PDE4 Inhibitors: Profiling Hits through the Multitude of Structural Classes

Cyclic nucleotide phosphodiesterases 4 (PDE4) are a family of enzymes which specifically promote the hydrolysis and degradation of cAMP. The inhibition of PDE4 enzymes has been widely investigated as a possible alternative strategy for the treatment of a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma, as well as psoriasis and other autoimmune disorders. In this context, the identification of new molecules as PDE4 inhibitors continues to be an active field of investigation within drug discovery. This review summarizes the medicinal chemistry journey in the design and development of effective PDE4 inhibitors, analyzed through chemical classes and taking into consideration structural aspects and binding properties, as well as inhibitory efficacy, PDE4 selectivity and the potential as therapeutic agents

Grace DAKASEP alkaline battery separator

The Grace DAKASEP separator was originally developed as a wicking layer for nickel-zinc alkaline batteries. The DAKASEP is a filled non-woven separator which is flexible and heat sealable. Through modification of formulation and processing variables, products with a variety of properties can be produced. Variations of DAKASEP were tested in Ni-H2, Ni-Zn, Ni-Cd, and primary alkaline batteries with good results. The properties of DAKASEP which are optimized for Hg-Zn primary batteries are shown in tabular form. This separator has high tensile strength, 12 micron average pore size, relatively low porosity at 46-48 percent, and consequently moderately high resistivity. Versions were produced with greater than 70 percent porosity and resistivities in 33 wt percent KOH as low as 3 ohm cm. Performance data for Hg-Zn E-1 size cells containing DAKASEP with the properties shown in tabular form, are more reproducible than data obtained with a competitive polypropylene non-woven separator. In addition, utilization of active material is in general considerably improved

Different carboxyl-rich alicyclic molecules proxy compounds select distinct bacterioplankton for oxidation of dissolved organic matter in the mesopelagic Sargasso Sea

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Liu, S., Parsons, R., Opalk, K., Baetge, N., Giovannoni, S., Bolanos, L. M., Kujawinski, E. B., Longnecker, K., Lu, Y., Halewood, E., & Carlson, C. A. Different carboxyl-rich alicyclic molecules proxy compounds select distinct bacterioplankton for oxidation of dissolved organic matter in the mesopelagic Sargasso Sea. Limnology and Oceanography, (2020), doi:10.1002/lno.11405.Marine dissolved organic matter (DOM) varies in its recalcitrance to rapid microbial degradation. DOM of varying recalcitrance can be exported from the ocean surface to depth by subduction or convective mixing and oxidized over months to decades in deeper seawater. Carboxyl‐rich alicyclic molecules (CRAM) are characterized as a major component of recalcitrant DOM throughout the oceanic water column. The oxidation of CRAM‐like compounds may depend on specific bacterioplankton lineages with oxidative enzymes capable of catabolizing complex molecular structures like long‐chain aliphatics, cyclic alkanes, and carboxylic acids. To investigate the interaction between bacteria and CRAM‐like compounds, we conducted microbial remineralization experiments using several compounds rich in carboxyl groups and/or alicyclic rings, including deoxycholate, humic acid, lignin, and benzoic acid, as proxies for CRAM. Mesopelagic seawater (200 m) from the northwest Sargasso Sea was used as media and inoculum and incubated over 28 d. All amendments demonstrated significant DOC removal (2–11 μmol C L−1) compared to controls. Bacterioplankton abundance increased significantly in the deoxycholate and benzoic acid treatments relative to controls, with fast‐growing Spongiibacteracea, Euryarcheaota, and slow‐growing SAR11 enriched in the deoxycholate treatment and fast‐growing Alteromonas, Euryarcheaota, and Thaumarcheaota enriched in the benzoic acid treatment. In contrast, bacterioplankton grew slower in the lignin and humic acid treatments, with oligotrophic SAR202 becoming significantly enriched in the lignin treatment. Our results indicate that the character of the CRAM proxy compounds resulted in distinct bacterioplankton removal rates of DOM and affected specific lineages of bacterioplankton capable of responding.We thank Z. Landry for the inspiring idea of SAR202 catabolism of CRAM. We thank the University of California, Santa Barbara Marine Science Institute Analytical Laboratory for analyzing inorganic nutrient samples. We thank C. Johnson for her help in FISH sample processing and BATS group in supporting our project. We thank N. K. Rubin‐Saika and R. Padula for their help with amino acid sample preparation. We thank Z. Liu, J. Xue, K. Lu, and Y. Shen for their help with amino acid protocol development and validation. We thank B. Stephens for his help on microscopic image analysis. We thank M. Dasenko and the staff of the CGRB at Oregon State University for amplicon library preparation and DNA sequencing. We are grateful for the help provided by the officers and crews of the R/V Atlantic Explorer. Bermuda Institute of Ocean Sciences (BIOS) provides us tremendous support in terms of facilities and lab space. We thank Bermuda government for its allowance of our water sampling and sample export (export permit number SP160904, issued 07 October 2016 under the Fisheries Act, 1972). This project was supported by Simons Foundation International's BIOS‐SCOPE program

Glatiramer acetate as a clinically and cost-effective treatment of relapsing multiple sclerosis over 10 years of use within the National Health Service: Final results from the UK Risk Sharing Scheme.

Background: The UK Risk Sharing Scheme (RSS) provided information on the effect of first-line multiple sclerosis (MS) disease-modifying treatments on long-term disability. Objective: The aim is to provide results specific to glatiramer acetate (GA; Copaxone®) from the final 10-year analysis of the RSS. Methods: A Markov model was used to assess clinical effectiveness measured as Expanded Disability Status Scale (EDSS) progression and utility loss. Untreated patients from the British Columbia MS cohort (1980-1995) were used as a 'virtual comparator' group. A separate Markov model assessed cost-effectiveness, based on a 50-year time horizon (with a 50% treatment waning effect imposed at 10 years) and using NHS list price (£513.95 per 28 days). Results were expressed in quality-adjusted life years (QALYs). Results: In total, 755 patients with relapsing-remitting MS (RRMS) received GA, with a mean follow-up of 7.1 (standard deviation 1.3) years. EDSS progression was reduced by 23% (progression ratio 76.7, 95% confidence interval [CI] 69.0-84.3) and utility loss by 39% (progression ratio 61.0, 95% CI 52.7-69.3) compared with no treatment. There was no persistent waning in GA treatment effect over time (EDSS: p = 0.093; utilities: p = 0.119). The cost per QALY was £17,841. Conclusion: GA had a beneficial effect on long-term disability and was a cost-effective treatment for RRMS

Exploring Vitamin B1 Cycling and Its Connections to the Microbial Community in the North Atlantic Ocean

Vitamin B1 (thiamin) is an essential coenzyme for all cells. Recent findings from experimental cell biology and genome surveys have shown that thiamin cycling by plankton is far more complex than was previously understood. Many plankton cells cannot produce thiamin (are auxotrophic) and obligately require an exogenous source of thiamin or one or more of 5 different thiamin-related compounds (TRCs). Despite this emerging evidence for the evolution among plankton of complex interactions related to thiamin, the influence of TRCs on plankton community structure and productivity are not understood. We report measurements of three dissolved TRCs 4-amino-5-aminomethyl-2-methylpyrimidine (AmMP), 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole-2-carboxylic acid (cHET), and 4-methyl-5-thiazoleethanol (HET) that have never before been assayed in seawater. Here we characterize them alongside other TRCs that were measured previously [thiamin and 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP)], in depth profiles from a latitudinal transect in the north Atlantic in March 2018. TRC concentrations ranged from femptomolar to picomolar. Surface depletion relative to a maximum near the bottom of the euphotic zone and low concentrations at deeper depths were consistent features. Our observations suggest that when bacterial abundance and production are low, TRC concentrations approach a steady state where TRC production and consumption terms are balanced. Standing stocks of TRCs also appear to be positively correlated with bacterial production. However, near the period of peak biomass in the accumulation phase of a bloom we observed an inverse relationship between TRCs and bacterial production, coincident with an increased abundance of Flavobacteria that comparative genomics indicates could be vitamin B1 auxotrophs. While these observations suggest that the dissolved pool of TRCs is often at steady state, with TRC production and consumption balanced, our data suggests that bloom induced shifts in microbial community structure and activity may cause a decoupling between TRC production and consumption, leading to increased abundances of some populations of bacteria that are putatively vitamin B1 auxotrophs

DEVELOPMENT OF CLINICAL AND PATIENT-REPORTED QUALITY METRICS FOR MULTIPLE SCLEROSIS: A UK PILOT STUDY REPORT

BackgroundQuality standards (QS) for people with multiple sclerosis (PwMS) are suboptimal, ambiguous and restricted to certain patient subgroups and care pathways.AimDevelop and pilot MS metrics measuring service provision quality to identify areas for improvement.MethodsA multidisciplinary Working Group developed clinician and patient-reported metrics and standardised data collection forms through an iterative process.ResultsMetrics covered: referral; diagnosis; treatment; annual review; general management; education. Pilot (n=76) showed: 31% of PwMS were referred to MS specialist within 4 weeks of suspected/confirmed demyelination; 28% and 56% had uncomplicated MS confirmed and were offered specialist MS nurse appointment, respectively, within 4 weeks of specialist referral; 75% of eligible PwMS were offered disease-modifying therapy within 8 weeks of confirmed MS diagnosis; 85% had comprehensive multidisciplinary team (MDT) annual review; 90% had a defined point of contact within the MS service; 86% of unscheduled contacts by PwMS, MDT or general practitioners were responded to within 3 days; 53% of MS services maintained a single database of PwMS; and 76% of PwMS were offered ongoing education. Data collection continues and updated findings will be reported.DiscussionMS metrics/data forms are feasible for routine clinical settings, simple to interpret and provide a valuable benchmark for guiding MS service improvements

Factors associated with the decision to investigate child protective services referrals: a systematic review

Background: Limited resources for child protection create challenging decision situations for child protective services (CPS) workers at the point of intake. A body of research has examined the factors associated with worker decisions and processes using a variety of methodological approaches to gain knowledge on decision-making. However, few attempts have been made to systematically review this literature. Objective: As part of a larger project on decision-making at intake, this systematic review addressed the question of the factors associated with worker decisions to investigate alleged maltreatment referrals. Methods: Quantitative studies that examined factors associated with screening decisions in CPS practice settings were included in the review. Database and other search methods were used to identify research published in English over a 35-year period (1980-2015). Findings: Of 1,147 identified sources, 18 studies were selected for full data extraction. The studies were conducted in the U.S., Canada, and Sweden and varied in methodological quality. Most studies examined case factors with few studies examining other domains. Conclusions: To inform CPS policy and practice, additional research is needed to examine the relationships between decision-making factors and case outcomes. Greater attention needs to be given to the organizational and external factors that influence decision-making

Treating multiple sclerosis with generic cladribine

Meeting AbstractEuropean Comm Treatment & Res Multiple Sclerosi

Identification of candidate structured RNAs in the marine organism 'Candidatus Pelagibacter ubique'

<p>Abstract</p> <p>Background</p> <p>Metagenomic sequence data are proving to be a vast resource for the discovery of biological components. Yet analysis of this data to identify functional RNAs lags behind efforts to characterize protein diversity. The genome of '<it>Candidatus </it>Pelagibacter ubique' HTCC 1062 is the closest match for approximately 20% of marine metagenomic sequence reads. It is also small, contains little non-coding DNA, and has strikingly low GC content.</p> <p>Results</p> <p>To aid the discovery of RNA motifs within the marine metagenome we exploited the genomic properties of '<it>Cand</it>. P. ubique' by targeting our search to long intergenic regions (IGRs) with relatively high GC content. Analysis of known RNAs (rRNA, tRNA, riboswitches etc.) shows that structured RNAs are significantly enriched in such IGRs. To identify additional candidate structured RNAs, we examined other IGRs with similar characteristics from '<it>Cand</it>. P. ubique' using comparative genomics approaches in conjunction with marine metagenomic data. Employing this strategy, we discovered four candidate structured RNAs including a new riboswitch class as well as three additional likely <it>cis</it>-regulatory elements that precede genes encoding ribosomal proteins S2 and S12, and the cytoplasmic protein component of the signal recognition particle. We also describe four additional potential RNA motifs with few or no examples occurring outside the metagenomic data.</p> <p>Conclusion</p> <p>This work begins the process of identifying functional RNA motifs present in the metagenomic data and illustrates how existing completed genomes may be used to aid in this task.</p

Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies

PMCID: PMC3729414The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/11/171. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited