Organ function depends on tissues adopting the correct architecture. However, insights into organ architecture are currently hampered by an absence of standardized quantitative 3D analysis. We aimed ...to develop a robust technology to visualize, digitalize, and segment the architecture of two tubular systems in 3D:
o
ble resin
asting micro computed
omography (DUCT). As proof of principle, we applied DUCT to a mouse model for Alagille syndrome (
mice), characterized by intrahepatic bile duct paucity, that can spontaneously generate a biliary system in adulthood. DUCT identified increased central biliary branching and peripheral bile duct tortuosity as two compensatory processes occurring in distinct regions of
liver, leading to full reconstitution of wild-type biliary volume and phenotypic recovery. DUCT is thus a powerful new technology for 3D analysis, which can reveal novel phenotypes and provide a standardized method of defining liver architecture in mouse models.
This paper introduces a novel implementation of the genetic algorithm exploiting a multi-GPU cluster. The proposed implementation employs an island-based genetic algorithm where every GPU evolves a ...single island. The individuals are processed by CUDA warps, which enables the solution of large knapsack instances and eliminates undesirable thread divergence. The MPI interface is used to exchange genetic material among isolated islands and collect statistical data. The characteristics of the proposed GAs are investigated on a two-node cluster composed of 14 Fermi GPUs and 4 six-core Intel Xeon processors. The overall GPU performance of the proposed GA reaches 5.67 TFLOPS.
The practice in Leninist political systems of assigning local leaders concurrent seats on higher-level leadership bodies presents a puzzle. In China, for example, a subset of provincial leaders hold ...seats in the central Politburo, while some city-level leaders hold seats in provincial party standing committees (PPSCs). While some scholars view these concurrent appointments as a form of top-down control or co-optation, others see these arrangements as a reflection of local power and a channel for the assertion of local interests. In this paper, we attempt to adjudicate between these different views empirically by analyzing the patterns and consequences of concurrent appointments of city leaders to China’s PPSCs. We introduce a new typology that distinguishes between the political and economic functions of concurrent appointments to differentiate four possible intergovernmental dynamics of control, co-optation, compromise, and concession. Through analysis of an original dataset on PPSC appointments and case studies of three Chinese cities, we show that concurrent appointments in China’s provinces can function as a means of concession, compromise, or co-optation, but we find little evidence that concurrent appointments allow higher-level authorities to firmly control or economically exploit localities.
Propositions about the relationship between Meyer and Allen's (1991) model of organizational commitment and turnover intentions were tested via field research. Specifically, we assessed concurrent ...and longitudinal effects of affective, continuance, and normative commitment on turnover intentions. We tested main and interaction effects and also assessed the effects of two continuance commitment sub-dimensions—CC-hisac and CC-loalt—on turnover intentions. Two studies were conducted to test these relationships. Data were collected from a sample of engineering personnel working at an aerospace firm, and from university students employed full time in a variety of organizations. The results revealed that, (1) contrary to expectations, the three components of commitment differed in the significance of their effects on turnover intentions, and (2) the CC subdimensions differed in their effects on turnover intentions. The discussion of these results focuses on their implications for theoretical and practical issues in commitment research.
Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.
We conducted a ...randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index on staining for the Ki-67 antigen of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel known in the United States as Depot, Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.
Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval CI, 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).
Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).
New Ag(I) coordination polymers, formulated as Ag(µ-PTAH)(NO3)2n (1) and Ag(µ-PTA)(NO2)n (2), were self-assembled as light- and air-stable microcrystalline solids and fully characterized by NMR and ...IR spectroscopy, electrospray ionization mass spectrometry (ESI-MS(±), elemental analysis, powder (PXRD) and single-crystal X-ray diffraction. Their crystal structures reveal resembling 1D metal-ligand chains that are driven by the 1,3,5-triaza-7-phospaadamantane (PTA) linkers and supported by terminal nitrate or nitrite ligands; these chains were classified within a 2C1 topological type. Additionally, the structure of 1 features a 1D→2D network extension through intermolecular hydrogen bonds, forming a two-dimensional hydrogen-bonded network with fes topology. Furthermore, both products 1 and 2 exhibit remarkable antimicrobial activity against different human pathogen bacteria (S. aureus, E. coli, and P. aeruginosa) and yeast (C. albicans), which is significantly superior to the activity of silver(I) nitrate as a reference topical antimicrobial.
An oxymetazoline 0.1% ophthalmic solution was recently approved for treatment of acquired blepharoptosis in adults. This study's objective was to evaluate the safety profile of oxymetazoline 0.1% ...when administered once daily for 14-84 days.
Pooled analysis examined safety outcomes from four randomized, double-masked, placebo-controlled clinical trials conducted at 6, 16, 27, and 35 sites, respectively, in the United States. In total, 568 participants with acquired blepharoptosis were evaluated. Median age was 66 years and 74.8% of participants were female. Overall, 375 participants self-administered oxymetazoline 0.1% to both eyes once/day and 193 self-administered placebo (vehicle) daily. Treatment-emergent adverse event (TEAE) rates, severity, and causality were evaluated in the overall population and within participant subgroups defined based on age, race, and ethnicity. Vital signs and ophthalmic findings were evaluated at predefined study visits. Patient-reported treatment tolerability was recorded at study end.
TEAE incidence was similar among participants using oxymetazoline 0.1% (31.2%) or vehicle (30.6%). Nearly all TEAEs were mild-to-moderate, and most were not suspected of being treatment related. Serious TEAEs occurred in four participants receiving oxymetazoline 0.1% and one participant receiving vehicle. Nine and two participants in the oxymetazoline 0.1% and vehicle groups, respectively, discontinued due to a TEAE. Ocular TEAEs occurring in ≥2% of participants receiving oxymetazoline 0.1% were punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, instillation site pain, and corneal vital dye staining, with none occurring in >3.5% of participants. TEAE rates were similar across subgroups based on age, race, and ethnicity. No clinically significant mean changes in vital signs or ophthalmologic findings occurred, and >98% of participants rated oxymetazoline 0.1% as causing no/mild discomfort.
Once-daily oxymetazoline 0.1% was safe and well tolerated in participants with acquired blepharoptosis when used for 14-84 days. Safety did not appear to differ based on age, race, or ethnicity.
Abstract Purpose Few studies have investigated restless legs syndrome (RLS) treatment effects on individual International RLS Study Group Rating Scale (IRLS) items. We assessed the effects of ...gabapentin enacarbil (GEn) on individual IRLS items and their correlation with sleep disturbances in adults with moderate-to-severe primary RLS. Methods Data were pooled from the randomized, double-blind, placebo-controlled, 12-week studies of XP052, XP053, and XP081 for adults who received GEn (600 or 1200 mg) or placebo once daily. Adults had primary RLS, IRLS total score ≥15, and RLS symptoms >15 days during the month before screening and for ≥4 of the 7 consecutive evenings at baseline. End points included mean change from baseline to week 12 in individual IRLS and post-sleep questionnaire (PSQ) items. For IRLS items, least squares mean treatment differences were calculated from a mixed model for repeated measures. For PSQ items, Cochran–Mantel–Haenszel row mean scores tests with integer scoring were used. Correlations between IRLS and PSQ items were assessed by Spearman’s rank coefficients. Safety profile outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. Findings The modified intent-to-treat population included 671 patients (GEn 600 mg = 161; GEn 1200 mg = 266; placebo = 244). GEn significantly improved mean SE differences versus placebo for all IRLS items at week 12, including severity of sleep disturbance (GEn 600 mg, −0.4 0.10; GEn 1200 mg, −0.4 0.09), daytime tiredness (−0.4 0.09; −0.4 0.08), RLS severity (−0.4 0.10; −0.3 0.08), impact on daily affairs (−0.3 0.07; −0.3 0.07), and mood disturbance (−0.2 0.07; −0.3 0.06); all P <0.001). For PSQ items, significant ( P <0.01) improvements occurred with both GEn doses versus placebo at week 12. The correlations between IRLS and PSQ items for change from baseline to week 12 were moderate to strong, and all correlations were significant ( P <0.001). The most frequent TEAEs were somnolence (GEn 600 mg, 20%; GEn 1200 mg, 23%; placebo, 5%) and dizziness (GEn 600 mg, 14%; GEn 1200 mg, 22%; placebo, 5%). Implications GEn significantly improved individual IRLS items and sleep disturbance versus placebo. Correlations between IRLS and PSQ items were moderate to strong. This was not a formal meta-analysis and was not powered to compare the GEn doses. Nevertheless, our study finds that the benefits of GEn extend to individual IRLS items and supports the importance of sleep quality in RLS treatment. ClinicalTrials.gov identifiers: NCT00298623, NCT00365352, and NCT01332305.
The molecular architecture of-and biochemical processes within-cell membranes play important roles in all living organisms, with many drugs and infectious disease agents targeting membranes. ...Experimental studies of biochemical reactions on membrane surfaces are challenging, as they require a membrane environment that is fluid (like cell membranes) but nevertheless allows for the efficient detection and characterization of molecular interactions. One approach uses lipid membranes supported on solid substrates such as silica or polymers: although the membrane is trapped near the solid interface, it retains natural fluidity and biological functionality and can be implanted with membrane proteins for functional studies. But the detection of molecular interactions involving membrane-bound species generally requires elaborate techniques, such as surface plasmon resonance or total internal reflection fluorescence microscopy. Here we demonstrate that colloidal phase transitions of membrane-coated silica beads provide a simple and label-free method for monitoring molecular interactions on lipid membrane surfaces. By adjusting the lipid membrane composition and hence the pair interaction potential between the membrane-supporting silica beads, we poise our system near a phase transition so that small perturbations on the membrane surface induce dramatic changes in the macroscopic organization of the colloid. We expect that this approach, used here to probe with high sensitivity protein binding events at membrane surfaces, can be applied to study a broad range of cell membrane processes.
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