Bias-free photoelectrochemical water splitting with photosystem II on a dye-sensitized photoanode wired to hydrogenase

Natural photosynthesis stores sunlight in chemical energy carriers, but it has not evolved for the efficient synthesis of fuels, such as H2. Semi-artificial photosynthesis combines the strengths of natural photosynthesis with synthetic chemistry and materials science to develop model systems that overcome Nature’s limitations, such as low-yielding metabolic pathways and non-complementary light absorption by Photosystem (PS) I and II. Here, we report a bias-free semi-artificial tandem platform that wires PSII to hydrogenase for overall water splitting. This photoelectrochemical cell integrated the red and blue light-absorber PSII with a green light-absorbing diketopyrrolopyrrole dye-sensitised TiO2 photoanode enabling complementary panchromatic solar light absorption. Effective electronic communication at the enzyme-material interface was engineered using an Os complex-modified redox polymer on a hierarchically-structured TiO2. This system provides a design protocol for bias-free semi-artificial Z-schemes in vitro and provides an extended toolbox of biotic and abiotic components to re-engineer photosynthetic pathways.ERC Consolidator Grant, EPSRC (nanoDTC, DTA studentship), Christian Doppler Research Association, OMV Group, Royal Society Newton International Fellowship, Cluster of Excellence RESOLV (DFG) and European Unions' Horizon 202

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.ResultsTwo hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.ConclusionDespite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives

Improving medication adherence in diabetes type 2 patients through Real Time Medication Monitoring: a Randomised Controlled Trial to evaluate the effect of monitoring patients' medication use combined with short message service (SMS) reminders

Contains fulltext : 97026.pdf (publisher's version ) (Open Access)BACKGROUND: Innovative approaches are needed to support patients' adherence to drug therapy. The Real Time Medication Monitoring (RTMM) system offers real time monitoring of patients' medication use combined with short message service (SMS) reminders if patients forget to take their medication. This combination of monitoring and tailored reminders provides opportunities to improve adherence. This article describes the design of an intervention study aimed at evaluating the effect of RTMM on adherence to oral antidiabetics. METHODS/DESIGN: Randomised Controlled Trial (RCT) with two intervention arms and one control arm involving diabetes type 2 patients with suboptimal levels of adherence to oral antidiabetics (less than 80% based on pharmacy refill data). Patients in the first intervention arm use RTMM including SMS reminders and a personal webpage where they can monitor their medication use. Patients in the second intervention arm use RTMM without SMS reminders or webpage access. Patients in the control arm are not exposed to any intervention. Patients are randomly assigned to one of the three arms. The intervention lasts for six months. Pharmacy refill data of all patients are available from 11 months before, until 11 months after the start of the intervention. Primary outcome measure is adherence to oral antidiabetics calculated from: 1) data collected with RTMM, as a percentage of medication taken as prescribed, and as percentage of medication taken within the correct time interval, 2) refill data, taking the number of days for which oral antidiabetics are dispensed during the study period divided by the total number of days of the study period. Differences in adherence between the intervention groups and control group are studied using refill data. Differences in adherence between the two intervention groups are studied using RTMM data. DISCUSSION: The intervention described in this article consists of providing RTMM to patients with suboptimal adherence levels. This system combines real time monitoring of medication use with SMS reminders if medication is forgotten. If RTMM proves to be effective, it can be considered for use in various patient populations to support patients with their medication use and improve their adherence. TRIAL REGISTRATION: Netherlands Trial Register NTR1882

A Helminth Immunomodulator Exploits Host Signaling Events to Regulate Cytokine Production in Macrophages

Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38-phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells

Utilisation of Mucin Glycans by the Human Gut Symbiont Ruminococcus gnavus Is Strain-Dependent

Commensal bacteria often have an especially rich source of glycan-degrading enzymes which allow them to utilize undigested carbohydrates from the food or the host. The species Ruminococcus gnavus is present in the digestive tract of ≥90% of humans and has been implicated in gut-related diseases such as inflammatory bowel diseases (IBD). Here we analysed the ability of two R. gnavus human strains, E1 and ATCC 29149, to utilize host glycans. We showed that although both strains could assimilate mucin monosaccharides, only R. gnavus ATCC 29149 was able to grow on mucin as a sole carbon source. Comparative genomic analysis of the two R. gnavus strains highlighted potential clusters and glycoside hydrolases (GHs) responsible for the breakdown and utilization of mucin-derived glycans. Transcriptomic and functional activity assays confirmed the importance of specific GH33 sialidase, and GH29 and GH95 fucosidases in the mucin utilisation pathway. Notably, we uncovered a novel pathway by which R. gnavus ATCC 29149 utilises sialic acid from sialylated substrates. Our results also demonstrated the ability of R. gnavus ATCC 29149 to produce propanol and propionate as the end products of metabolism when grown on mucin and fucosylated glycans. These new findings provide molecular insights into the strain-specificity of R. gnavus adaptation to the gut environment advancing our understanding of the role of gut commensals in health and disease

Targeting medication non-adherence behavior in selected autoimmune diseases: a systematic approach to digital health program development

Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns

Carbon Dioxide Utilisation -The Formate Route

UIDB/50006/2020 CEEC-Individual 2017 Program Contract.The relentless rise of atmospheric CO2 is causing large and unpredictable impacts on the Earth climate, due to the CO2 significant greenhouse effect, besides being responsible for the ocean acidification, with consequent huge impacts in our daily lives and in all forms of life. To stop spiral of destruction, we must actively reduce the CO2 emissions and develop new and more efficient “CO2 sinks”. We should be focused on the opportunities provided by exploiting this novel and huge carbon feedstock to produce de novo fuels and added-value compounds. The conversion of CO2 into formate offers key advantages for carbon recycling, and formate dehydrogenase (FDH) enzymes are at the centre of intense research, due to the “green” advantages the bioconversion can offer, namely substrate and product selectivity and specificity, in reactions run at ambient temperature and pressure and neutral pH. In this chapter, we describe the remarkable recent progress towards efficient and selective FDH-catalysed CO2 reduction to formate. We focus on the enzymes, discussing their structure and mechanism of action. Selected promising studies and successful proof of concepts of FDH-dependent CO2 reduction to formate and beyond are discussed, to highlight the power of FDHs and the challenges this CO2 bioconversion still faces.publishersversionpublishe

Conceptual design of a hybrid neutron-gamma detector for study of beta-delayed neutrons at the RIB facility of RIKEN

The conceptual design of the BRIKEN neutron detector at the radioactive ion beam factory (RIBF) of the RIKEN Nishina Center is reported. The BRIKEN setup is a complex system aimed at detecting heavy-ion implants, β particles, γ rays and β-delayed neutrons. The whole setup includes the Advanced Implantation Detection Array (AIDA), two HPGe Clover detectors and up to 166 3He-filled counters embedded in a high-density polyethylene moderator. The design is quite complex due to the large number and different types of 3He-tubes involved and the additional constraints introduced by the ancillary detectors for charged particles and γ rays. This article reports on a novel methodology developed for the conceptual design and optimisation of the 3He-counter array, aiming for the best possible performance in terms of neutron detection. The algorithm is based on a geometric representation of two selected detector parameters of merit, namely, the average neutron detection efficiency and the efficiency flatness as a function of a reduced number of geometric variables. The response of the neutron detector is obtained from a systematic Monte Carlo simulation implemented in Geant4. The robustness of the algorithm allowed us to design a versatile detection system, which operated in hybrid mode includes the full neutron counter and two clover detectors for high-precision gamma spectroscopy. In addition, the system can be reconfigured into a compact mode by removing the clover detectors and re-arranging the 3He tubes in order to maximize the neutron detection performance. Both operation modes shows a rather flat and high average efficiency. In summary, we have designed a system which shows an average efficiency for hybrid mode (3He tubes + clovers) of 68.6% and 64% for neutron energies up to 1 and 5 MeV, respectively. For compact mode (only 3He tubes), the average efficiency is 75.7% and 71% for neutron energies up to 1 and 5 MeV, respectively. The performance of the BRIKEN detection system has been also quantified by means of Monte Carlo simulations with different neutron energy distributions