Profiling of Glycan Receptors for Minute Virus of Mice in Permissive Cell Lines Towards Understanding the Mechanism of Cell Recognition

The recognition of sialic acids by two strains of minute virus of mice (MVM), MVMp (prototype) and MVMi (immunosuppressive), is an essential requirement for successful infection. To understand the potential for recognition of different modifications of sialic acid by MVM, three types of capsids, virus-like particles, wild type empty (no DNA) capsids, and DNA packaged virions, were screened on a sialylated glycan microarray (SGM). Both viruses demonstrated a preference for binding to 9-O-methylated sialic acid derivatives, while MVMp showed additional binding to 9-O-acetylated and 9-O-lactoylated sialic acid derivatives, indicating recognition differences. The glycans recognized contained a type-2 Galβ1-4GlcNAc motif (Neu5Acα2-3Galβ1-4GlcNAc or 3′SIA-LN) and were biantennary complex-type N-glycans with the exception of one. To correlate the recognition of the 3′SIA-LN glycan motif as well as the biantennary structures to their natural expression in cell lines permissive for MVMp, MVMi, or both strains, the N- and O-glycans, and polar glycolipids present in three cell lines used for in vitro studies, A9 fibroblasts, EL4 T lymphocytes, and the SV40 transformed NB324K cells, were analyzed by MALDI-TOF/TOF mass spectrometry. The cells showed an abundance of the sialylated glycan motifs recognized by the viruses in the SGM and previous glycan microarrays supporting their role in cellular recognition by MVM. Significantly, the NB324K showed fucosylation at the non-reducing end of their biantennary glycans, suggesting that recognition of these cells is possibly mediated by the Lewis X motif as in 3′SIA-LeX identified in a previous glycan microarray screen

Scaling up malaria elimination management and leadership: a pilot in three provinces in Zimbabwe, 2016-2018

BACKGROUND: Focus for improved malaria programme performance is often placed on the technical challenges, while operational issues are neglected. Many of the operational challenges that inhibit malaria programme effectiveness can be addressed by improving communication and coordination, increasing accountability, maintaining motivation, providing adequate training and supervision, and removing bureaucratic silos. METHODS: A programme of work was piloted in Zimbabwe with one malaria eliminating province, Matabeleland South in 2016-2017, and scaled up to include two other provinces, Matabeleland North and Midlands, in 2017-2018. The intervention included participatory, organization development and quality improvement methods. RESULTS: Workshop participants in Matabeleland South reported an improvement in data management. In Matabeleland North, motivation among nurses improved as they gained confidence in case management from training, and overall staff morale improved. There was also an improvement in data quality and data sharing. In Midlands, the poorly performing district was motivated to improve, and both participating districts became more goal-oriented. They also became more focused on monitoring their data regularly. Participants from all provinces reported having gained skills in listening, communicating, facilitating discussions, and making presentations. Participation in the intervention changed the mindset of malaria programme staff, increasing ownership and accountability, and empowering them to identify and solve problems, make decisions, and act within their sphere of influence, elevating challenges when appropriate. CONCLUSIONS: This pilot demonstrates that a participatory, organization development and quality improvement approach has broad ranging effects, including improving local delivery of interventions, tailoring strategies to target specific populations, finding efficiencies in the system that could not be found using the traditional top-down approach, and improving motivation and communication between different cadres of health workers. Scale-up of this simple model can be achieved and benefits sustained over time if the process is imbedded into the programme with the training of health staff who can serve as management improvement coaches. Methods to improve operational performance that are scalable at the district level are urgently needed: this approach is a possible tactic that can significantly contribute to the achievement of global malaria eradication goals

Interventions aimed at improving the nursing work environment: a systematic review

<p>Abstract</p> <p>Background</p> <p>Nursing work environments (NWEs) in Canada and other Western countries have increasingly received attention following years of restructuring and reported high workloads, high absenteeism, and shortages of nursing staff. Despite numerous efforts to improve NWEs, little is known about the effectiveness of interventions to improve NWEs. The aim of this study was to review systematically the scientific literature on implemented interventions aimed at improving the NWE and their effectiveness.</p> <p>Methods</p> <p>An online search of the databases CINAHL, Medline, Scopus, ABI, Academic Search Complete, HEALTHstar, ERIC, Psychinfo, and Embase, and a manual search of Emerald and Longwoods was conducted. (Quasi-) experimental studies with pre/post measures of interventions aimed at improving the NWE, study populations of nurses, and quantitative outcome measures of the nursing work environment were required for inclusion. Each study was assessed for methodological strength using a quality assessment and validity tool for intervention studies. A taxonomy of NWE characteristics was developed that would allow us to identify on which part of the NWE an intervention targeted for improvement, after which the effects of the interventions were examined.</p> <p>Results</p> <p>Over 9,000 titles and abstracts were screened. Eleven controlled intervention studies met the inclusion criteria, of which eight used a quasi-experimental design and three an experimental design. In total, nine different interventions were reported in the included studies. The most effective interventions at improving the NWE were: primary nursing (two studies), the educational toolbox (one study), the individualized care and clinical supervision (one study), and the violence prevention intervention (one study).</p> <p>Conclusions</p> <p>Little is known about the effectiveness of interventions aimed at improving the NWE, and published studies on this topic show weaknesses in their design. To advance the field, we recommend that investigators use controlled studies with pre/post measures to evaluate interventions that are aimed at improving the NWE. Thereby, more evidence-based knowledge about the implementation of interventions will become available for healthcare leaders to use in rebuilding nursing work environments.</p

Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box

A tumour biomarker is a characteristic that is objectively measured and evaluated in tumour samples as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The development of a biomarker contemplates distinct phases, including discovery by hypothesis-generating preclinical or exploratory studies, development and qualification of the assay for the identification of the biomarker in clinical samples, and validation of its clinical significance. Although guidelines for the development and validation of biomarkers are available, their implementation is challenging, owing to the diversity of biomarkers being developed. The term 'validation' undoubtedly has several meanings; however, in the context of biomarker research, a test may be considered valid if it is 'fit for purpose'. In the process of validation of a biomarker assay, a key point is the validation of the methodology. Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges

Hindered rolling and friction anisotropy in supported carbon nanotubes

Carbon nanotubes (CNTs) are well known for their exceptional thermal, mechanical and electrical properties. For many CNT applications it is of the foremost importance to know their frictional properties. However, very little is known about the frictional forces between an individual nanotube and a substrate or tip. Here, we present a combined theoretical and experimental study of the frictional forces encountered by a nanosize tip sliding on top of a supported multiwall CNT along a direction parallel or transverse to the CNT axis. Surprisingly, we find a higher friction coefficient in the transverse direction compared with the parallel direction. This behaviour is explained by a simulation showing that transverse friction elicits a soft 'hindered rolling' of the tube and a frictional dissipation that is absent, or partially absent for chiral CNTs, when the tip slides parallel to the CNT axis. Our findings can help in developing better strategies for large-scale CNT assembling and sorting on a surface.Comment: 8 pages, 5 figure

Variable responses of human microbiomes to dietary supplementation with resistant starch

Abstract Background The fermentation of dietary fiber to various organic acids is a beneficial function provided by the microbiota in the human large intestine. In particular, butyric acid contributes to host health by facilitating maintenance of epithelial integrity, regulating inflammation, and influencing gene expression in colonocytes. We sought to increase the concentration of butyrate in 20 healthy young adults through dietary supplementation with resistant starch (unmodified potato starch—resistant starch (RS) type 2). Methods Fecal samples were collected from individuals to characterize butyrate concentration via liquid chromatography and composition of the microbiota via surveys of 16S rRNA-encoding gene sequences from the Illumina MiSeq platform. Random Forest and LEfSe analyses were used to associate responses in butyrate production to features of the microbiota. Results RS supplementation increased fecal butyrate concentrations in this cohort from 8 to 12 mmol/kg wet feces, but responses varied widely between individuals. Individuals could be categorized into three groups based upon butyrate concentrations before and during RS: enhanced, high, and low (n = 11, 3, and 6, respectively). Fecal butyrate increased by 67 % in the enhanced group (from 9 to 15 mmol/kg), while it remained ≥11 mmol/kg in the high group and ≤8 mmol/kg in the low group. Microbiota analyses revealed that the relative abundance of RS-degrading organisms—Bifidobacterium adolescentis or Ruminococcus bromii—increased from ~2 to 9 % in the enhanced and high groups, but remained at ~1.5 % in the low group. The lack of increase in RS-degrading bacteria in the low group may explain why there was no increase in fecal butyrate in response to RS. The microbiota of individuals in the high group were characterized by an elevated abundance of the butyrogenic microbe Eubacterium rectale (~6 % in high vs. 3 % in enhanced and low groups) throughout the study. Conclusions We document the heterogeneous responses in butyrate concentrations upon RS supplementation and identify characteristic of the microbiota that appear to underlie this variation. This study complements and extends other studies that call for personalized approaches to manage beneficial functions provided by gut microbiomes.http://deepblue.lib.umich.edu/bitstream/2027.42/134598/1/40168_2016_Article_178.pd

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis

Background. We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods. Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Results. Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. Conclusion. Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. © 2010 Christiansen et al; licensee BioMed Central Ltd.link_to_subscribed_fulltex

"A convenient truth": air travel passengers' willingness to pay to offset their CO2 emissions

Several economic reviews demonstrate the substantial costs related to climate change and consequently call for early action. These reviews, however, have been limited to measuring ‘objective’ risks and expected material damage related to climate change. The ‘subjective’ perceived risk of climate change and society’s willingness to pay (WTP) to avoid these risks are expected to provide an important additional motivation for direct action. We investigate whether and why air travel passengers—an increasingly important source of greenhouse gas emissions—are supportive of measures that increase the cost of their travel based on the polluter pays principle and compensate the damage caused by their flight. Compared to the results of the few previous studies that have elicited WTP estimates for climate policy more generally, our results appear to be at the lower end of the scale, while a comparison to estimates of the social cost of carbon shows that the average WTP estimate in this study is close to the estimated marginal damage cost. Although significant differences are found between travellers from Europe, North America, Asia and the rest of the world, we show that there exists a substantial demand for climate change mitigation action. The positive risk premium over and above the expected property damage cost assessments should be accounted for more explicitly in economic reviews as it will add to the burden of proof of direct action. Measurements of passenger WTP will help policy makers to design effective financial instruments aimed at discouraging climate-unfriendly travel activities as well as to generate funds for the measures directed at climate change mitigation and adaptation. Based on stated WTP by travellers to offset their greenhouse gas emissions, funds in the order of magnitude of €23 billion could be generated annually to finance climate change mitigation activities

Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate

Background/Objectives: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible. Subjects/Methods:C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated. Results:In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity. Conclusions:This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including ‘browning’ and enhancement of hepatic mitochondrial function

Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

Data are presented on pharmacodynamic (PD) method validation and preliminary clinical qualification of three PD biomarker assays. M65 Elisa, which quantitates different forms of circulating cytokeratin 18 (CK18) as putative surrogate markers of both apoptotic and nonapoptotic tumour cell death, was shown to be highly reproducible: calibration curve linearity r2=0.996, mean accuracy >91% and mean precision <3%, n=27. Employing recombinant (r) CK18 and caspase cleaved CK18 (CK18 Asp396 neo-epitope) as external standards, kit to kit reproducibly was <6% (n=19). rCK18 was stable in plasma for 4 months at −20°C and −80°C, for 4 weeks at 4°C and had a half-life of 2.3 days at 37°C. Cytokeratin 18 Asp396 NE, the M30 Apoptosense Elisa assay antigen, was stable in plasma for 6 months at −20°C and −80°C, for 3 months at 4°C, while its half-life at 37°C was 3.8 days. Within-day variations in endogenous plasma concentrations of the M30 and M65 antigens were assessed in two predose blood samples collected from a cohort of 15 ovarian cancer patients receiving carboplatin chemotherapy and were shown to be no greater than the variability associated with methods themselves. Between-day fluctuations in circulating levels of the M30 and M65 antigens and in XIAP mRNA levels measured in peripheral blood mononuclear cells by quantitative (q) RT–PCR were evaluated in two predose blood samples collected with a 5- to 7-day gap from 23 patients with advanced cancer enrolled in a phase I trial. The mean variation between the two pretreatment values ranged from 13 to 14 to 25%, respectively, for M65, M30 and qRT–PCR. These data suggest that the M30 and M65 Elisa's and qRT–PCR as PD biomarker assays have favourable performance characteristics for further investigation in clinical trials of anticancer agents which induce tumour apoptosis/necrosis or knockdown of the anti-apoptotic protein XIAP