bluuebunny/crossref_metadata_2025_split huggingface dataset:
Problematizing ‘wickedness’: a critique of the wicked problems concept, from philosophy to practice
Authors: Turnbull Nick , Hoppe Robert 
Published: July 2018

AbstractThe concept of ‘wicked problems’ is a major current in the fields of policy analysis and planning. However, the basis of the concept has been insufficiently examined. This re-examination of its conceptual basis explains the origins of the limitations and flaws in the wicked problems concept. This paper analyses and rejects the notion of ‘wicked problems’ on philosophical and practical grounds. We argue instead that the policy sciences already had better conceptualizations of public problems before Rittel and Webber’s flawed formulation. We return to this literature, and build upon it by reframing ‘wickedness’ in terms of higher and lower levels of problematicity in problem structuring efforts. In doing so, we offer an alternative, novel combination of the philosophy of questioning and the policy work approach to policy practice. ‘Wickedness’ is re-conceptualized as problematicity, conceived as the distance between those who question or inquire into a policy problem. This is primarily a political distance, articulated in terms of ideas, interests, institutions and practices. High problematicity arises only when wide political distances are explicitly maintained, such that partial answers cannot be reached. Practitioners deal with problematicity by a dual practical strategy of balancing closing-down and opening-up sub-questions to the problem in order to structure them such that they become amenable to action through partial answers. This simultaneously incorporates a politics of negotiating political distance via partisan adjustment and serial strategic analysis. The argument constitutes a theoretically and practically superior alternative to the ‘wicked problems’ perspective.
The 21st Century Cures Act and electronic health records one year later: will patients see the benefits?
Authors: Lye Carolyn T , Forman Howard P , Daniel Jodi G , Krumholz Harlan M 
Published: July 2018

Abstract
While federal regulation provides patients the right to access their electronic health records and promotes increased use of health information technology, patient access to electronic health records remains limited. The 21st Century Cures Act, signed into law over a year ago, has important provisions that could significantly improve access and availability of health data. Specifically, the provisions call for partnerships among health information exchange networks, educational and research initiatives, and health information technology certification requirements that encourage interoperability. The article reviews the potential benefits and concerns regarding implementation of these provisions, particularly the difficulty of aligning incentives and requirements for data sharing and the question of whether currently proposed rules and guidance will support the goal of improved patient access and health information exchange. Researchers, clinicians, and patients have the power to advocate for improved patient access and interoperability as policy development and implementation of the 21st Century Cures Act continues.
In Vitro Activity of Ceftolozane/Tazobactam vs Nonfermenting, Gram-Negative Cystic Fibrosis Isolates
Authors: Forrester Jeanne B , Steed Lisa L , Santevecchi Barbara A , Flume Patrick , Palmer-Long Gloria E , Bosso John A 
Published: July 2018

Abstract
Ceftolozane/tazobactam (C/T) was tested and compared against 93 nonfermenting, Gram-negative clinical isolates from cystic fibrosis specimens. Based on current breakpoints for intra-abdominal and urinary tract infections (which may not be appropriate for pulmonary infections), C/T was found to be the most active agent against P. aeruginosa (95.7% susceptible), followed by piperacillin/tazobactam (89.4% susceptible). For other Gram-negative pathogens included, C/T had varying activity.
Coronal Imbalance After Three-Column Osteotomy in Thoracolumbar Congenital Kyphoscoliosis
Authors: Xu Liang , Chen Xi , Qiao Jun , Chen Zhonghui , Shi Benlong , Li Song , Du Changzhi , Zhou Qingshuang , Zhu Zezhang , Qiu Yong , Sun Xu 
Published: July 2018

Study Design.
Retrospective radiographical clinical study.

Objective.
To investigate the incidence and risk factors of coronal imbalance (CI) after three-column osteotomy (3-CO) in patients with thoracolumbar congenital kyphoscoliosis (CKS).

Summary of Background Data.
The incidence and risk factors of postoperative CI have been reported in adolescent idiopathic and degenerative lumbar scoliosis. However, limited data exists for patients with CKS after 3-CO.

Methods.
We reviewed a consecutive series of patients with CKS who underwent posterior-only 3-CO. Coronal curve patterns were classified according to absolute C7 translation values into: Type A, C7 translation is less than 30 mm; Type B, C7 translation more than or equal to 30 mm and C7 plumb line (C7PL) shifted to the concave side of the main curve; and Type C, C7 translation more than or equal to 30 mm and C7PL shifted to the convex side. CI was defined as C7 translation on either side more than or equal to 30 mm. According to C7 translation at the latest follow-up, patients was subdivided into an imbalanced group and a balanced group.

Results.
One-hundred-thirty patients (mean age, 17.7 ± 5.2 yr) were recruited. The mean follow-up was 41.3 ± 18.5 months. Twenty-six patients (20%) were identified as having CI at the latest follow-up. Compared with the balanced group, the imbalanced group had a larger proportion of preoperative Type C pattern, higher main curve correction, and greater lowest instrumented vertebra (LIV) tilt before and after surgery. Multiple logistic regression showed that risk factors for CI were preoperative type C pattern, preoperative LIV tilt more than or equal to 23.5° and immediate postoperative LIV tilt more than or equal to 12.3°.

Conclusion.
The incidence of CI in patients with CKS after 3-CO was 20%. A preoperative type C pattern, preoperative LIV tilt more than or equal to 23.5°, and immediate postoperative LIV tilt more than or equal to 12.3° were found to be associated with CI at the latest follow-up.

Level of Evidence: 3
Dose Escalation in Stereotactic Body Radiation Therapy for Pancreatic Cancer
Authors: Zaorsky Nicholas G. , Lehrer Eric J. , Handorf Elizabeth , Meyer Joshua E. 
Published: July 2018

Objective:
To determine whether increasing biologically effective dose (BED) with stereotactic body radiation therapy (SBRT) is associated with improved local control (LC) or toxicities in patients with locally advanced pancreatic cancer.

Methods:
A PICOS/PRISMA/MOOSE selection protocol was used to identify 15 studies across 12 institutions in 5 countries where patients received definitive SBRT for nonmetastatic disease. Biologically equivalent doses were calculated with an α/β of 10 (ie, BED10) for LC and acute toxicity and 3 (ie, BED3) for late toxicity. Fixed and random effects models were used to characterize LC and grade 3/4 toxicities by BED.

Results:
There were 508 patients included with a median follow-up time of 9.1 months. The median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. There was no significant difference in LC rates at 1 year between the BED10<70 Gy versus ≥70 Gy groups, with an estimate of 0.60 (95% confidence interval [CI], 0.36-0.81) versus 0.83 (95% CI, 0.63-0.97), respectively. There was no significant difference in acute toxicity rates between the BED10<70 Gy versus ≥70 Gy groups, with an estimate of 0.02 (95% CI, 0.00-0.08) versus 0.05 (95% CI, 0.00-0.22), respectively. Given the dose distribution across studies, 3 intervals were used to characterize BED3. There were no significant differences in late toxicity among those receiving BED3<100, 100 to 200, or >200 Gy.

Conclusions:
SBRT for pancreatic cancer results in LC rates of 60% to 83% and clinically significant toxicity of <7%. Increasing BED10 beyond 70 Gy was not associated with increased rates of 1-year LC or acute toxicity. Increasing BED3 beyond 100 Gy was not associated with increased rates of late toxicity.
Programmed genome editing of the omega-1 ribonuclease 1 of the blood fluke,Schistosoma mansoni
Authors: Ittiprasert Wannaporn , Mann Victoria H. , Karinshak Shannon E. , Coghlan Avril , Rinaldi Gabriel , Sankaranarayanan Geetha , Chaidee Apisit , Tanno Toshihiko , Kumkhaek Chutima , Prangtaworn Pannathee , Mentink-Kane Margaret , Cochran Christina J. , Driguez Patrick , Holroyd Nancy , Tracey Alan , Rodpai Rutchanee , Everts Bart , Hokke Cornelis H. , Hoffmann Karl F. , Berriman Matthew , Brindley Paul J. 
Published: July 2018

AbstractCRISPR/Cas9 based genome editing has yet been reported in parasitic or indeed any species of the phylum Platyhelminthes. We tested this approach by targeting omega-1 (ω1) ofSchistosoma mansonias a proof of principle. This secreted ribonuclease is crucial for Th2 priming and granuloma formation, providing informative immuno-pathological readouts for programmed genome editing. Schistosome eggs were either exposed to Cas9 complexed with a synthetic guide RNA (sgRNA) complementary to exon 6 of ω1 by electroporation or transduced with pseudotyped lentivirus encoding Cas9 and the sgRNA. Some eggs were also transduced with a single stranded oligodeoxynucleotide donor transgene that encoded six stop codons, flanked by 50 nt-long 5’-and 3’-microhomology arms matching the predicted Cas9-catalyzed double stranded break (DSB) within ω1. CRISPResso analysis of amplicons spanning the DSB revealed ∼4.5% of the reads were mutated by insertions, deletions and/or substitutions, with an efficiency for homology directed repair of 0.19% insertion of the donor transgene. Transcripts encoding ω1 were reduced >80% and lysates of ω1-edited eggs displayed diminished ribonuclease activity indicative that programmed editing mutated the ω1 gene. Whereas lysates of wild type eggs polarized Th2 cytokine responses including IL-4 and IL-5 in human macrophage/T cell co-cultures, diminished levels of the cytokines followed the exposure to lysates of ω1-mutated schistosome eggs. Following injection of schistosome eggs into the tail vein of mice, the volume of pulmonary granulomas surrounding ω1-mutated eggs was 18-fold smaller than wild type eggs. Programmed genome editing was active in schistosomes, Cas9-catalyzed chromosomal breakage was repaired by homology directed repair and/or non-homologous end joining, and mutation of ω1 impeded the capacity of schistosome eggs both to drive Th2 polarization and to provoke formation of pulmonary circumoval granulomas. Knock-out of ω1 and the impaired immunological phenotype showcase the novel application of programmed gene editing in and functional genomics for schistosomes.
Comparative genomic analysis revealed rapid differentiation in the pathogenicity-related gene repertoires betweenPyricularia oryzaeandPyricularia pennisetiisolated from aPennisetumgrass
Authors: Zheng Huakun , Zhong Zhenhui , Shi Mingyue , Zhang Limei , Lin Lianyu , Hong Yonghe , Fang Tian , Zhu Yangyan , Guo Jiayuan , Zhang Limin , Fang Jie , Lin Hui , Norvienyeku Justice , Chen Xiaofeng , Lu Guodong , Hu Hongli , Wang Zonghua 
Published: July 2018

AbstractBackgroundsPyriculariais a multispecies complex that could infect and cause severe blast disease on diverse hosts, including rice, wheat and many other grasses. Although the genome size of this fungal complex is small [~40 Mbp forPyricularia oryzae(syn.Magnaporthe oryzae), and ~45 Mbp forP. grisea], the genome plasticity allows the fungus to jump and adapt to new hosts. Therefore, deciphering the genome basis of individual species could facilitate the evolutionary and genetic study of this fungus. However, except for theP. oryzaesubgroup, many other species isolated from diverse hosts, such as thePennisetumgrasses, remain largely uncovered genetically.ResultsHere, we report the genome sequence of a pyriform-shaped fungal strainP. pennisetiP1609 isolated from aPennisetumgrass (JUJUNCAO) using PacBio SMRT sequencing technology. We performed a phylogenomic analysis of 28 Magnaporthales species and 5 non-Magnaporthales species and addressed P1609 into aPyriculariasubclade that is distant fromP. oryzae. Comparative genomic analysis revealed that the pathogenicity-related gene repertoires were fairly different between P1609 and theP. oryzaestrain 70-15, including the cloned avirulence genes, other putative secreted proteins, as well as some other predictedPathogen-Host Interaction(PHI) genes. Genomic sequence comparison also identified many genomic rearrangements.ConclusionTaken together, our results suggested that the genomic sequence of theP. pennisetiP1609 could be a useful resource for the genetic study of thePennisetum-infectingPyriculariaspecies.
Multifunctional CRISPR/Cas9 with engineered immunosilenced human T cell epitopes
Authors: Ferdosi Shayesteh R. , Ewaisha Radwa , Moghadam Farzaneh , Krishna Sri , Park Jin G. , Ebrahimkhani Mo R. , Kiani Samira , Anderson Karen S. 
Published: July 2018

AbstractThe application of Cas9 for genetic and epigenetic therapies in humans raises concerns over immunogenicity of this foreign protein. We report pre-existing human CD8+ T cell immunity to Streptococcus pyogenes Cas9 in the majority of healthy individuals screened. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity.
Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication
Authors: Ferreira André C. , Reis Patrícia A. , de Freitas Caroline S. , Sacramento Carolina Q. , Bôas Hoelz Lucas Villas , Bastos Mônica M. , Mattos Mayara , Loiola Erick Correia , Trindade Pablo , Vieira Yasmine Rangel , Barbosa-Lima Giselle , de Castro Faria Neto Hugo C. , Boechat Nubia , Rehen Stevens K. , Brüning Karin , Bozza Fernando A. , Bozza Patrícia T. , Souza Thiago Moreno L. 
Published: July 2018

AbstractChikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is a consolidated public health problem, in tropical and subtropical regions of the world, where control of CHIKV vector, mosquitos of theAedesgenus, failed. Since there is no vaccine or specific treatment against CHIKV, infected patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. Recently, the structure and activity of CHIKV RNA polymerase was partially resolved, revealing similar aspects with the enzyme counterparner on other positive sense RNA viruses, such as members of the Flaviviridae family. We then evaluated if sofosbuvir, clinically approved against hepatitis C virus RNA polymerase, which also aims to dengue, Zika and yellow fever viruses replication, would inhibit CHIKV replication. Indeed, sofosbuvir was 5-times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell (iPS)-derived astrocytes was less sensitive to sofosbuvir’s, compared to hepatoma cells – this drug still impaired virus production and cell death in a MOI-dependent manner. Sofosbuvir also exhibited antiviral activityin vivo, by preventing CHIKV-induced paw oedeme in adult mice, at 20 mg/kg/day, and mortality on neonate mice model, at 40 and 80 mg/kg/day. Our data demonstrates that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. Since this is a clinically approved drug, it could pave the way to become a therapeutic option against CF.
PRSS56 is required for the developmental positioning of ocular angle structures
Authors: Labelle-Dumais Cassandre , Tolman Nicholas G , Paylakhi Seyyedhassan , John Simon WM , Nair K Saidas 
Published: July 2018

AbstractAngle-closure glaucoma (ACG) is a severe form of glaucoma affecting up to 16 million people worldwide. In ACG, physical blockage of the ocular drainage tissue by the peripheral iris impedes the drainage of aqueous humor resulting in elevated intraocular pressure (IOP) and subsequent optic nerve damage. Despite the high prevalence of ACG, the precise mechanism(s) underlying pathogenesis are only partially understood. We have previously demonstrated that a mutation in the gene encoding the serine protease PRSS56 causes an ACG phenotype in mice. Notably,Prss56mutant mice exhibit a reduced ocular axial length and a lens occupying a larger ocular volume compared to WT mice, recapitulating characteristic features of human AGC. Our findings utilizing mouse genetic models demonstrate that loss of PRSS56 function results in altered configuration of ocular angle structures characterized by a posterior shift in the positioning of the ocular drainage tissue relative to the ciliary body and iris during development, leading to a physical blockage of drainage structure (angle closure) and high IOP. Utilizing a previously employed genetic strategy of rescuing mutantPrss56mediated reduction in ocular size by inactivation of EGR1 (Egr1;Prss56double mutants) we determined the influence of ocular size on developmental positioning of the ocular angle tissues. Our findings suggest that abnormal positioning of the drainage structure as a result of loss of PRSS56 function is uncoupled from its effect on ocular axial length reduction. Furthermore, we demonstrate that the IOP elevation observed inPrss56mutant mice is genetic context-dependent and identify a dominant modifier locus on Chromosome 2 of the C3H/HeJ genome conferring susceptibility to high IOP. Overall, our findings reveal a novel role for PRSS56 in the proper configuration of the iridocorneal angle and provide new insight into the developmental pathways implicated in glaucoma pathogenesis.
VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression
Authors: Tang Bo , Wu Jilin , Zhu Michael X. , Sun Xuemei , Liu Jingjing , Xie Rui , Dong Tobias Xiao , Xiao Yufeng , Carethers John M. , Yang Shiming , Dong Hui 
Published: July 2018

AbstractAlthough VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+ entry, and eventually promoted gastric cancer progression in a Ca2+ signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+ signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+ signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.
Genetic mapping with Allele Dosage Information in TetraploidUrochloa decumbens(Stapf) R.D. Webster Reveals Insights into Spittlebug (Notozulia entrerianaBerg) Resistance
Authors: Ulbricht Ferreira Rebecca Caroline , de Castro Lara Letícia Aparecida , Chiari Lucimara , Lima Barrios Sanzio Carvalho , do Valle Cacilda Borges , Valério José Raul , Vilela Torres Fabrícia Zimermann , Franco Garcia Antonio Augusto , de Souza Anete Pereira 
Published: July 2018

AbstractUrochloa decumbens(Stapf) R.D. Webster is one of the most important African forage grasses in Brazilian beef production. Currently available genetic-genomic resources for this species are restricted mainly due to polyploidy and apomixis. Therefore, crucial genomic-molecular studies such as the construction of genetic maps and the mapping of quantitative trait loci (QTLs) are very challenging and consequently affect the advancement of molecular breeding. The objectives of this work were to (i) construct an integratedU. decumbensgenetic map for a full-sibling progeny using GBS-based markers with allele dosage information, (ii) detect QTLs for spittlebug (Notozulia entreriana) resistance, and (iii) seek putative candidate genes involved in resistance/defense against pathogens. We used theSetaria viridisgenome as reference to align GBS reads and selected 4,240 high-quality SNPs markers with allele dosage information. Of these markers, 1,000 were distributed throughout nine homologous groups with a cumulative map length of 1,335.09 cM and an average marker density of 1.33 cM. We detected QTLs for resistance to spittlebug, an important pasture insect pest, that explained between 4.66% and 6.24% of the phenotypic variation. These QTLs are in regions containing putative candidate genes related to resistance/defense against pathogens. Because this is the first genetic map with SNP autotetraploid dosage data and QTL detection inU. decumbens, it will be useful for future evolutionary studies, genome assembly, and other QTL analyses inUrochloaspp. Moreover, the results might facilitate the isolation of spittlebug-related candidate genes and help clarify the mechanism of spittlebug resistance. These approaches will improve selection efficiency and accuracy inU. decumbensmolecular breeding and shorten the breeding cycle.
Tracking disease resistance deployment in potato breeding by enrichment sequencing
Authors: Armstrong Miles R , Vossen Jack , Lim Tze Yin , Hutten Ronald C B , Xu Jianfei , Strachan Shona M , Harrower Brian , Champouret Nicolas , Gilroy Eleanor M , Hein Ingo 
Published: July 2018

SummaryFollowing the molecular characterisation of functional disease resistance genes in recent years, methods to track and verify the integrity of multiple genes in varieties are needed for crop improvement through resistance stacking. Diagnostic resistance gene enrichment sequencing (dRenSeq) enables the high-confidence identification and complete sequence validation of known functional resistance genes in crops. As demonstrated for tetraploid potato varieties, the methodology is more robust and cost-effective in monitoring resistances than whole-genome sequencing and can be used to appraise (trans)gene integrity efficiently. All currently known NB-LRRs effective against viruses, nematodes and the late blight pathogen Phytophthora infestans can be tracked with dRenSeq in potato and hitherto unknown polymorphisms have been identified. The methodology provides a means to improve the speed and efficiency of future disease resistance breeding in crops by directing parental and progeny selection towards effective combinations of resistance genes.