Evolution of substrate-specific gene expression and RNA editing in brown rot wood-decaying fungi.

Fungi that decay wood have characteristic associations with certain tree species, but the mechanistic bases for these associations are poorly understood. We studied substrate-specific gene expression and RNA editing in six species of wood-decaying fungi from the 'Antrodia clade' (Polyporales, Agaricomycetes) on three different wood substrates (pine, spruce, and aspen) in submerged cultures. We identified dozens to hundreds of substrate-biased genes (i.e., genes that are significantly upregulated in one substrate relative to the other two substrates) in each species, and these biased genes are correlated with their host ranges. Evolution of substrate-biased genes is associated with gene family expansion, gain and loss of genes, and variation in cis- and trans- regulatory elements, rather than changes in protein coding sequences. We also demonstrated widespread RNA editing events in the Antrodia clade, which differ from those observed in the Ascomycota in their distribution, substitution types, and the genomic environment. Moreover, we found that substrates could affect editing positions and frequency, including editing events occurring in mRNA transcribed from wood-decay-related genes. This work shows the extent to which gene expression and RNA editing differ among species and substrates, and provides clues into mechanisms by which wood-decaying fungi may adapt to different hosts

Towards the development of an Inter-Cultural Scale to Measure Trust in Automation

Trust is conceived as an attitude leading to intentions resulting in user actions involving automation. It is generally believed that trust is dynamic and that a user’s prior experience with automation affects future behavior indirectly through causing changes in trust. Additionally, individual differences and cultural factors have been frequently cited as the contributors to influencing trust beliefs about using and monitoring automation. The presented research focuses on modeling human’s trust when interacting with automated systems across cultures. The initial trust assessment instrument, comprising 110 items along with 2 perceptions (general vs. specific use of automation), has been empirically validated. Detailed results comparing items and dimensionality with our new pooled measure will be presented

Structural characterization of the family GH115 alpha-glucuronidase from Amphibacillus xylanus yields insight into its coordinated action with alpha-arabinofuranosidases

The coordinated action of carbohydrate-active enzymes has mainly been evaluated for the purpose of complete saccharification of plant biomass (lignocellulose) to sugars. By contrast, the coordinated action of accessory hemicellulases on xylan debranching and recovery is less well characterized. Here, the activity of two family GH115 alpha-glucuronidases (SdeAgu115A from Saccharophagus degradans, and AxyAgu115A from Amphibacillus xylanus) on spruce arabinoglucuronoxylan (AGX) was evaluated in combination with an alpha-arabinofuranosidase from families GH51 (AniAbf51A, aka E-AFASE from Aspergillus niger) and GH62 (SthAbf62A from Streptomyces thermoviolaceus). The alpha-arabinofuranosidases boosted (methyl)-glucuronic acid release by SdeAgu115A by approximately 50 % and 30 %, respectively. The impact of the alpha-arabinofuranosidases on AxyAgu115A activity was comparatively low, motivating its structural characterization. The crystal structure of AxyAgu115A revealed increased length and flexibility of the active site loop compared to SdeAgu115A. This structural difference could explain the ability of AxyAgu115A to accommodate more highly substituted arabinoglucuronoxylan, and inform enzyme selections for improved AGX recovery and use.Peer reviewe

Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption

Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact

Survival from XDR-TB Is Associated with Modifiable Clinical Characteristics in Rural South Africa

Drug-resistant tuberculosis (TB) is a major threat to global public health. Patients with extensively drug-resistant TB (XDR-TB), particularly those with HIV-coinfection, experience high and accelerated mortality with limited available interventions. To determine modifiable factors associated with survival, we evaluated XDR-TB patients from a community-based hospital in rural South Africa where a large number of XDR-TB cases were first detected.A retrospective case control study was conducted of XDR-TB patients diagnosed from 2005-2008. Survivors, those alive at 180 days from diagnostic sputum collection date, were compared with controls who died within 180 days. Clinical, laboratory and microbiological correlates of survival were assessed in 69 survivors (median survival 565 days [IQR 384-774] and 73 non-survivors (median survival 34 days [IQR 18-90]). Among 129 HIV+ patients, multivariate analyses of modifiable factors demonstrated that negative AFB smear (AOR 8.4, CI 1.84-38.21), a lower laboratory index of routine laboratory findings (AOR 0.48, CI 0.22-1.02), CD4>200 cells/mm(3) (AOR 11.53, 1.1-119.32), and receipt of antiretroviral therapy (AOR 20.9, CI 1.16-376.83) were independently associated with survival from XDR-TB.Survival from XDR-TB with HIV-coinfection is associated with less advanced stages of both diseases at time of diagnosis, absence of laboratory markers indicative of multiorgan dysfunction, and provision of antiretroviral therapy. Survival can be increased by addressing these modifiable risk factors through policy changes and improved clinical management. Health planners and clinicians should develop programmes focusing on earlier case finding and integration of HIV and drug-resistant TB diagnostic, therapeutic, and preventive activities

Xylo- and cello-oligosaccharide oxidation by gluco-oligosaccharide oxidase from Sarocladium strictum and variants with reduced substrate inhibition

Peer reviewe

RTOG/NRG 1115 Quality of Life of Phase III Dose Escalated Radiation Therapy (RT) and Standard Androgen Deprivation Therapy (ADT) with GnRH Agonist vs. Dose Escalated RT and ADT with GnRH Agonist and Orteronel (TAK-700) for Men with High-Risk Prostate

Purpose/Objective(s): Quality of life (QOL) was assessed with the hypothesis that QOL and fatigue scores would not differ significantly between the ADT + RT (Arm A) and the experimental group receiving ADT + RT + oreteronel (Arm B). Materials/Methods: In both arms, ADT with GnRH agonist was given for 24 mos, and dose escalated RT started 8-10 wks after initiation of ADT. In Arm B, oreteronel was given BID for 24 mos. QOL was measured with Expanded Prostate Cancer Index Composite (EPIC) and EQ-5D global QOL assessment. EPIC has 4 domains: bowel, urinary, sexual, and hormonal. EQ-5D index score was calculated using health states obtained from 5 dimensions, and a visual analog score (VAS). For EPIC, EQ-5D index and VAS, higher scores indicate better QOL. Fatigue was measured by the 7-item Patient-Reported Outcome Measurement Information System (PROMIS) short form. Total score is standardized into a T-score with mean of 50 and standard deviation of 10 with higher score representing more fatigue. Change scores, calculated as follow-up minus baseline, were compared between arms. Longitudinal analysis using repeated measures mixed effects models was conducted (prior to ADT [baseline], one wk prior to starting RT, last wk of RT, and 1 and 2.5 yrs after initiation of therapy). Results: Of 231 eligible patients, 196 consented to QOL, 102 on Arm A and 94 on Arm B. Compliance prior to start of RT and end of RT was 83%. At 1 and 2.5 yrs, 80% and 62% of pts, respectively, completed the EPIC. There were no differences between any EPIC domain between arms from the start of RT through the end of follow-up. Men on oreteronel had a significantly greater decline in bowel score prior to starting RT then control patients (-6.12, 95% confidence interval [CI]: -9.24, -3.01 vs. -1.93, 95% CI: -4.48, 0.63, respectively, p=0.038). Arm B patients also had a statistically significant and clinically meaningful worse change in urinary score vs control from baseline to pre-RT (-2.33, 95% CI: -5.02, 0.36 vs. 1.38, 95% CI: -1.07, 3.83, respectively, p=0.043). No other timepoints were significant. The only sig. between arm difference in EPIC sexual and hormonal scores was also at pre-RT in favor of Arm A over Arm B; p=0.024 and p=0.0024 respectively). Fatigue was also greater in the oreteronel patients prior to starting RT (3.81, 95% CI: 1.88, 5.74 vs. 1.18, 95% CI: -0.23, 2.60, p=0.028). Conclusion: The addition of oreteronel to RT and ADT resulted in greater declines in QOL prior to the start of RT but did not result in significant differences at any other time points. Although oreteronel development has been halted, the QOL results are encouraging for other drugs in this class that remain under investigation. In ongoing prospective trials, QOL impacts should be measured in conjunction with changes in clinical outcome and survival. This project was supported by grants UG1CA189867, U10CA180868, U10CA180822 from the National Cancer Institute and Takeda Pharmaceutical

The complex TIE between macrophages and angiogenesis

Macrophages are primarily known as phagocytic immune cells, but they also play a role in diverse processes, such as morphogenesis, homeostasis and regeneration. In this review, we discuss the influence of macrophages on angiogenesis, the process of new blood vessel formation from the pre-existing vasculature. Macrophages play crucial roles at each step of the angiogenic cascade, starting from new blood vessel sprouting to the remodelling of the vascular plexus and vessel maturation. Macrophages form promising targets for both pro- and anti-angiogenic treatments. However, to target macrophages, we will first need to understand the mechanisms that control the functional plasticity of macrophages during each of the steps of the angiogenic cascade. Here, we review recent insights in this topic. Special attention will be given to the TIE2-expressing macrophage (TEM), which is a subtype of highly angiogenic macrophages that is able to influence angiogenesis via the angiopoietin-TIE pathway

Delayed-type hypersensitivity in classic Kaposi sarcoma patients and controls

BACKGROUND: Immune perturbation likely affects the development of Kaposi sarcoma (KS) among people infected with the KS-associated herpesvirus (KSHV). We tested whether KSHV-seropositive individuals or cases of classic KS (cKS), which typically originates in the leg, had differing delayed-type hypersensitivity (DTH) in the forearm or leg. METHODS: Mantoux DTH with three antigens (Candida, tetanus, PPD) was performed on the forearm and leg of 15 cKS cases, 14 KSHV-positives without KS, and 15 KSHV-negative controls. The diameters of induration responses were compared by group and body site. RESULTS: Leg DTH was greater than forearm DTH among controls (mean difference 5.6 mm, P\ubc0.0004), whereas this was not observed in cKS cases ( 2.2 mm, P\ubc0.32) or KSHV-positives (0.5 mm, P\ubc0.56). Leg-minus-forearm DTH difference was greater in controls compared with cKS cases (P\ubc0.004) and KSHV-positives (P\ubc0.002). Leg-plus-forearm DTH was similar in controls (mean 28.2 mm) and cKS cases (24.5 mm, P\ubc0.60), but it was reduced in KSHV-positives (11.8 mm, P\ubc0.02), particularly in the leg (P\ubc0.004) and marginally in the forearm (P\ubc0.07). CONCLUSION: KS cases had weaker DTH only in the leg, whereas both body sites appeared weaker in KSHV-positives without KS. Both systemic and regional immune alterations may influence the development of this malignancy

Towards nanomedicines of the future: Remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields

The paper describes the concept of magneto-mechanical actuation of single-domain magnetic nanoparticles (MNPs) in super-low and low frequency alternating magnetic fields (AMFs) and its possible use for remote control of nanomedicines and drug delivery systems. The applications of this approach for remote actuation of drug release as well as effects on biomacromolecules, biomembranes, subcellular structures and cells are discussed in comparison to conventional strategies employing magnetic hyperthermia in a radio frequency (RF) AMF. Several quantitative models describing interaction of functionalized MNPs with single macromolecules, lipid membranes, and proteins (e.g. cell membrane receptors, ion channels) are presented. The optimal characteristics of the MNPs and an AMF for effective magneto-mechanical actuation of single molecule responses in biological and bio-inspired systems are discussed. Altogether, the described studies and phenomena offer opportunities for the development of novel therapeutics both alone and in combination with magnetic hyperthermia