Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra.

The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen1. Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response2-7. Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models6-11. Here, we examined B6.Sst1S congenic mice that carry the 'susceptible' allele of the Sst1 locus that results in exacerbated Mtb disease12-14. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections6,7,15-18. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1S mice. Our results illustrate the value of the B6.Sst1S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo

Rethinking ‘Advanced Search’: A New Approach to Complex Query Formulation

Knowledge workers such as patent agents, recruiters and media monitoring professionals undertake work tasks where search forms a core part of their duties. In these instances, the search task often involves the formulation of complex queries expressed as Boolean strings. However, creating effective Boolean queries remains an ongoing challenge, often compromised by errors and inefficiencies. In this demo paper, we present a new approach to query formulation in which concepts are expressed on a two-dimensional canvas and relationships are articulated using direct manipulation. This has the potential to eliminate many sources of error, makes the query semantics more transparent, and offers new opportunities for query refinement and optimisatio

OPERATION OF CENTRIFUGAL COMPRESSORS IN CHOKE CONDITIONS

TutorialCentrifugal compressors are at times required to operate in or near the choke region. Various limits of the degree of allowable operation in choke have been established. Based on test data and numerical data, the behavior of centrifugal compressors in the choke region is studied. Changes in aerodynamic performance, thrust load, volute behavior and radial loading are considered. The issue of excitation of impeller vanes is addressed. Particular consideration is given to multistage machines, as well as dual compartment machines, in particular regarding the effects of impeller mismatch during operating conditions at flows significantly higher than the design flow. Limitations in the overload operating range of a compressor not only impact the operational flexibility , but also can require more complicated control systems. The paper addresses aerodynamic, structural as well as rotordynamic issues related to the operation in choke

Tunable photonic Bloch oscillations in electrically modulated photonic crystals

We exploit theoretically the occurrence and tunability of photonic Bloch oscillations (PBOs) in one-dimensional photonic crystals (PCs) containing nonlinear composites. Because of the enhanced third-order nonlinearity (Kerr type nonlinearity) of composites, photons undergo oscillations inside tilted photonic bands, which are achieved by the application of graded external pump electric fields on such PCs, varying along the direction perpendicular to the surface of layers. The tunability of PBOs (including amplitude and period) is readily achieved by changing the field gradient. With an appropriate graded pump AC or DC electric field, terahertz PBOs can appear and cover a terahertz band in electromagnetic spectrum

Measuring Accuracy of Automated Parsing and Categorization Tools and Processes in Digital Investigations

This work presents a method for the measurement of the accuracy of evidential artifact extraction and categorization tasks in digital forensic investigations. Instead of focusing on the measurement of accuracy and errors in the functions of digital forensic tools, this work proposes the application of information retrieval measurement techniques that allow the incorporation of errors introduced by tools and analysis processes. This method uses a `gold standard' that is the collection of evidential objects determined by a digital investigator from suspect data with an unknown ground truth. This work proposes that the accuracy of tools and investigation processes can be evaluated compared to the derived gold standard using common precision and recall values. Two example case studies are presented showing the measurement of the accuracy of automated analysis tools as compared to an in-depth analysis by an expert. It is shown that such measurement can allow investigators to determine changes in accuracy of their processes over time, and determine if such a change is caused by their tools or knowledge.Comment: 17 pages, 2 appendices, 1 figure, 5th International Conference on Digital Forensics and Cyber Crime; Digital Forensics and Cyber Crime, pp. 147-169, 201

Adaptive Bayesian Iterative Transmission Reconstruction for Attenuation Correction in Myocardial Perfusion Imaging with SPECT/Slow-Rotation Low-Output CT Systems

Objectives. SPECT/slow-rotation low-output CT systems can produce streak artifacts in filtered backprojection (FBP) attenuation maps, impacting attenuation correction (AC) in myocardial perfusion imaging. This paper presents an adaptive Bayesian iterative transmission reconstruction (ABITR) algorithm for more accurate AC. Methods. In each iteration, ABITR calculated a three-dimensional prior containing the pixels with attenuation coefficients similar to water, then used it to encourage these pixels to the water value. ABITR was tested with a cardiac phantom and 4 normal patients acquired by a GE Millennium VG/Hawkeye system. Results. FBP AC and ABITR AC produced similar phantom results. For the patients, streak artifacts were observed in the FBP and ordered-subsets expectation-maximization (OSEM) maps but not in the ABITR maps, and ABITR AC produced more uniform images than FBP AC and OSEM AC. Conclusion. ABITR can improve the quality of the attenuation map, producing more uniform images for normal studies

Embedding of printed electronic interconnections in additively manufactured metal components

Ultrasonic Additive Manufacturing (UAM) is an advanced hybrid manufacturing technology, which enables the embedding of electronic components and interconnections within solid metal structures, due to the low temperature/high plastic flow encountered during ultrasonic bonding. The UAM process is based on the ultrasonic metal welding of thin metal foils in a layer-by-layer fashion. This work summarises the recent advances made towards the integration of UAM with printed electronics and other advanced manufacturing technologies for the encapsulation of conductive tracks between the interfaces of the welded foils. Two different approaches were followed: Screen printing was utilized in the first approach, for the deposition of an insulating polymer layer and silver-loaded conductive adhesive tracks on the surface of an aluminium substrate prepared with UAM. In the second approach, the aluminium foils were surface modified prior to welding, in order to selectively create an insulating ceramic layer directly onto the foil surface. These modified foils were bonded using UAM and a syringe system was used for the dispensing of the silver conductive tracks. The effectiveness and advantages of each of these two methodologies are illustrated and commented upon. The results of this ongoing research project are promising and showcase the successful integration of advanced manufacturing technologies for the fabrication of intricate metal structural electronic components

Identification of Single Nucleotide Polymorphisms Associated with Hyperproduction of Alpha-Toxin in Staphylococcus aureus

The virulence factor α-toxin (hla) is needed by Staphylococcus aureus in order to cause infections in both animals and humans. Although the complicated regulation of hla expression has been well studied in human S. aureus isolates, the mechanisms of of hla regulation in bovine S. aureus isolates remain undefined. In this study, we found that many bovine S. aureus isolates, including the RF122 strain, generate dramatic amounts of α-toxin in vitro compared with human clinical S. aureus isolates, including MRSA WCUH29 and MRSA USA300. To elucidate potential regulatory mechanisms, we analyzed the hla promoter regions and identified predominant single nucleotide polymorphisms (SNPs) at positions −376, −483, and −484 from the start codon in α-toxin hyper-producing isolates. Using site-directed mutagenesis and hla promoter-gfp-luxABCDE dual reporter approaches, we demonstrated that the SNPs contribute to the differential control of hla expression among bovine and human S. aureus isolates. Using a DNA affinity assay, gel-shift assays and a null mutant, we identified and revealed that an hla positive regulator, SarZ, contributes to the involvement of the SNPs in mediating hla expression. In addition, we found that the bovine S. aureus isolate RF122 exhibits higher transcription levels of hla positive regulators, including agrA, saeR, arlR and sarZ, but a lower expression level of hla repressor rot compared to the human S. aureus isolate WCUH29. Our results indicate α-toxin hyperproduction in bovine S. aureus is a multifactorial process, influenced at both the genomic and transcriptional levels. Moreover, the identification of predominant SNPs in the hla promoter region may provide a novel method for genotyping the S. aureus isolates

Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy

In eukaryotic cells, control mechanisms have developed that restrain cell-cycle transitions in response to stress. These regulatory pathways are termed cell-cycle checkpoints. The G2/M checkpoint prevents cells from entering mitosis when DNA is damaged in order to afford these cells an opportunity to repair the damaged DNA before propagating genetic defects to the daughter cells. If the damage is irreparable, checkpoint signaling might activate pathways that lead to apoptosis. Since alteration of cell-cycle control is a hallmark of tumorigenesis, cell-cycle regulators represent potential targets for therapy. The centrosome has recently come into focus as a critical cellular organelle that integrates G2/M checkpoint control and repairs signals in response to DNA damage. A growing number of G2/M checkpoint regulators have been found in the centrosome, suggesting that centrosome has an important role in G2/M checkpoint function. In this review, we discuss centrosome-associated regulators of the G2/M checkpoint, the dysregulation of this checkpoint in cancer, and potential candidate targets for cancer therapy