77 research outputs found
Performance and long-term stability of the barley hordothionin gene in multiple transgenic apple lines
Introduction of sustainable scab resistance in elite apple cultivars is of high importance for apple cultivation when aiming at reducing the use of chemical crop protectants. Genetic modification (GM) allows the rapid introduction of resistance genes directly into high quality apple cultivars. Resistance genes can be derived from apple itself but genetic modification also opens up the possibility to use other, non-host resistance genes. A prerequisite for application is the long-term performance and stability of the gene annex trait in the field. For this study, we produced and selected a series of transgenic apple lines of two cultivars, i.e. âElstarâ and âGalaâ in which the barley hordothionin gene (hth) was introduced. After multiplication, the GM hth-lines, non-GM susceptible and resistant controls and GM non-hth controls were planted in a random block design in a field trial in 40 replicates. Scab resistance was monitored after artificial inoculation (first year) and after natural infection (subsequent years). After the trial period, the level of expression of the hth gene was checked by quantitative RT-PCR. Four of the six GM hth apple lines proved to be significantly less susceptible to apple scab and this trait was found to be stable for the entire 4-year period. Hth expression at the mRNA level was also stable
Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue
Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway
Identification and development of a functional marker from 6-SFT-A2 associated with grain weight in wheat
Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study
This is the final version. Available from Elsevier via the DOI in this record.âŻBackground We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment
and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of
response.
Methods Personalised Anti-TNF therapy in Crohnâs disease (PANTS) is a UK-wide, multicentre, prospective
observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients
with active luminal Crohnâs disease aged 6 years and older. At the end of the first year, sites were invited to enrol
participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across
the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation
testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response
in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined
in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed
symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional
surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449,
and is now complete.
Findings Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and
209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age
32·5 years [IQR 22·1â46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of
patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7â43·7),
34·4% (29·9â39·0), and 34·7% (29·8â39·5), and for adalimumab 35·9% (95% CI 31·2â40·5), 32·9% (26·8â39·2),
and 28·9% (21·9â36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later
timepoints were 6·1â10·0 mg/L for infliximab and 10·1â12·0 mg/L for adalimumab. After excluding patients who
had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3
were, for infliximab 34·4% (95% CI 30·4â38·2), 54·5% (49·4â59·0), and 60·0% (54·1â65·2), and for adalimumab
32·1% (26·7â37·1), 47·2% (40·2â53·4), and 68·4% (50·9â79·7), respectively. In multivariable analysis, loss of
response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug
concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45
[95% CI 0·30â0·67], adalimumab: 0·39 [0·22â0·70]). For patients treated with infliximab, loss of response was
also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11â1·95]), obesity (vs not obese 1·62 [1·08â2·42]),
baseline white cell count (1·06 [1·02â1·11) per 1 Ă 10âč increase in cells per L), and thiopurine dose quartile. Among
patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response
(HR 1·95 [95% CI 1·17â3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug
antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1â49·4) among patients
treated with infliximab and 20·3% (13·8â26·2) among those treated with adalimumab. The development of antidrug antibodies associated with undetectable drug concentrations was significantly associated with treatment
without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40
[95% CI 0·31â0·52], adalimumab 0·42 [95% CI 0·24â0·75]), and with carriage of HLA-DQA1*05 risk variant for
infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13â1·88]) but not for adalimumab (HR 1·60
[0·92â2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated
with increased time without the development of anti-drug antibodies associated with undetectable drug
concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20â3·74]) or introduction of an
immunomodulator after anti-TNF initiation (1·70 [1·11â2·59]). In years 2 and 3, 16 (4%) of 389 patients treated
with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal.
Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections
in years 2 and 3.
Interpretation Only around a third of patients with active luminal Crohnâs disease treated with an anti-TNF drug were
in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict
loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment,
particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with
undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05
and mitigated by concomitant immunomodulator use for both drugs.Guts UKCrohnâs and Colitis UKCure Crohnâs ColitisAbbVieMerck Sharp and DohmeNapp PharmaceuticalsPfizerCelltrion Healthcar
International Consensus Statement on Rhinology and Allergy: Rhinosinusitis
Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICARâRS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICARâRSâ2021 as well as updates to the original 140 topics. This executive summary consolidates the evidenceâbased findings of the document. Methods: ICARâRS presents over 180 topics in the forms of evidenceâbased reviews with recommendations (EBRRs), evidenceâbased reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICARâRSâ2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidenceâbased management algorithm is provided. Conclusion: This ICARâRSâ2021 executive summary provides a compilation of the evidenceâbased recommendations for medical and surgical treatment of the most common forms of RS
Designing wearable technologies for users with disabilities: Accessibility, usability, and connectivity factors
Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval.
Over the past 20 years, the management of gastrointestinal stromal tumors has acted as an important model in the advancement of molecularly targeted therapies for solid tumors. The success of imatinib has established it as a lasting therapy in the management of early-stage and advanced disease in the first-line setting. Imatinib resistance inevitably develops, resulting in the need for further lines of therapy. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor, specifically developed to target both primary and secondary KIT and PDGFRα resistance mutations. Herein, the authors discuss the molecular rationale, the preclinical evidence and the clinical use of ripretinib in the treatment of gastrointestinal stromal tumors in the advanced stages of disease
Studying implementation beyond deficit analysis: The top-down view reconsidered
__Abstract__
Contemporary researchers of policy implementation make a plea for explaining variation in policy outputs. At the same time still much implementation research, dispersed across the social sciences, entails studies of single cases in which a perceived gap between the intentions and the results of a public policy is analyzed. In this article a case is made for the lasting relevance of studying single policy processes, seen âfrom the topâ, provided that the multi-dimensional character of these processes is taken into account. Empirical material from a study of educational inclusion policy in the United Kingdom shows how public policies may refer to different values (normative dimension), imply ongoing policy formation between a variety of actors, each with particular stakes (political dimension), while policy goals seldom speak for themselves (practical dimension). By consequence, in implementation research the issues of, respectively, what needs explanation (the explanandum), locus specification, and the appropriate unit of observation and analysis need attention
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