Cyanobacteria net community production in the Baltic Sea as inferred from profiling pCO(2) measurements

Organic matter production by cyanobacteria blooms is a major environmental concern for the Baltic Sea, as it promotes the spread of anoxic zones. Partial pressure of carbon dioxide (pCO(2)) measurements carried out on Ships of Opportunity (SOOP) since 2003 have proven to be a powerful tool to resolve the carbon dynamics of the blooms in space and time. However, SOOP measurements lack the possibility to directly constrain depth-integrated net community production (NCP) in moles of carbon per surface area due to their restriction to the sea surface. This study tackles the knowledge gap through (1) providing an NCP best guess for an individual cyanobacteria bloom based on repeated profiling measurements of pCO(2) and (2) establishing an algorithm to accurately reconstruct depth-integrated NCP from surface pCO(2) observations in combination with modelled temperature profiles.Goal (1) was achieved by deploying state-of-the-art sensor technology from a small-scale sailing vessel. The low-cost and flexible platform enabled observations covering an entire bloom event that occurred in July-August 2018 in the Eastern Gotland Sea. For the biogeochemical interpretation, recorded pCO(2) profiles were converted to C-T*, which is the dissolved inorganic carbon concentration normalised to alkalinity. We found that the investigated bloom event was dominated by Nodularia and had many biogeochemical characteristics in common with blooms in previous years. In particular, it lasted for about 3 weeks, caused a C-T* drawdown of 90 mu mol kg(-1), and was accompanied by a sea surface temperature increase of 10 degrees C. The novel finding of this study is the vertical extension of the C-T* drawdown up to the compensation depth located at around 12 m. Integration of the C-T* drawdown across this depth and correction for vertical fluxes leads to an NCP best guess of similar to 1:2 mol m(-2) over the productive period.Addressing goal (2), we combined modelled hydrographical profiles with surface pCO(2) observations recorded by SOOP Finnmaid within the study area. Introducing the temperature penetration depth (TPD) as a new parameter to integrate SOOP observations across depth, we achieve an NCP reconstruction that agrees to the best guess within 10 %, which is considerably better than the reconstruction based on a classical mixed-layer depth constraint.Applying the TPD approach to almost 2 decades of surface pCO(2) observations available for the Baltic Sea bears the potential to provide new insights into the control and long-term trends of cyanobacteria NCP. This understanding is key for an effective design and monitoring of conservation measures aiming at a Good Environmental Status of the Baltic Sea

mir-181A/B-1 controls thymic selection of treg cells and tunes their suppressive capacity

The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1–deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte–associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function

Position statement : topical calcineurin inhibitors in atopic dermatitis

Background Atopic dermatitis (AD) is a common inflammatory skin disease in both adults and children. Whilst topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, have proven efficacy for the treatment of AD, it is important to involve experts to obtain their opinion on its optimal treatment. Objective Methods Using a modified Delphi approach, this project aimed to generate consensus amongst experts on the use of TCIs in the treatment of AD, with a focus on the differentiation between tacrolimus and pimecrolimus. Six expert dermatologists from different European countries participated in this project based on their experience with AD and its treatment, which was evaluated by literature analysis and expert opinion. Consensus amongst the experts was generated using a modified Delphi approach, consisting of three distinct phases, during which a web meeting (June 2017), two online rounds of blinded Delphi voting (July-September 2017) and a face-to-face meeting (November 2017) were conducted. The consensus statements concerned two main topics: (i) Background of AD; and (ii) TCIs in AD. Hot topics in the treatment of AD not supported by meta-analysis, clinical trials or large observational studies were also discussed based on clinical experience. Results Conclusion In total, 25 consensus statements were defined and validated: eight statements on the general background of AD and 17 statements on the use of TCIs in AD, including their mechanism of action and therapeutic indications in AD, efficacy in adult and paediatric AD patients, pharmacokinetics, incidence of adverse events and safety concerns. Hot topics on the use of TCIs for the treatment of AD included cream vs. ointment, dosages, TCIs contact allergy, burning sensation management, superinfection and vaccination concerns. Topical calcineurin inhibitors are a suitable therapy for AD, and selection of the specific TCI should be based on factors which differentiate tacrolimus from pimecrolimus.Peer reviewe

Sensitization of the histamine H1 receptor by increased ligand affinity.

Histamine regulates a variety of physiological processes including inflammation, gastric acid secretion, and neurotransmission. The cellular response to histamine is subject to dynamic control, and exaggerated histamine reactivity in response to cysteinyl leukotrienes and other stimuli is important in a variety of different pathological conditions. The molecular mechanisms controlling histamine responsiveness are still unresolved. In investigating histamine responses in embryonic stem (ES5) and F9 embryonic carcinoma cells, we encountered a novel mechanism controlling the cellular reaction to histamine. Unstimulated cells displayed neither

Methylated Nucleobases: Synthesis and Evaluation for Base Pairing In Vitro and In Vivo

The synthesis, base pairing properties and in vitro (polymerase) and in vivo (E. coli) recognition of 2′‐deoxynucleotides with a 2‐amino‐6‐methyl‐8‐oxo‐7,8‐dihydro‐purine (X), a 2‐methyl‐6‐thiopurine (Y) and a 6‐methyl‐4‐pyrimidone (Z) base moiety are described. As demonstrated by Tm measurements, the X and Y bases fail to form a self‐complementary base pair. Despite this failure, enzymatic incorporation experiments show that selected DNA polymerases recognize the X nucleotide and incorporate this modified nucleotide versus X in the template. In vivo, X is mainly recognized as a A/G or C base; Y is recognized as a G or C base and Z is mostly recognized as T or C. Replacing functional groups in nucleobases normally involved in W−C recognition (6‐carbonyl and 2‐amino group of purine; 6‐carbonyl of pyrimidine) readily leads to orthogonality (absence of base pairing with natural bases)

Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation

Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme