64 research outputs found
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Interfamilial relationships in order Fabales: new insights from the nuclear regions sqd1 and 26S rDNA
Leguminosae, Polygalaceae, Quillajaceae and Surianaceae together comprise the order Fabales. Phylogenetic relationships within Fabales remain an unsolved problem even though interfamilial relationships have been examined in a number of studies using different sampling approaches and both molecular and morphological data. In this study, we gather information from the nuclear 26S rDNA region as well as previously published data from the sqd1,matK and rbcL regions. Phylogenetic analyses were performed by maximum parsimony, maximum likelihood and Bayesian inference. Overall, the best-supported topology for the relationships among families within the order places the pair of Leguminosae and Polygalaceae as sister to the pair of Quillajaceae and Surianaceae. However, our approximately unbiased (AU) test of the combined data results has shown that none of the seven different topologies rejected. Furthermore, three topologies were not significantly different from each other. Therefore, similar to the previous studies, this study did not find well-supported dichotomous relationships among the four Fabales families. The Fabales topology was very sensitive to both data choice and the phylogenetic methods used, which may indicate a rapid-near-simultaneous evolution of the four Fabales families. Our results also show that while nuclear sqd1 can be helpful as a complementary region, both the nuclear sqd1 and rDNA 26S regions could be problematic when analyzed individually
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Reconstructing an historical pollination syndrome: keel flowers
Background: Keel flowers are bilaterally symmetrical, pentamerous flowers with three different petal types and reproductive organs enclosed by keel petals; generally there is also connation of floral parts such as stamens and keel petals. In this study, the evolution of keel flowers within the order Fabales is explored to investigate whether the establishment of this flower type within one of the species-rich families, the Fabaceae (Leguminosae), preceded and could have influenced the evolution of keel flowers in the Polygalaceae. We conducted molecular dating, and ancestral area and ancestral state analyses for a phylogeny constructed for 678 taxa using published matK, rbcL and trnL plastid gene regions.
Results: We reveal the temporal and spatial origins of keel flowers and traits associated with pollinators, specifically floral symmetry, the presence or absence of a pentamerous corolla and three distinct petal types, the presence or absence of enclosed reproductive organs, androecium types, inflorescence types, inflorescence size, flower size, plant height and habit. Ancestral area reconstructions show that at the time keel flowers appeared in the Polygaleae, subfamily Papilionoideae of the Fabaceae was already distributed almost globally; at least eight clades of the Papilionoideae had keel flowers with a functional morphology broadly similar to the morphology of the first evolving Polygaleae flowers.
Conclusions: The multiple origins of keel flowers within angiosperms likely represent convergence due to bee specialization, and therefore pollinator pressure. In the case of the Fabales, the first evolving keel flowers of Polygaleae have a functional morphology that corresponds with keel flowers of species of the Papilionoideae already present in the environment. These findings are consistent with the keel-flowered Polygaleae exploiting pollinators of keel-flowered Papilionoideae. The current study is the first to use ancestral reconstructions of traits associated with pollination to demonstrate that the multiple evolutionary origins of the keel flower pollinator syndrome in Fabales are consistent with, though do not prove, mimicry
Integration of mental health screening and treatment into cystic fibrosis clinics: Evaluation of initial implementation in 84 programs across the United States
Background: A largeâscale epidemiological study of 6088 individuals with cystic fibrosis (CF) and 4102 caregivers in nine countries documented elevated symptoms of depression and anxiety, leading to international guidelines for annual screening and followâup. To facilitate national implementation, 84 CF programs funded a mental health coordinators (MHC). Implementation was evaluated after 1 year using the consolidated framework for implementation research (CFIR) to identify facilitators and barriers.
Methods: A 45âitem internet survey was developed to assess relevant CFIR implementation steps. Surveys were completed in 2016. It assessed five domains tailored to study aims: (a) Intervention characteristics, (b) outer setting, (c) inner setting, (d) characteristics of individuals, and (e) process of implementation.
Results: Response rate was 88%, with pediatric and adult programs equally represented. A majority of MHCs were social workers (54.1%) and psychologists (41.9%); 41% had joined the team in the past year. Facilitators across the five domains included universal uptake of screening tools, greater awareness and detection of psychological symptoms, reduced stigma, and positive feedback from patients and families. Barriers included limited staff time, space, and logistics.
Discussion: This is the largest systematic effort to integrate mental health screening and treatment into the care of individuals with a serious, chronic illness and their caregivers. MHCs implementing screening, interpretation and followâup reported
positive results, and significant barriers. This national implementation effort demonstrated that depression and anxiety can be efficiently evaluated and treated in a complex, chronic disease. Future efforts include recommending the addition of screening scores to national CF Registries and examining their effects on health outcomes
Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors
The authors examined the affinities of 36 typical and atypical antipsychotic agents for the cloned rat 5-hydroxytryptamine-6 (5-HT6) and rat 5-hydroxytryptamine-7 (5-HT7) receptors in transiently expressed COS-7 cells (5-HT7) or stably transfected HEK-293 cells (5-HT6 receptors). Clozapine and several related atypical antipsychotic agents (rilapine, olanzepine, tiospirone, fluperlapine, clorotepine and zotepine) had high affinities for the newly discovered 5-HT6 receptor (Kis less than 20 nM). The 5-HT7 receptor bound clozapine, rilapine, fluperlapine, clorotepine, zotepine and risperidone but not tiospirone and olanzepine, with affinities less than 15 nM. In addition, several typical antipsychotic agents (chloroprothixene, chlorpromazine, clothiapine and fluphenazine) had high affinities for both the 5-HT6 and 5-HT7 receptors. Pimozide, a diphenylbutylpiperidine, had the highest affinity of all the typical antipsychotic agents tested for the 5-HT7 receptor (Ki = 0.5 nM). Three putative atypical antipsychotic agents melperone, amperozide and MDL 100907 did not bind with high affinities to either the 5-HT6 or 5-HT7 receptors (Kis > 50 nM). Several dopamine-selective antipsychotic agents (raclopride, rimcazole and penfluridol) had essentially no affinity for either the 5-HT6 or 5-HT7 receptors (Ki values > 5000 nM)
An automated integrated platform for rapid and sensitive multiplexed protein profiling using human saliva samples
During the last decade, saliva has emerged as a potentially ideal diagnostic biofluid for noninvasive testing. In this paper, we present an automated, integrated platform useable by minimally trained personnel in the field for the diagnosis of respiratory diseases using human saliva as a sample specimen. In this platform, a saliva sample is loaded onto a disposable microfluidic chip containing all the necessary reagents and components required for saliva analysis. The chip is then inserted into the automated analyzer, the SDReader, where multiple potential protein biomarkers for respiratory diseases are measured simultaneously using a microsphere-based array via fluorescence sandwich immunoassays. The results are read optically, and the images are analyzed by a custom-designed algorithm. The fully automated assay requires as little as 10 ÎŒL of saliva sample, and the results are reported in 70 min. The performance of the platform was characterized by testing protein standard solutions, and the results were comparable to those from the 3.5-h lab bench assay that we have previously reported. The device was also deployed in two clinical environments where 273 human saliva samples collected from different subjects were successfully tested, demonstrating the deviceâs potential to assist clinicians with the diagnosis of respiratory diseases by providing timely protein biomarker profiling information. This platform, which combines non-invasive sample collection and fully automated analysis, can also be utilized in point-of-care diagnostics
VX-659-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles
Background The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659âtezacaftorâivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. Methods We evaluated the effects of VX-659âtezacaftorâivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659âtezacaftorâivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508delâMF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508delâPhe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). Results VX-659âtezacaftorâivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659âtezacaftorâivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659âtezacaftorâivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508delâMF genotypes; in patients with the Phe508delâPhe508del genotype already receiving tezacaftorâivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis QuestionnaireâRevised improved in both patient populations. Conclusions Robust in vitro activity of VX-659âtezacaftorâivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508delâMF or Phe508delâPhe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455.
VX-659âTezacaftorâIvacaftor in patients with cystic fibrosis and one or two Phe508del alleles
BACKGROUND: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659âtezacaftorâivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. METHODS: We evaluated the effects of VX-659âtezacaftorâivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659âtezacaftorâivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508delâMF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508delâPhe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). RESULTS: VX-659âtezacaftorâivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659âtezacaftorâivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659âtezacaftorâivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508delâMF genotypes; in patients with the Phe508delâPhe508del genotype already receiving tezacaftorâivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis QuestionnaireâRevised improved in both patient populations. CONCLUSIONS: Robust in vitro activity of VX-659âtezacaftorâivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508delâMF or Phe508delâPhe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351. opens in new tab and NCT03029455. opens in new tab.
Effect of VX-770 in Persons with Cystic Fibrosis and the G551D- CFTR Mutation
A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro
Safety and efficacy of vanzacaftorâtezacaftorâdeutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials
Background
Elexacaftorâtezacaftorâivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing.
Methods
We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftorâtezacaftorâdeutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftorâtezacaftorâdeutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftorâdeutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)âtezacaftorâdeutivacaftor or tezacaftorâivacaftor active control for 4 weeks, following a 4-week tezacaftorâivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete.
Findings
In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI â0·8 to 7·0) and 2·7 percentage points (â1·0 to 6·5) from baseline at week 12, respectively, versus â0·8 percentage points (â6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)âtezacaftorâdeutivacaftor (n=9), vanzacaftor (10 mg)âtezacaftorâdeutivacaftor (n=19), vanzacaftor (20 mg)âtezacaftorâdeutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (â1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (â4·1 to 8·0), respectively, in sweat chloride concentration of â42·8 mmol/L (â51·7 to â34·0), â45·8 mmol/L (95% CI â51·9 to â39·7), â49·5 mmol/L (â55·9 to â43·1), and 2·3 mmol/L (â7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (â10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)âtezacaftorâdeutivacaftor (n=18) and tezacaftorâivacaftor (n=10) had mean changes relative to baseline (taking tezacaftorâivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and â0·1 percentage points (â6·4 to 6·1), respectively, in sweat chloride concentration of â45·5 mmol/L (â49·7 to â41·3) and â2·6 mmol/L (â8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and â5·0 points (â16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftorâtezacaftorâdeutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity.
Interpretation
Once-daily dosing with vanzacaftorâtezacaftorâdeutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftorâtezacaftorâdeutivacaftor in phase 3 clinical trials compared with elexacaftorâtezacaftorâivacaftor.
Funding
Vertex Pharmaceuticals
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