Dynamic Radio Sky with the Long Wavelength Demonstrator Array

This paper presents a search for radio transients at a frequency of 73.8 MHz (4 m wavelength) using the all-sky imaging capabilities of the Long Wavelength Demonstrator Array (LWDA). The LWDA was a 16-dipole phased array telescope, located on the site of the Very Large Array in New Mexico. The field of view of the individual dipoles was essentially the entire sky, and the number of dipoles was sufficiently small that a simple software correlator could be used to make all-sky images. From 2006 October to 2007 February, we conducted an all-sky transient search program, acquiring a total of 106 hr of data; the time sampling varied, being 5 minutes at the start of the program and improving to 2 minutes by the end of the program. We were able to detect solar flares, and in a special-purpose mode, radio reflections from ionized meteor trails during the 2006 Leonid meteor shower. We detected no transients originating outside of the solar system above a flux density limit of 500 Jy, equivalent to a limit of no more than about 10^{-2} events/yr/deg^2, having a pulse energy density >~ 1.5 x 10^{-20} J/m^2/Hz at 73.8 MHz for pulse widths of about 300 s. This event rate is comparable to that determined from previous all-sky transient searches, but at a lower frequency than most previous all-sky searches. We believe that the LWDA illustrates how an all-sky imaging mode could be a useful operational model for low-frequency instruments such as the Low Frequency Array, the Long Wavelength Array station, the low-frequency component of the Square Kilometre Array, and potentially the Lunar Radio Array.Comment: 20 pages; accepted for publication in A

A powerful bursting radio source towards the Galactic Centre

Transient astronomical sources are typically powered by compact objects and usually signify highly explosive or dynamic events. While radio astronomy has an impressive record of obtaining high time resolution observations, usually it is achieved in quite narrow fields-of-view. Consequently, the dynamic radio sky is poorly sampled, in contrast to the situation in the X- and gamma-ray bands in which wide-field instruments routinely detect transient sources. Here we report a new transient source, GCRT J1745-3009, detected in 2002 during a moderately wide-field radio transient monitoring program of the Galactic center (GC) region at 0.33 GHz. The characteristics of its bursts are unlike those known for any other class of radio transient. If located in or near the GC, its brightness temperature (~10^16 K) and the implied energy density within GCRT J1745-3009 vastly exceeds that observed in most other classes of radio astronomical sources, and is consistent with coherent emission processes rarely observed. We conclude that GCRT J1745-3009 is the first member of a new class of radio transient sources, the first of possibly many new classes to be identified through current and upcoming radio surveys.Comment: 16 pages including 3 figures. Appears in Nature, 3 March 200

U.S. Government engagement in support of global disease surveillance

Global cooperation is essential for coordinated planning and response to public health emergencies, as well as for building sufficient capacity around the world to detect, assess and respond to health events. The United States is committed to, and actively engaged in, supporting disease surveillance capacity building around the world. We recognize that there are many agencies involved in this effort, which can become confusing to partner countries and other public health entities. This paper aims to describe the agencies and offices working directly on global disease surveillance capacity building in order to clarify the United States Government interagency efforts in this space