Objective To evaluate the effectiveness of a structured group education programme on biomedical, psychosocial, and lifestyle measures in people with newly diagnosed type 2 diabetes.Design Multicentre ...cluster randomised controlled trial in primary care with randomisation at practice level.Setting 207 general practices in 13 primary care sites in the United Kingdom.Participants 824 adults (55% men, mean age 59.5 years).Intervention A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care.Main outcome measures Haemoglobin A1c levels, blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, and emotional impact of diabetes at baseline and up to 12 months.Main results Haemoglobin A1c levels at 12 months had decreased by 1.49% in the intervention group compared with 1.21% in the control group. After adjusting for baseline and cluster, the difference was not significant: 0.05% (95% confidence interval −0.10% to 0.20%). The intervention group showed a greater weight loss: −2.98 kg (95% confidence interval −3.54 to −2.41) compared with 1.86 kg (−2.44 to −1.28), P=0.027 at 12 months. The odds of not smoking were 3.56 (95% confidence interval 1.11 to 11.45), P=0.033 higher in the intervention group at 12 months. The intervention group showed significantly greater changes in illness belief scores (P=0.001); directions of change were positive indicating greater understanding of diabetes. The intervention group had a lower depression score at 12 months: mean difference was −0.50 (95% confidence interval −0.96 to −0.04); P=0.032. A positive association was found between change in perceived personal responsibility and weight loss at 12 months (β=0.12; P=0.008).Conclusion A structured group education programme for patients with newly diagnosed type 2 diabetes resulted in greater improvements in weight loss and smoking cessation and positive improvements in beliefs about illness but no difference in haemoglobin A1c levels up to 12 months after diagnosis.Trial registration Current Controlled Trials ISRCTN17844016.
The link between cancer and aberrant glycosylation has recently become evident. Glycans and their altered forms, known as tumour-associated carbohydrate antigens (TACAs), are diverse, complex and ...difficult to target therapeutically. Lectins are naturally occurring glycan-binding proteins that offer a unique opportunity to recognise TACAs. T cells expressing chimeric antigen receptors (CARs) have proven to be a successful immunotherapy against leukaemias, but so far have shown limited success in solid tumours. We developed a panel of lectin-CARs that recognise the glycosphingolipid globotriaosylceramide (Gb3), which is overexpressed in various cancers, such as Burkitt's lymphoma, colorectal, breast and pancreatic. We have selected the following lectins: Shiga toxin's B-subunit from
Shigella dysenteriae
, LecA from
Pseudomonas aeruginosa
, and the engineered lectin Mitsuba from
Mytilus galloprovincialis
as antigen-binding domains and fused them to a well-known second-generation CAR. The Gb3-binding lectin-CARs have demonstrated target-specific cytotoxicity against Burkitt's lymphoma-derived cell lines as well as solid tumour cells from colorectal and triple-negative breast cancer. Our findings reveal the big potential of lectin-based CARs as therapeutical applications to target Gb3 and other TACAs expressed in haematological malignancies and solid tumours.
subsp.
Pcc (formerly
subsp.
) PC1 causes soft-rot disease in a wide variety of plant species by secreting multiple pathogenicity-related traits. In this study, regulatory mechanism of
ir-
iquid (AL) ...biofilm formation was studied using a
homolog gene deletion mutant (Δ
) of Pcc PC1. Compared to the wild type (Pcc PC1), the Δ
mutant produced fragile and significantly (
< 0.001) lower amounts of AL biofilm on
alt-
ptimized
roth plus 2%
lycerol (SOBG), yeast peptone dextrose adenine, and also on King's B at 27°C after 72 h incubation in static condition. The wild type also produced significantly higher quantities of AL biofilm on SOBGMg
(magnesium deprived) containing Cupper (Cu
), Zinc (Zn
), Manganese (Mn
), Magnesium (Mg
), and Calcium (Ca
) compared to the Δ
mutant. Moreover, the wild type was produced higher amounts of biofilms compared to the mutant while responding to pH and osmotic stresses. The Δ
(encoding flagellin),
::Tn5 (encoding a master regulator) and Δ
(a membrane protein essential for flagellar rotation) mutants produced a lighter and more fragile AL biofilm on SOBG compared to their wild counterpart. All these mutants resulted in having weak bonds with the cellulose specific dye (Calcofluor) producing lower quantities of cellulose compared to the wild type. Gene expression analysis using mRNA collected from the AL biofilms showed that Δ
mutant significantly (
< 0.001) reduced the expressions of multiple genes responsible for cellulose production (
, and
), motility (
, and
) and type III secretion system (
, and
) compared to the wild type. The CytR homolog was therefore, argued to be able to regulate the AL biofilm formation by controlling cellulose production, motility and T3SS in Pcc PC1. In addition, all the mutants exhibited poorer attachment to radish sprouts and AL biofilm cells of the wild type was resistant than stationary-phase and planktonic cells to acidity and oxidative stress compared to the same cells of the Δ
mutant. The results of this study therefore suggest that CytR homolog is a major determinant of Pcc PC1's virulence, attachment and its survival mechanism.
New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, ...this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.
Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.
Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.
In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.
Homogeneous transition‐metal catalysis is a crucial technology for the sustainable preparation of valuable chemicals. The catalyst concentration is usually kept as low as possible, typically at mM or ...μM levels, and the effect of high catalyst concentration is hardly exploited because of solubility issues and the inherent unfavorable catalyst/substrate ratio. Herein, a self‐assembly strategy is reported which leads to local catalyst concentrations ranging from 0.05 M to 1.1 M, inside well‐defined nanospheres, whilst the overall catalyst concentration in solution remains at the conventional mM levels. We disclose that only at this high concentration, the gold(I) chloride is reactive and shows high selectivity in intramolecular CO and CC bond‐forming cyclization reactions.
A(u)ll in!! A self‐assembly strategy which allows catalysis at extremely high local catalyst concentration inside a well‐defined nanosphere is reported. The resulting intrinsically inactive gold(I) chloride complexes become catalytically active with high selectivities.
A comparison of genotyping arrays Verlouw, Joost A M; Clemens, Eva; de Vries, Jard H ...
European journal of human genetics : EJHG,
11/2021, Letnik:
29, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Array technology to genotype single-nucleotide variants (SNVs) is widely used in genome-wide association studies (GWAS), clinical diagnostics, and linkage studies. Arrays have undergone a tremendous ...growth in both number and content over recent years making a comprehensive comparison all the more important. We have compared 28 genotyping arrays on their overall content, genome-wide coverage, imputation quality, presence of known GWAS loci, mtDNA variants and clinically relevant genes (i.e., American College of Medical Genetics (ACMG) actionable genes, pharmacogenetic genes, human leukocyte antigen (HLA) genes and SNV density). Our comparison shows that genome-wide coverage is highly correlated with the number of SNVs on the array but does not correlate with imputation quality, which is the main determinant of GWAS usability. Average imputation quality for all tested arrays was similar for European and African populations, indicating that this is not a good criterion for choosing a genotyping array. Rather, the additional content on the array, such as pharmacogenetics or HLA variants, should be the deciding factor. As the research question of a study will in large part determine which class of genes are of interest, there is not just one perfect array for all different research questions. This study can thus help as a guideline to determine which array best suits a study's requirements.
Abstract
Observational evidence is presented for transfer of energy from the internal tide to near-inertial motions near 29°N in the Pacific Ocean. The transfer is accomplished via parametric ...subharmonic instability (PSI), which involves interaction between a primary wave (the internal tide in this case) and two smaller-scale waves of nearly half the frequency. The internal tide at this location is a complex superposition of a low-mode waves propagating north from Hawaii and higher-mode waves generated at local seamounts, making application of PSI theory challenging. Nevertheless, a statistically significant phase locking is documented between the internal tide and upward- and downward-propagating near-inertial waves. The phase between those three waves is consistent with that expected from PSI theory. Calculated energy transfer rates from the tide to near-inertial motions are modest, consistent with local dissipation rate estimates. The conclusion is that while PSI does befall the tide near a critical latitude of 29°N, it does not do so catastrophically.
Accurate protein inference in the presence of shared peptides is still one of the key problems in bottom-up proteomics. Most protein inference tools employing simple heuristic inference strategies ...are efficient but exhibit reduced accuracy. More advanced probabilistic methods often exhibit better inference quality but tend to be too slow for large data sets. Here, we present a novel protein inference method, EPIFANY, combining a loopy belief propagation algorithm with convolution trees for efficient processing of Bayesian networks. We demonstrate that EPIFANY combines the reliable protein inference of Bayesian methods with significantly shorter runtimes. On the 2016 iPRG protein inference benchmark data, EPIFANY is the only tested method that finds all true-positive proteins at a 5% protein false discovery rate (FDR) without strict prefiltering on the peptide-spectrum match (PSM) level, yielding an increase in identification performance (+10% in the number of true positives and +14% in partial AUC) compared to previous approaches. Even very large data sets with hundreds of thousands of spectra (which are intractable with other Bayesian and some non-Bayesian tools) can be processed with EPIFANY within minutes. The increased inference quality including shared peptides results in better protein inference results and thus increased robustness of the biological hypotheses generated. EPIFANY is available as open-source software for all major platforms at https://OpenMS.de/epifany.
The TRAPPIST-1 system is unique in that it has a chain of seven terrestrial Earth-like planets located close to or in its habitable zone. In this paper, we study the effect of potential cometary ...impacts on the TRAPPIST-1 planets and how they would affect the primordial atmospheres of these planets. We consider both atmospheric mass loss and volatile delivery with a view to assessing whether any sort of life has a chance to develop. We ran N-body simulations to investigate the orbital evolution of potential impacting comets, to determine which planets are more likely to be impacted and the distributions of impact velocities. We consider three scenarios that could potentially throw comets into the inner region (i.e. within 0.1 au where the seven planets are located) from an (as yet undetected) outer belt similar to the Kuiper belt or an Oort cloud: planet scattering, the Kozai–Lidov mechanism, and Galactic tides. For the different scenarios, we quantify, for each planet, how much atmospheric mass is lost and what mass of volatiles can be delivered over the age of the system depending on the mass scattered out of the outer belt. We find that the resulting high-velocity impacts can easily destroy the primordial atmospheres of all seven planets, even if the mass scattered from the outer belt is as low as that of the Kuiper belt. However, we find that the atmospheres of the outermost planets f, g, and h can also easily be replenished with cometary volatiles (e.g. ∼ an Earth ocean mass of water could be delivered). These scenarios would thus imply that the atmospheres of these outermost planets could be more massive than those of the innermost planets, and have volatiles-enriched composition.
One-third of the world population is infected with Mycobacterium tuberculosis and multi-drug resistant strains are rapidly evolving. The noticeable absence of a whole organism high-throughput ...screening system for studying the progression of tuberculosis is fast becoming the bottleneck in tuberculosis research. We successfully developed such a system using the zebrafish Mycobacterium marinum infection model, which is a well-characterized model for tuberculosis progression with biomedical significance, mimicking hallmarks of human tuberculosis pathology. Importantly, we demonstrate the suitability of our system to directly study M. tuberculosis, showing for the first time that the human pathogen can propagate in this vertebrate model, resulting in similar early disease symptoms to those observed upon M. marinum infection. Our system is capable of screening for disease progression via robotic yolk injection of early embryos and visual flow screening of late-stage larvae. We also show that this system can reliably recapitulate the standard caudal vein injection method with a throughput level of 2,000 embryos per hour. We additionally demonstrate the possibility of studying signal transduction leading to disease progression using reverse genetics at high-throughput levels. Importantly, we use reference compounds to validate our system in the testing of molecules that prevent tuberculosis progression, making it highly suited for investigating novel anti-tuberculosis compounds in vivo.
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