Aerosol Jet Printing (AJP) is an emerging contactless direct write approach aimed at the production of fine features on a wide range of substrates. Originally developed for the manufacture of ...electronic circuitry, the technology has been explored for a range of applications, including, active and passive electronic components, actuators, sensors, as well as a variety of selective chemical and biological responses. Freeform deposition, coupled with a relatively large stand-off distance, is enabling researchers to produce devices with increased geometric complexity compared to conventional manufacturing or more commonly used direct write approaches. Wide material compatibility, high resolution and independence of orientation have provided novelty in a number of applications when AJP is conducted as a digitally driven approach for integrated manufacture. This overview of the technology will summarise the underlying principles of AJP, review applications of the technology and discuss the hurdles to more widespread industry adoption. Finally, this paper will hypothesise where gains may be realised through this assistive manufacturing process.
Congruent, low-friction relative movement between the articulating elements of a synovial joint is an essential pre-requisite for sustained, efficient, function. Where disorders of joint formation or ...maintenance exist, mechanical overloading and osteoarthritis (OA) follow. The heritable component of OA accounts for ~ 50% of susceptible risk. Although almost 100 genetic risk loci for OA have now been identified, and the epidemiological relationship between joint development, joint shape and osteoarthritis is well established, we still have only a limited understanding of the contribution that genetic variation makes to joint shape and how this modulates OA risk. In this article, a brief overview of synovial joint development and its genetic regulation is followed by a review of current knowledge on the genetic epidemiology of established joint shape disorders and common shape variation. A summary of current genetic epidemiology of OA is also given, together with current evidence on the genetic overlap between shape variation and OA. Finally, the established genetic risk loci for both joint shape and osteoarthritis are discussed.
The interaction between slip bands and grain boundaries in commercial-purity titanium was examined using cross-correlation-based electron backscatter diffraction. At a low strain level, three types ...of interactions were observed: blocked slip band with stress concentration; slip transfer; and blocked slip band with no stress concentration. The stress concentration induced by the blocked slip band was fitted with Eshelby’s theoretical model, from which a Hall–Petch coefficient was deduced. It was found that the Hall–Petch coefficient varies with the individual grain boundary. We investigated the geometric alignment between the slip band and various slip systems to the neighbouring grain. Stress concentration can be induced by the blocked slip band if the slip system is poorly aligned with 〈a〉 prismatic, pyramidal or basal slip systems in the neighbouring grain. Transfer of slip across the boundary occurs when there is good alignment on 〈a〉 prismatic or 〈a〉 pyramidal slip systems. Other stress-relieving mechanisms are possible when the best alignment is not with the slip system that has the lower critical resolved shear stress.
The immune response in tuberculosis O'Garra, Anne; Redford, Paul S; McNab, Finlay W ...
Annual review of immunology,
01/2013, Letnik:
31
Journal Article
Recenzirano
There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of ...these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
The evolution of dislocation storage in deformed copper was studied with cross-correlation-based high-resolution electron backscatter diffraction. Maps of 500μm×500μm areas with 0.5μm step size were ...collected and analysed for samples deformed in tension to 0%, 6%, 10%, 22.5% and 40% plastic strain. These maps cover ∼1500 grains each while also containing very good resolution of the geometrically necessary dislocation (GND) content. We find that the average GND density increases with imposed macroscopic strain in accord with Ashby’s theory of work hardening. The dislocation density distributions can be described well with a log-normal function. These data sets are very rich and provide ample data such that quantitative statistical analysis can also be performed to assess the impact of grain morphology and local crystallography on the storage of dislocations and resultant deformation patterning. Higher GND densities accumulate near grain boundaries and triple junctions as anticipated by Ashby’s theory, while lower densities are rather more spread through the material. At lower strains (⩽6%) the grain-averaged GND density was higher in smaller grains, showing a good correlation with the reciprocal of the grain size. When combined with a Taylor hardening model this last observation is consistent with the Hall–Petch grain size effect for the yield or flow stress.
Over the last 8000 years the Fertile Crescent of the Near East has seen the emergence of urban agglomerations, small scale polities and large territorial empires, all of which had profound effects on ...settlement patterns. Computational approaches, including the use of remote sensing data, allow us to analyse these changes at unprecedented geographical and temporal scales. Here we employ these techniques to examine and compare long term trends in urbanisation, population and climate records. Maximum city size is used as a proxy for the intensity of urbanisation, whilst population trends are modelled from settlement densities in nine archaeological surveys conducted over the last 30 years across the region. These two measures are then compared with atmospheric moisture levels derived from multiple proxy analyses from two locations close to the study area, Soreq Cave in Israel and Lake Van in south-eastern Turkey, as well as wider literature. The earliest urban sites emerged during a period of relatively high atmospheric moisture levels and conform to a series of size thresholds. However, after the Early Bronze Age maximum urban size and population levels increase rapidly whilst atmospheric moisture declines. We argue that although the initial phase of urbanization may have been linked to climate conditions, we can see a definitive decoupling of climate and settlement patterns after 2000 BC. We relate this phenomenon to changes in socio-economic organisation and integration in large territorial empires. The complex relationships sustaining urban growth during this later period resulted in an increase in system fragility and ultimately impacted on the sustainability of cities in the long term.
Globally there are approximately 9 million new active tuberculosis cases and 1.4 million deaths annually. Effective antituberculosis treatment monitoring is difficult as there are no existing ...biomarkers of poor adherence or inadequate treatment earlier than 2 months after treatment initiation. Inadequate treatment leads to worsening disease, disease transmission and drug resistance.
To determine if blood transcriptional signatures change in response to antituberculosis treatment and could act as early biomarkers of a successful response.
Blood transcriptional profiles of untreated active tuberculosis patients in South Africa were analysed before, during (2 weeks and 2 months), at the end of (6 months) and after (12 months) antituberculosis treatment, and compared to individuals with latent tuberculosis. An active-tuberculosis transcriptional signature and a specific treatment-response transcriptional signature were derived. The specific treatment response transcriptional signature was tested in two independent cohorts. Two quantitative scoring algorithms were applied to measure the changes in the transcriptional response. The most significantly represented pathways were determined using Ingenuity Pathway Analysis.
An active tuberculosis 664-transcript signature and a treatment specific 320-transcript signature significantly diminished after 2 weeks of treatment in all cohorts, and continued to diminish until 6 months. The transcriptional response to treatment could be individually measured in each patient.
Significant changes in the transcriptional signatures measured by blood tests were readily detectable just 2 weeks after treatment initiation. These findings suggest that blood transcriptional signatures could be used as early surrogate biomarkers of successful treatment response.
A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood ...RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test.
Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis M.TB from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI 87-100; specificity 90%, 95% CI 80-97) and TB from OD (sensitivity 93%, 95% CI 83-100; specificity 88%, 95% CI 74-97). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI 85-100; specificity 94%, 95% CI 84-100) and OD patients (sensitivity 100%, 95% CI 100-100; specificity 96%, 95% CI 93-100). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group.
In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary.
Breast cancer bone metastases are incurable, highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment ...stimulate outgrowth into overt metastases. Here we show that endogenous production of IL1B by tumor cells drives metastasis and growth in bone.
Tumor/stromal IL1B and IL1 receptor 1 (IL1R1) expression was assessed in patient samples and effects of the IL1R antagonist, Anakinra, or the IL1B antibody canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL1B on bone colonization and parameters associated with metastasis were measured in MDA-MB-231, MCF7, and T47D cells transfected with
/control.
In tissue samples from >1,300 patients with stage II/III breast cancer, IL1B in tumor cells correlated with relapse in bone (HR = 1.85; 95% CI, 1.05-3.26;
= 0.02) and other sites (HR = 2.09; 95% CI, 1.26-3.48;
= 0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL1B by tumor cells promoted epithelial-to-mesenchymal transition (altered E-Cadherin, N-Cadherin, and G-Catenin), invasion, migration, and bone colonization. Contact between tumor and osteoblasts or bone marrow cells increased IL1B secretion from all three cell types. IL1B alone did not stimulate tumor cell proliferation. Instead, IL1B caused expansion of the bone metastatic niche leading to tumor proliferation.
Pharmacologic inhibition of IL1B has potential as a novel treatment for breast cancer metastasis.
When silage is exposed to air on opening the silo, or after its removal from the silo, fermentation acids and other substrates are oxidized by aerobic bacteria, yeasts and moulds. The aerobic ...stability of silage is a key factor in ensuring that silage provides well‐preserved nutrients to the animal with minimal amounts of mould spores and toxins. In this paper, key findings and recent developments are reviewed, and findings of recent research are integrated in terms of four themes: (i) the most significant biochemical and microbiological factors, (ii) physical and management factors, (iii) type of additive and (iv) silo sealing. The development of yeasts and moulds during plant growth, and during field wilting or storage, and the concentration of undissociated acetic acid in silage are important microbiological and biochemical factors affecting aerobic stability. Silage density and porosity are key physical factors that affect the rate of ingress of oxygen into the silage mass during the feed‐out period. A target for potential silage aerobic stability is 7 d including time in the feed trough. To achieve this target, speed of harvest should be coordinated with packing tractor weight to achieve a minimum silage density by the time of feed‐out of 210 kg DM m−3, maximum proportional porosity of 0·4 and a rate of silage removal, which matches or exceeds the depth of air penetration into the silo. The use of additives to increase aerobic stability is advisable when there is the risk of these objectives not being met. Novel microbial approaches to solving the problem of silage aerobic deterioration are needed.
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