Influence of management and precipitation on carbon fluxes in Great Plains grasslands

Suitable management and sufficient precipitation on grasslands can provide carbon sinks. The net carbon accumulation of a site from the atmosphere, modeled as the Net Ecosystem Productivity (NEP), is a useful means to gauge carbon balance. Previous research has developed methods to integrate flux tower data with satellite biophysical datasets to estimate NEP across large regions. A related method uses the Ecosystem Performance Anomaly (EPA) as a satellite-derived indicator of disturbance intensity (e.g., livestock stocking rate, fire, and insect damage). To better understand the interactions among management, climate, and carbon dynamics, we evaluated the relationship between EPA and NEP data at the 250 m scale for grasslands in the Central Great Plains, USA (ranging from semi-arid to mesic). We also used weekly estimates of NEP to evaluate the phenology of carbon dynamics, classified by EPA (i.e., by level of disturbance impact). Results show that the cumulative carbon balance over these grasslands from 2000 to 2008 was a weak net sink of 13.7 g C m−2 yr−1. Overall, NEP increased with precipitation (R2 = 0.39, P \u3c 0.05) from west to east. Disturbance influenced NEP phenology; however, climate and biophysical conditions were usually more important. The NEP response to disturbance varies by ecoregion, and more generally by grassland type, where the shortgrass prairie NEP is most sensitive to disturbance, the mixed-grass prairie displays a moderate response, and tallgrass prairie is the least impacted by disturbance (as measured by EPA). Sustainable management practices in the tallgrass and mixed-grass prairie may potentially induce a period of average net carbon sink until a new equilibrium soil organic carbon is achieved. In the shortgrass prairie, management should be considered sustainable if carbon stocks are simply maintained. The consideration of site carbon balance adds to the already difficult task of managing grasslands appropriately to site conditions. Results clarify the seasonal and interannual dynamics of NEP, specifically the influence of disturbance and moisture availability

Antibacterial assessment of TMPyP-incorporated p(HEMA-co-MMA)

IntroductionLight-triggered therapy to treat infectious diseases is called photodynamic antimicrobial therapy (PACT).PACT has been widely shown to have a lethal effect against bacteria, fungi, viruses, and parasites and it impacts different biofilms (Garcez et al., 2007) TMPyP (tetrakis(4-N-methylpyridyl)porphyrin) is a porphyrin frequently used in PACT, and exerts its phototoxic effect upon both gram-negative and gram-positive bacteria, via two reactions First, Type II reaction is considered the major pathway of photodynamic therapy. The second pathway, Type I reaction, involves transferring electrons/protons to a substrate and releasing a radical that can react with oxygen to produce reactive oxygen species (ROS) (Brady et al., 2007). This study aims to develop a novel surface loading with TMPyP capable of reducing the adherence of bacteria.Materials and methodsTMPyP (tetrakis(4-N-methylpyridyl)porphyrin) IS the photosensitizer loaded into p(HEMA-co-MMA)hydrogel. S. aureus ATCC 29213 and E. coli ATCC 700928 which are required for the microbiological assessments. The LED light array activates TMPyP-incorporated p(HEMA-co-MMA). TMPyP was incorporated onto the surface of the p(HEMA-co-MMA) copolymer by swell-encapsulation shrink(SES) technique. Samples were prepared by loading them in different TMPyP soaking solutions for 2min. First, a TMPyP stock solution was prepared (2.18 mg/ml). Next, further dilutions to the appropriate concentration were made using PBS (at pH 7.4). S. aureus ATCC 29213 and E. coli ATCC 700928 represent gram-positive and gram-negative bacteria and are used for assessing adherence percentages.ResultsThe percentage adherence (%) compared to dark control of S. aureus and E. coli when TMPyP-incorporated and unincorporated p(HEMA-co-MMA) were illuminated for 120 min using a whiteLED source providing a power of 5.33 mW/cm2, integrated between 450–700 nm, or in dark condition has been presented in Figure 1.DiscussionTMPyP incorporated copolymers (7.33x10-4 M and7.33x10-5 M) significantly reduced the percentage adherence of S. aureus and E. coli compared to dark control illustrating that these materials are less likely to colonize. This antimicrobial behaviour for hydrogels loaded with 7.33x10-4 M of TMPyP shows significant promise for the development of biomaterials to prevent the colonization of gram-positive and gram-negative bacteria and prevent biofilm formation.ConclusionOverall, the attachment of TMPyP into the surface of p(HEMA-co-MMA) copolymers resulted in a material with antimicrobial behaviour

Liposomal Encapsulation of Amoxicillin via Microfluidics with Subsequent Investigation of the Significance of PEGylated Therapeutics

With an increasing concern of global antimicrobial resistance, the efforts to improve the formulation of a narrowing library of therapeutic antibiotics must be confronted. The liposomal encapsulation of antibiotics using a novel and sustainable microfluidic method has been employed in this study to address this pressing issue, via a targeted, lower-dose medical approach. The study focusses upon microfluidic parameter optimisation, formulation stability, cytotoxicity, and future applications. Particle sizes of circa. 130 nm, with viable short-term (28-day) physical stability were obtained, using two different non-cytotoxic liposomal formulations, both of which displayed suitable antibacterial efficacy. The microfluidic method allowed for high encapsulation efficiencies (≈77 %) and the subsequent in vitro release profile suggested high limits of antibiotic dissociation from the nanovessels, achieving 90% release within 72 h. In addition to the experimental data, the growing use of poly(ethylene) glycol (PEG) within lipid-based formulations is discussed in relation to anti-PEG antibodies, highlighting the key pharmacological differences between PEGylated and non-PEGylated formulations and their respective advantages and drawbacks. It's surmised that in the case of the formulations used in this study, the addition of PEG upon the liposomal membrane would still be a beneficial feature to possess owing to beneficial features such as stability, antibiotic efficacy and the capacity to further modify the liposomal membrane.</p

An empirical approach to modeling ion production rates in Titan’s ionosphere I: Ion production rates on the dayside and globally

Titan's ionosphere is created when solar photons, energetic magnetospheric electrons or ions, and cosmic rays ionize the neutral atmosphere. Electron densities generated by current theoretical models are much larger than densities measured by instruments on board the Cassini orbiter. This model density overabundance must result either from overproduction or from insufficient loss of ions. This is the first of two papers that examines ion production rates in Titan's ionosphere, for the dayside and nightside ionosphere, respectively. The first (current) paper focuses on dayside ion production rates which are computed using solar ionization sources (photoionization and electron impact ionization by photoelectrons) between 1000 and 1400 km. In addition to theoretical ion production rates, empirical ion production rates are derived from CH4, CH3+, and CH4+ densities measured by the INMS (Ion Neutral Mass Spectrometer) for many Titan passes. The modeled and empirical production rate profiles from measured densities of N2+ and CH4+ are found to be in good agreement (to within 20%) for solar zenith angles between 15 and 90°. This suggests that the overabundance of electrons in theoretical models of Titan's dayside ionosphere is not due to overproduction but to insufficient ion losses

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup

Maturation of the functional mouse CRES amyloid from globular form

The epididymal lumen contains a complex cystatin-rich nonpathological amyloid matrix with putative roles in sperm maturation and sperm protection. Given our growing understanding for the biological function of this and other functional amyloids, the problem still remains: how functional amyloids assemble including their initial transition to early oligomeric forms. To examine this, we developed a protocol for the purification of nondenatured mouse CRES, a component of the epididymal amyloid matrix, allowing us to examine its assembly to amyloid under conditions that may mimic those in vivo. Herein we use X-ray crystallography, solution-state NMR, and solid-state NMR to follow at the atomic level the assembly of the CRES amyloidogenic precursor as it progressed from monomeric folded protein to an advanced amyloid. We show the CRES monomer has a typical cystatin fold that assembles into highly branched amyloid matrices, comparable to those in vivo, by forming β-sheet assemblies that our data suggest occur via two distinct mechanisms: a unique conformational switch of a highly flexible disulfide-anchored loop to a rigid β-strand and by traditional cystatin domain swapping. Our results provide key insight into our understanding of functional amyloid assembly by revealing the earliest structural transitions from monomer to oligomer and by showing that some functional amyloid structures may be built by multiple and distinctive assembly mechanisms

Adding 6 Months of Androgen Deprivation Therapy to Postoperative Radiotherapy for Prostate Cancer: A Comparison of Short-Course Versus No Androgen Deprivation Therapy in the Radicals-HD Randomised Controlled Trial

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476)

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10−9) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group

Genome modeling system: A knowledge management platform for genomics

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms

Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium

As genomic and exomic testing expands in both the research and clinical arenas, determining whether, how, and which incidental findings to return to the ordering clinician and patient becomes increasingly important. Although opinion is varied on what should be returned to consenting patients or research participants, most experts agree that return of medically actionable results should be considered. There is insufficient evidence to fully inform evidence-based clinical practice guidelines regarding return of results from genome-scale sequencing, and thus generation of such evidence is imperative, given the rapidity with which genome-scale diagnostic tests are being incorporated into clinical care. We present an overview of the approaches to incidental findings by members of the Clinical Sequencing Exploratory Research network, funded by the National Human Genome Research Institute, to generate discussion of these approaches by the clinical genomics community. We also report specific lists of “medically actionable” genes that have been generated by a subset of investigators in order to explore what types of findings have been included or excluded in various contexts. A discussion of the general principles regarding reporting of novel variants, challenging cases (genes for which consensus was difficult to achieve across Clinical Sequencing Exploratory Research network sites), solicitation of preferences from participants regarding return of incidental findings, and the timing and context of return of incidental findings are provided