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81.
Mark R. Herbert Dana L. Siegel Lena Staszewski Charmagne Cayanan Urmi Banerjee Sangeeta Dhamija Jennifer Anderson Amy Fan Li Wang Peter Rix Andrew K. Shiau Tadimeti S. Rao Stewart A. Noble Richard A. Heyman Eric Bischoff Mausumee Guha Ayman Kabakibi Anthony B. Pinkerton 《Bioorganic & medicinal chemistry letters》2010,20(19):5718-5721
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes. 相似文献
82.
Adam R. Boyko Pascale Quignon Lin Li Jeffrey J. Schoenebeck Jeremiah D. Degenhardt Kirk E. Lohmueller Keyan Zhao Abra Brisbin Heidi G. Parker Bridgett M. vonHoldt Michele Cargill Adam Auton Andy Reynolds Abdel G. Elkahloun Marta Castelhano Dana S. Mosher Nathan B. Sutter Gary S. Johnson John Novembre Melissa J. Hubisz Adam Siepel Robert K. Wayne Carlos D. Bustamante Elaine A. Ostrander 《PLoS biology》2010,8(8)
Domestic dogs exhibit tremendous phenotypic diversity, including a greater
variation in body size than any other terrestrial mammal. Here, we generate a
high density map of canine genetic variation by genotyping 915 dogs from 80
domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across
60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource
with external measurements from breed standards and individuals as well as
skeletal measurements from museum specimens, we identify 51 regions of the dog
genome associated with phenotypic variation among breeds in 57 traits. The
complex traits include average breed body size and external body dimensions and
cranial, dental, and long bone shape and size with and without allometric
scaling. In contrast to the results from association mapping of quantitative
traits in humans and domesticated plants, we find that across dog breeds, a
small number of quantitative trait loci (≤3) explain the majority of
phenotypic variation for most of the traits we studied. In addition, many
genomic regions show signatures of recent selection, with most of the highly
differentiated regions being associated with breed-defining traits such as body
size, coat characteristics, and ear floppiness. Our results demonstrate the
efficacy of mapping multiple traits in the domestic dog using a database of
genotyped individuals and highlight the important role human-directed selection
has played in altering the genetic architecture of key traits in this important
species. 相似文献
83.
Marko Simunovic Angela Coates Charles H. Goldsmith Lehana Thabane Dana Reeson Andrew Smith Robin S. McLeod Franco DeNardi Timothy J. Whelan Mark N. Levine 《CMAJ》2010,182(12):1301-1306
Background
Following surgery for rectal cancer, two unfortunate outcomes for patients are permanent colostomy and local recurrence of cancer. We tested whether a quality-improvement strategy to change surgical practice would improve these outcomes.Methods
Sixteen hospitals were cluster-randomized to the intervention (Quality Initiative in Rectal Cancer strategy) or control (normal practice) arm. Consecutive patients with primary rectal cancer were accrued from May 2002 to December 2004. Surgeons at hospitals in the intervention arm could voluntarily participate by attending workshops, using opinion leaders, inviting a study team surgeon to demonstrate optimal techniques of total mesorectal excision, completing postoperative questionnaires, and receiving audits and feedback. Main outcome measures were hospital rates of permanent colostomy and local recurrence of cancer.Results
A total of 56 surgeons (n = 558 patients) participated in the intervention arm and 49 surgeons (n = 457 patients) in the control arm. The median follow-up of patients was 3.6 years. In the intervention arm, 70% of surgeons participated in workshops, 70% in intraoperative demonstrations and 71% in postoperative questionnaires. Surgeons who had an intraoperative demonstration provided care to 86% of the patients in the intervention arm. The rates of permanent colostomy were 39% in the intervention arm and 41% in the control arm (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.63–1.48). The rates of local recurrence were 7% in the intervention arm and 6% in the control arm (OR 1.06, 95% CI 0.68–1.64).Interpretation
Despite good participation by surgeons, the resource-intense quality-improvement strategy did not reduce hospital rates of permanent colostomy or local recurrence compared with usual practice. (ClinicalTrials.gov trial register no. .)Following surgery for rectal cancer, two unfortunate outcomes for patients are permanent colostomy and local recurrence of the cancer. Local recurrence is especially feared, because it is usually inoperable and patients can suffer a slow, painful death. NCT001821301 The use of total mesorectal excision, which involves dissection of the lymph node-bearing portion of the rectum,2 has resulted in improved outcomes, with local recurrence rates as low as 1%–5% and rates of permanent colostomy of 10%–15%.3–6 Population-based rates of local recurrence are unavailable for any North American jurisdiction, although a Canadian hospital series found that rates varied from 10% to 45% based on the practice volume and training of surgeons.7 A surgical report on health regions in the province of Ontario (population 13 million) found that rates of permanent colostomy varied from 31% to 41%.8 This geographic variation in outcomes, together with rates of inferior outcomes as compared to outcomes specific to total mesorectal excision, suggest that gaps exist in the quality of rectal surgery provided to patients with rectal cancer.Quality-improvement strategies for encouraging physicians to change practice include continuing medical education, the use of opinion leaders, and audit and feedback.9–11 As well, improvement may be enhanced by using a participatory and supportive approach that focuses on the system and not on individual practitioners.12,13 The small number of studies that have evaluated changes in surgeons’ practices often have targeted process measures, such as preoperative ordering of antibiotics, rather than patient outcomes, such as recurrence of cancer.14,15We tested whether use of a surgeon-directed quality-improvement strategy would improve hospital rates of permanent colostomy and local recurrence of cancer among patients undergoing surgery for rectal cancer. We used the Quality Initiative in Rectal Cancer (QIRC) strategy, which integrates quality-improvement interventions and principles to encourage surgeons to provide optimal total mesorectal excision to patients with rectal cancer.16 相似文献84.
Udom Chaithong Wej Choochote Kittichai Kamsuk Atchariya Jitpakdi Pongsri Tippawangkosol Dana Chaiyasit Daruna Champakaew Benjawan Tuetun Benjawan Pitasawat 《Journal of vector ecology》2006,31(1):138-144
Ethanolic extracts derived from three species of the Piperaceae (pepper) family, Piper longum L., P. ribesoides Wall., and P. sarmentosum Roxb. ex Hunt., were evaluated for efficacy against early 4th instar larvae of Aedes aegypti mosquitoes using larvicidal bioassays. The highest larvicidal efficacy was established from P. longum, followed by P. sarmentosum and P. ribesoides, with LC50 values of 2.23, 4.06, and 8.13 ppm, respectively. Observations of morphological alterations on treated 4th instar larvae revealed that most organs, except anal papillae, had a normal structural appearance that was similar to controls. Under light microscopy, the internal structures of anal papillae in the treated larvae showed shrinkage, while the external features were normal in appearance. Ultrastructural studies, however, clearly demonstrated external destruction, with extensive damage and shrunken cuticle of the anal papillae. The structural deformation of anal papillae probably led to their dysfunction, which may be intrinsically associated with the death of the larvae. This study affords some evidence regarding the action site of the pepper extracts and suggests their potential in developing new types of larvicides used for mosquito control. 相似文献
85.
86.
Kristopher P. Croome David D. Lee Justin M. Burns Dana K. Perry Andrew P. Keaveny C. Burcin Taner 《PloS one》2015,10(10)
Background
Traveling to seek specialized care such as liver transplantation (LT) is a reality in the United States. Patient migration has been attributed to organ availability. The aims of this study were to delineate patterns of patient migration and outcomes after LT.Study Design
All deceased donor LT between 2008–2013 were extracted from UNOS data. Migrated patients were defined as those patients who underwent LT at a center in a different UNOS region from the region in which they resided and traveled a distance > 100 miles.Results
Migrated patients comprised 8.2% of 28,700 LT performed. Efflux and influx of patients were observed in all 11 UNOS regions. Regions 1, 5, 6, and 9 had a net efflux, while regions 2, 3, 4, 7, 10, and 11 had a net influx of patients. After multivariate adjustment for donor and recipient factors, graft (p = 0.68) and patient survival (p = 0.52) were similar between migrated and non-migrated patients.Conclusion
A significant number of patients migrated in patterns that could not be explained alone by regional variations in MELD score and wait time. Migration may be a complex interplay of factors including referral patterns, specialized services at centers of excellence and patient preference. 相似文献87.
88.
Rebecca M. Broeckel Friederike Feldmann Kristin L. McNally Abhilash I. Chiramel Gail L. Sturdevant Jacqueline M. Leung Patrick W. Hanley Jamie Lovaglio Rebecca Rosenke Dana P. Scott Greg Saturday Fadila Bouamr Angela L. Rasmussen Shelly J. Robertson Sonja M. Best 《PLoS pathogens》2021,17(12)
Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures. 相似文献
89.
Galili S Guenoune D Wininger S Hana B Schupper A Ben-Dor B Kapulnik Y 《Transgenic research》2000,9(2):137-144
Threonine, lysine, methionine, and tryptophan are essential amino acids for humans and monogastric animals. Many of the commonly used diet formulations, particularly for pigs and poultry, contain limiting amounts of these amino acids. One approach for raising the level of essential amino acids is based on altering the regulation of their biosynthetic pathways in transgenic plants. Here we describe the first production of a transgenic forage plant, alfalfa (Medicago sativa L.) with modified regulation of the aspartate-family amino acid biosynthetic pathway. This was achieved by over-expressing the Escherichia coli feedback-insensitive aspartate kinase (AK) in transgenic plants. These plants showed enhanced levels of both free and protein-bound threonine. In many transgenic plants the rise in free threonine was accompanied by a significant reduction both in aspartate and in glutamate. Our data suggest that in alfalfa, AK might not be the only limiting factor for threonine biosynthesis, and that the free threonine pool in this plant limits its incorporation into plant proteins. 相似文献
90.
In order to investigate the effects of HBK3, a spruce gene member of the class I KNOX family, during somatic embryogenesis, sense (HBK3-S) and antisense (HBK3-A) Norway spruce (Picea abies) lines were generated. Somatic embryos produced from these lines were then analysed at morphological and structural levels. Compared with control, differentiation of immature somatic embryos from pro-embryogenic masses (PEMs) was accelerated in lines overexpressing HBK3 (HBK3-S). Such immature embryos showed enlarged embryogenic heads and were able to produce fully developed cotyledonary embryos at higher frequency. Furthermore, HBK3-S embryos had enlarged shoot apical meristems (SAMs) and enlarged expression pattern of PgAGO, a molecular marker gene specific to meristematic cells. Lines in which HBK3 (HBK3-A) was down-regulated had reduced ability to produce immature somatic embryos from PEMs and were not able to complete the maturation processes. To assess the function of HBK3 in comparison with that of angiosperm KNOX genes, this gene was ectopically expressed in Arabidopsis plants. As observed for spruce, Arabidopsis embryos overexpressing HBK3 had enlarged meristems and enlarged expression pattern of SHOOTMERISTEMLESS, a SAM molecular marker gene. In addition, transformed embryos were able to germinate at a higher rate and the resulting plants showed a variety of phenotypic aberrations, including abnormal leaves and reduced apical dominance. Overall, these data confirm the importance of KNOTTED genes during development and reveal the participation of HBK3 in conifer embryogeny. Furthermore, the results show redundant functions of this gene during embryonic growth of spruce and Arabidopsis, but not during post-embryonic growth. 相似文献