Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies

Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents.

HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal. Here we report the comparative performance of lead bryologs, including their effects in reducing cell surface expression of HIV entry receptors, inducing proinflammatory cytokines, inhibiting short-term HIV replication, and synergizing with histone deacetylase inhibitors to reverse HIV latency. These data provide unique insights into structure-function relationships between A- and B-ring bryolog modifications and activities in primary cells, and suggest that bryologs represent promising leads for preclinical advancement

How significant to plant N nutrition is the direct consumption of soil microbes by roots?

The high degree to which plant roots compete with soil microbes for organic forms of nitrogen (N) is becoming increasingly apparent. This has culminated in the finding that plants may consume soil microbes as a source of N, but the functional significance of this process remains unknown. We used 15N- and 14C-labelled cultures of soil bacteria to measure rates of acquisition of microbes by sterile wheat roots and plants growing in soil. We compared these rates with acquisition of 15N delivered as nitrate, amino acid monomer (l-alanine) and short peptide (l-tetraalanine), and the rate of decomposition of [14C] microbes by indigenous soil microbiota. Acquisition of microbe 15N by both sterile roots and roots growing in soil was one to two orders of magnitude slower than acquisition of all other forms of 15N. Decomposition of microbes was fast enough to account for all 15N recovered, but approximately equal recovery of microbe 14C suggests that microbes entered roots intact. Uptake of soil microbes by wheat (Triticum aestivum) roots appears to take place in soil. If wheat is typical, the importance of this process to terrestrial N cycling is probably minor in comparison with fluxes of other forms of soil inorganic and organic N

Head-to-head trials of antibiotics for bronchiectasis

Background The diagnosis of bronchiectasis is defined by abnormal dilation of the airways related to a pathological mechanism of progressive airway destruction that is due to a 'vicious cycle' of recurrent bacterial infection, inflammatory mediator release, airway damage, and subsequent further infection. Antibiotics are the main treatment option for reducing bacterial burden in people with exacerbations of bronchiectasis and for longer‐term eradication, but their use is tempered against potential adverse effects and concerns regarding antibiotic resistance. The comparative effectiveness, cost‐effectiveness, and safety of different antibiotics have been highlighted as important issues, but currently little evidence is available to help resolve uncertainty on these questions. Objectives To evaluate the comparative effects of different antibiotics in the treatment of adults and children with bronchiectasis. Search methods We identified randomised controlled trials (RCTs) through searches of the Cochrane Airways Group Register of trials and online trials registries, run 30 April 2018. We augmented these with searches of the reference lists of published studies. Selection criteria We included RCTs reported as full‐text articles, those published as abstracts only, and unpublished data. We included adults and children (younger than 18 years) with a diagnosis of bronchiectasis by bronchography or high‐resolution computed tomography who reported daily signs and symptoms, such as cough, sputum production, or haemoptysis, and those with recurrent episodes of chest infection; we included studies that compared one antibiotic versus another when they were administered by the same delivery method. Data collection and analysis Two review authors independently assessed trial selection, data extraction, and risk of bias. We assessed overall quality of the evidence using GRADE criteria. We made efforts to collect missing data from trial authors. We have presented results with their 95% confidence intervals (CIs) as mean differences (MDs) or odds ratios (ORs). Main results Four randomised trials were eligible for inclusion in this systematic review ‐ two studies with 83 adults comparing fluoroquinolones with β‐lactams and two studies with 55 adults comparing aminoglycosides with polymyxins. None of the included studies reported information on exacerbations ‐ one of our primary outcomes. Included studies reported no serious adverse events ‐ another of our primary outcomes ‐ and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and β‐lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low‐quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low‐quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low‐quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV₁). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low‐quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low‐quality evidence). The evidence for changes in FEV₁ was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. Authors' conclusions Limited low‐quality evidence favours short‐term oral fluoroquinolones over beta‐lactam antibiotics for patients hospitalised with exacerbations. Very low‐quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head‐to‐head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short‐term or long‐term therapy. More research on this topic is needed

Objective cough frequency, airway inflammation, and disease control in asthma

Background Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. Methods Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). Results Eighty-nine subjects with asthma (mean ± SD age, 57 ± 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P < .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. Conclusions Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent independent dimensions of asthma control

A new fireworm (Amphinomidae) from the Cretaceous of Lebanon identified from three-dimensionally preserved myoanatomy

© 2015 Parry et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The attached file is the published version of the article

Spectral properties of anomalous X-ray pulsars

In this paper, the spectra of the persistent emission from anomalous X-ray pulsars (AXPs) and their variation with spin-down rate $\dot{\Omega}$ is considered. Firstly, based on an accretion-powered model, the influences of both magnetic field and mass accretion rate on the spectra properties of AXPs are addressed. Subsequently, the relation between the spectral property of AXPs and mass accretion rate $\dot{M}$ is investigated. The result shows that there exists a linear correlation between the photon index and mass accretion rate, and the spectral hardness increases with increasing $\dot{M}$. A possible emission mechanism for the explanation of spectral properties of AXPs is also discussed.Comment: 11pages, 3 figures, Chin. J. Astron. Astrophys. in pres

Standing up in Multiple Sclerosis (SUMS): Protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.

This study is funded by the NIHR Health Technology Assessment Programme (14/176/12), United Kingdom.Background:  Impaired mobility is a cardinal feature of multiple sclerosis (MS) and is rated by people with MS as their highest priority. By the secondary progressive phase, balance, mobility and physical activity levels are significantly compromised; an estimated 70% of people with secondary progressive MS fall regularly. Our ongoing research has systematically developed ‘Balance Right in MS’ (BRiMS), an innovative, manualised 13-week guided self-management programme tailored to the needs of people with MS, designed to improve safe mobility and minimise falls. Our eventual aim is to assess the clinical and cost effectiveness of BRiMS in people with secondary progressive MS by undertaking an appropriately statistically powered, multi-centre, assessor-blinded definitive, randomised controlled trial. This feasibility study will assess the acceptability of the intervention and test the achievability of running such a definitive trial. Methods/design:  This is a pragmatic multi-centre feasibility randomised controlled trial with blinded outcome assessment. Sixty ambulant people with secondary progressive MS who self-report two or more falls in the previous 6 months will be randomly allocated (1:1) to either the BRiMS programme plus usual care or to usual care alone. All participants will be assessed at baseline and followed up at 15 weeks and 27 weeks post-randomisation. The outcomes of this feasibility trial include: • Feasibility outcomes, including trial recruitment, retention and completion • Assessment of the proposed outcome measures for the anticipated definitive trial (including measures of walking, quality of life, falls, balance and activity level) • Measures of adherence to the BRiMS programme • Data to inform the economic evaluation in a future trial • Process evaluation (assessment of treatment fidelity and qualitative evaluation of participant and treating therapist experience) Discussion:  The BRiMS intervention aims to address a key concern for MS service users and providers. However, there are several uncertainties which need to be addressed prior to progressing to a full-scale trial, including acceptability of the BRiMS intervention and practicality of the trial procedures. This feasibility trial will provide important insights to resolve these uncertainties and will enable a protocol to be finalised for use in the definitive trial.Publisher PDFPeer reviewe