513 research outputs found
Global search algorithm for optimal control
Random-search algorithm employs local and global properties to solve two-point boundary value problem in Pontryagin maximum principle for either fixed or variable end-time problems. Mixed boundary value problem is transformed to an initial value problem. Mapping between initial and terminal values utilizes hybrid computer
Shuttle-launch triangular space station
A triangular space station deployable in orbit is described. The framework is comprized of three trusses, formed of a pair of generally planar faces consistine of foldable struts. The struts expand and lock into rigid structural engagement forming a repetition of equilater triangles and nonfolding diagonal struts interconnecting the two faces. The struts are joined together by node fittings. The framework can be packaged into a size and configuration transportable by a space shuttle. When deployed, the framework provides a large work/construction area and ample planar surface area for solar panels and thermal radiators. A plurity of modules are secured to the framework and then joined by tunnels to make an interconnected modular display. Thruster units for the space station orientation and altitude maintenance are provided
Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters.
Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in Drosophila Males
Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-FruM neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway
Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in \u3ci\u3eDrosophila\u3c/i\u3e Males
Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-FruM neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway
Achieving minimal disease activity in psoriatic arthritis predicts meaningful improvements in patientsâ health-related quality of life and productivity
Background
Although psoriatic arthritis is complex and involves multiple domains, recent advances in treatments have made remission or near-remission of most symptoms a potentially achievable goal for many patients. We sought to evaluate whether achieving minimal disease activity (MDA) criteria represented meaningful improvement from the patient perspective.
Methods
Data were combined from two randomized, multinational, 24 week clinical studies of ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, in biological drug-naĂŻve or experienced adults. MDA required 5 of 7 of: tender joint count â€1; swollen joint count â€1; Psoriasis Area and Severity Index total scoreââ€â1 or body surface areaââ€â3%; patientâs assessment of pain visual analogue scale (VAS) â€15; patientâs global assessment of disease activity VAS â€20; Health Assessment Questionnaire Disability Index â€0.5; and tender entheseal pointsââ€â1. MDA responders and non-responders were compared for mean change from baseline on the 36-Item Short Form Health Survey (SF-36), European Quality of Life 5 Dimension 5 Level Health Questionnaire (EQ-5D-5 L); EQ-5D-5 L VAS; and Work Productivity and Activity ImpairmentâSpecific Health Problem (WPAI-SHP) questionnaire.
Results
MDA responders had significantly greater improvements versus non-responders in each SF-36 domain and in the SF-36 physical summary score; improvements were also greater in the EQ-5D-5 L and EQ-5D-5 L VAS, and in 3 of the 4 WPAI-SHP domains. MDA responders were more likely to achieve minimal clinically important differences than non-responders.
Conclusion
These findings support MDA response as being strongly associated with achieving improved disease status based on measures of patient reported health-related quality of life and productivity.
Trial registration
SPIRIT-P1, NCT01695239, First Posted: September 27, 2012; and SPIRIT-P2, NCT02349295, First Posted: January 28, 2015
Pharmacology and Surface Electrostatics of the K Channel Outer Pore Vestibule
In spite of a generally well-conserved outer vestibule and pore structure, there is considerable diversity in the pharmacology of K channels. We have investigated the role of specific outer vestibule charged residues in the pharmacology of K channels using tetraethylammonium (TEA) and a trivalent TEA analog, gallamine. Similar to Shaker K channels, gallamine block of Kv3.1 channels was more sensitive to solution ionic strength than was TEA block, a result consistent with a contribution from an electrostatic potential near the blocking site. In contrast, TEA block of another type of K channel (Kv2.1) was insensitive to solution ionic strength and these channels were resistant to block by gallamine. Neutralizing either of two lysine residues in the outer vestibule of these Kv2.1 channels conferred ionic strength sensitivity to TEA block. Kv2.1 channels with both lysines neutralized were sensitive to block by gallamine, and the ionic strength dependence of this block was greater than that for TEA. These results demonstrate that Kv3.1 (like Shaker) channels contain negatively charged residues in the outer vestibule of the pore that influence quaternary ammonium pharmacology. The presence of specific lysine residues in wild-type Kv2.1 channels produces an outer vestibule with little or no net charge, with important consequences for quaternary ammonium block. Neutralizing these key lysines results in a negatively charged vestibule with pharmacological properties approaching those of other types of K channels
Impaired Competence for Pretense in Children with Autism: Exploring Potential Cognitive Predictors.
Lack of pretense in children with autism has been explained by a number of theoretical explanations, including impaired mentalising, impaired response inhibition, and weak central coherence. This study aimed to empirically test each of these theories. Children with autism (n=60) were significantly impaired relative to controls (n=65) when interpreting pretense, thereby supporting a competence deficit hypothesis. They also showed impaired mentalising and response inhibition, but superior local processing indicating weak central coherence. Regression analyses revealed that mentalising significantly and independently predicted pretense. The results are interpreted as supporting the impaired mentalising theory and evidence against competing theories invoking impaired response inhibition or a local processing bias. The results of this study have important implications for treatment and intervention
Barriers and facilitators to implementing a patient-centered model of contraceptive provision in community health centers
Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial
Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents.
Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100â
kg/>100â
kg), methotrexate use) to ustekinumab 45â
mg or 90â
mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45â
mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placeboâ45â
mg, 45â
mgâ90â
mg, 90â
mgâ90â
mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naĂŻve (n=132) patients and anti-TNF-experienced (n=180) patients.
Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change â0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change â0.13). No unexpected adverse events were observed through week 60.
Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90â
mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients
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