bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of an M-Cluster-Substituted Nitrogenase VFe Protein
Authors: Rebelein Johannes G. , Lee Chi Chung , Newcomb Megan , Hu Yilin , Ribbe Markus W. 
Published: March 2018

ABSTRACT

The Mo- and V-nitrogenases are two homologous members of the nitrogenase family that are distinguished mainly by the presence of different heterometals (Mo or V) at their respective cofactor sites (M- or V-cluster). However, the V-nitrogenase is ~600-fold more active than its Mo counterpart in reducing CO to hydrocarbons at ambient conditions. Here, we expressed an M-cluster-containing, hybrid V-nitrogenase in
Azotobacter vinelandii
and compared it to its native, V-cluster-containing counterpart in order to assess the impact of protein scaffold and cofactor species on the differential reactivities of Mo- and V-nitrogenases toward CO. Housed in the VFe protein component of V-nitrogenase, the M-cluster displayed electron paramagnetic resonance (EPR) features similar to those of the V-cluster and demonstrated an ~100-fold increase in hydrocarbon formation activity from CO reduction, suggesting a significant impact of protein environment on the overall CO-reducing activity of nitrogenase. On the other hand, the M-cluster was still ~6-fold less active than the V-cluster in the same protein scaffold, and it retained its inability to form detectable amounts of methane from CO reduction, illustrating a fine-tuning effect of the cofactor properties on this nitrogenase-catalyzed reaction. Together, these results provided important insights into the two major determinants for the enzymatic activity of CO reduction while establishing a useful framework for further elucidation of the essential catalytic elements for the CO reactivity of nitrogenase.

IMPORTANCE
This is the first report on the
in vivo
generation and
in vitro
characterization of an M-cluster-containing V-nitrogenase hybrid. The “normalization” of the protein scaffold to that of the V-nitrogenase permits a direct comparison between the cofactor species of the Mo- and V-nitrogenases (M- and V-clusters) in CO reduction, whereas the discrepancy between the protein scaffolds of the Mo- and V-nitrogenases (MoFe and VFe proteins) housing the same cofactor (M-cluster) allows for an effective assessment of the impact of the protein environment on the CO reactivity of nitrogenase. The results of this study provide a first look into the “weighted” contributions of protein environment and cofactor properties to the overall activity of CO reduction; more importantly, they establish a useful platform for further investigation of the structural elements attributing to the CO-reducing activity of nitrogenase.
QStatin, a Selective Inhibitor of Quorum Sensing in
Vibrio
Species
Authors: Kim Byoung Sik , Jang Song Yee , Bang Ye-ji , Hwang Jungwon , Koo Youngwon , Jang Kyung Ku , Lim Dongyeol , Kim Myung Hee , Choi Sang Ho 
Published: March 2018

ABSTRACT

Pathogenic
Vibrio
species cause diseases in diverse marine animals reared in aquaculture. Since their pathogenesis, persistence, and survival in marine environments are regulated by quorum sensing (QS), QS interference has attracted attention as a means to control these bacteria in aquatic settings. A few QS inhibitors of
Vibrio
species have been reported, but detailed molecular mechanisms are lacking. Here, we identified a novel, potent, and selective
Vibrio
QS inhibitor, named QStatin [1-(5-bromothiophene-2-sulfonyl)-1H-pyrazole], which affects
Vibrio harveyi
LuxR homologues, the well-conserved master transcriptional regulators for QS in
Vibrio
species. Crystallographic and biochemical analyses showed that QStatin binds tightly to a putative ligand-binding pocket in SmcR, the LuxR homologue in
V. vulnificus
, and changes the flexibility of the protein, thereby altering its transcription regulatory activity. Transcriptome analysis revealed that QStatin results in SmcR dysfunction, affecting the expression of SmcR regulon required for virulence, motility/chemotaxis, and biofilm dynamics. Notably, QStatin attenuated representative QS-regulated phenotypes in various
Vibrio
species, including virulence against the brine shrimp (
Artemia franciscana
). Together, these results provide molecular insights into the mechanism of action of an effective, sustainable QS inhibitor that is less susceptible to resistance than other antimicrobial agents and useful in controlling the virulence of
Vibrio
species in aquacultures.

IMPORTANCE
Yields of aquaculture, such as penaeid shrimp hatcheries, are greatly affected by vibriosis, a disease caused by pathogenic
Vibrio
infections. Since bacterial cell-to-cell communication, known as quorum sensing (QS), regulates pathogenesis of
Vibrio
species in marine environments, QS inhibitors have attracted attention as alternatives to conventional antibiotics in aquatic settings. Here, we used target-based high-throughput screening to identify QStatin, a potent and selective inhibitor of
V. harveyi
LuxR homologues, which are well-conserved master QS regulators in
Vibrio
species. Structural and biochemical analyses revealed that QStatin binds tightly to a putative ligand-binding pocket on SmcR, the LuxR homologue in
V. vulnificus
, and affects expression of QS-regulated genes. Remarkably, QStatin attenuated diverse QS-regulated phenotypes in various
Vibrio
species, including pathogenesis against brine shrimp, with no impact on bacterial viability. Taken together, the results suggest that QStatin may be a sustainable antivibriosis agent useful in aquacultures.
Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey
Authors: Jamison James , Ayerbe Luis , Di Tanna Gian Luca , Sutton Stephen , Mant Jonathan , De Simoni Anna 
Published: March 2018

ObjectivesTo design a questionnaire and use it to explore unmet needs with practical aspects of medicine taking after stroke, predictors of medicine taking and to estimate the proportion of survivors who get support with daily medication taking.DesignFour workshops with stroke survivors and caregivers to design the questionnaire.A cross-sectional postal questionnaire in primary care.Setting18 general practitioner practices in the East of England and London. Questionnaires posted between September 2016 and February 2017.Participants1687 stroke survivors living in the community outside institutional long-term care.Primary outcome measuresThe proportion of community stroke survivors receiving support from caregivers for practical aspects of medicine taking; the proportion with unmet needs in this respect; the predictors of experiencing unmet needs and missing taking medications.ResultsA five-item questionnaire was developed to cover the different aspects of medicine taking. 596/1687 (35%) questionnaires were returned. 56% reported getting help in at least one aspect of taking medication and 11% needing more help. 35% reported missing taking their medicines. Unmet needs were associated with receiving help with medications (OR 5.9, P<0.001), being on a higher number of medications (OR 1.2, P<0.001) and being dependent for activities of daily living (OR 4.9, P=0.001). Missing medication was associated with having unmet needs (OR 5.3, P<0.001), receiving help with medications (OR 2.1, P<0.001), being on a higher number of medicines (OR 1.1, P=0.008) and being older than 70 years (OR 0.6, P=0.006).ConclusionsMore than half of patients who replied needed help with taking medication, and 1 in 10 had unmet needs in this regard. Stroke survivors dependent on others have more unmet needs, are more likely to miss medicines and might benefit from focused clinical and research attention. Novel primary care interventions focusing on the practicalities of taking medicines are warranted.
What factors are critical to attracting NHS foundation doctors into specialty or core training? A discrete choice experiment
Authors: Scanlan Gillian Marion , Cleland Jennifer , Johnston Peter , Walker Kim , Krucien Nicolas , Skåtun Diane 
Published: March 2018

ObjectivesMultiple personal and work-related factors influence medical trainees’ career decision-making. The relative value of these diverse factors is under-researched, yet this intelligence is crucially important for informing medical workforce planning and retention and recruitment policies. Our aim was to investigate the relative value of UK doctors’ preferences for different training post characteristics during the time period when they either apply for specialty or core training or take time out.MethodsWe developed a discrete choice experiment (DCE) specifically for this population. The DCE was distributed to all Foundation Programme Year 2 (F2) doctors across Scotland as part of the National Career Destination Survey in June 2016. The main outcome measure was the monetary value of training post characteristics, based on willingness to forgo additional potential income and willingness to accept extra income for a change in each job characteristic calculated from regression coefficients.Results677/798 F2 doctors provided usable DCE responses. Location was the most influential characteristic of a training position, followed closely by supportive culture and then working conditions. F2 doctors would need to be compensated by an additional 45.75% above potential earnings to move from a post in a desirable location to one in an undesirable location. Doctors who applied for a training post placed less value on supportive culture and excellent working conditions than those who did not apply. Male F2s valued location and a supportive culture less than female F2s.ConclusionThis is the first study focusing on the career decision-making of UK doctors at a critical careers decision-making point. Both location and specific job-related attributes are highly valued by F2 doctors when deciding their future. This intelligence can inform workforce policy to focus their efforts in terms of making training posts attractive to this group of doctors to enhance recruitment and retention.
Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: study protocol for a systematic review and network meta-analysis
Authors: Zhang Yuqing , Zhou Xinyu , Yang Lining , Hetrick Sarah E , Weisz John R , Cuijpers Pim , Barth Jürgen , Del Giovane Cinzia , Yuan Shuai , Cohen David , Gillies Donna , Jiang Xiaofeng , Teng Teng , Xie Peng 
Published: March 2018

IntroductionPost-traumatic stress disorder (PTSD) is common among children and adolescents who are exposed to trauma, and it is often associated with significant negative impacts on their psychosocial functioning and quality of life. Many types of psychotherapies have been found to be effective for PTSD in children and adolescents. However, due to the lack of direct comparisons between different psychotherapies, the hierarchy of treatment efficacy is still unclear. Therefore, we plan to conduct a systematic review and network meta-analysis to evaluate the efficacy and acceptability of various types of psychotherapies for PTSD in children and adolescents.Methods and analysisA systematic search will be conducted among eight electronic databases, including PubMed, Cochrane, Embase, Web of Science, PsycINFO, Cumulative Index of Nursing and Allied Health, Published International Literature on Traumatic Stress (PILOTS) and ProQuest Dissertations, from inception to October 2017. Randomised controlled trials, regardless of language, publication year and publication type, comparing any psychotherapies for PTSD to any control condition or alternative treatment in children and adolescents (18 years old or less) diagnosed with full or subclinical PTSD will be included. Study duration and the number of treatment sessions will not be limited. The primary outcome will be PTSD symptom severity at post-treatment as measured by a rating scale reported by the child, parent or a clinician. The secondary outcomes will include: (1) efficacy at follow-up; (2) acceptability (all-cause discontinuation); (3) anxiety symptom severity; (4) depressive symptom severity and (5) quality of life and functional improvement. Bayesian network meta-analyses for all relative outcome measures will be performed. We will conduct subgroup and sensitivity network meta-analyses to determine whether the findings are affected by study characteristics. The quality of the evidence contributing to network estimates of the primary outcome will be evaluated by the Grading of Recommendations, Assessment, Development and Evaluations framework.Ethics and disseminationNo ethical issues are foreseen. The results will be published in a peer-reviewed journal, which will be disseminated electronically and in print. This network meta-analysis may be updated to inform and guide the clinical management of PTSD in children and adolescents.PROSPERO registration numberCRD42016051786.
High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)
Authors: Chumsri Saranya , Sperinde Jeff , Liu Heshan , Gligorov Joseph , Spano Jean-Philippe , Antoine Martine , Moreno Aspitia Alvaro , Tan Winston , Winslow John , Petropoulos Christos J. , Chenna Ahmed , Bates Michael , Weidler Jodi Marie , Huang Weidong , Dueck Amylou , Perez Edith A. 
Published: March 2018

Abstract
Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials.
Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples.
Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P &lt; 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02).
Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053–8. ©2018 AACR.
The Obligations concerning Negotiations Cases and the “Dispute” Requirement in the International Court of Justice
Authors: Pomson Ori 
Published: March 2018

Abstract
In the Obligations concerning Negotiations cases, the International Court of Justice (icj) ruled that it lacked jurisdiction to proceed to the merits since there was no dispute prior to the filing of the application by the Republic of the Marshall Islands (rmi) against the three respondent states – India, Pakistan and the United Kingdom – respectively. The present article considers more closely the basis of the requirement that a “dispute” exists for the icj to exercise its jurisdiction. It submits that the condition that a “dispute” exists relates to the essence of the Court’s judicial function. It then questions whether the respondent’s awareness of the applicant’s opposition to its views is a requirement for engaging the Court’s judicial function. After answering this question affirmatively, it questions whether reasons of judicial propriety dictate that a dispute must exist prior to the filing of an application. This question is also answered affirmatively.
Second malignancy versus recurrence after complete resection of thymoma
Authors: Hamaji Masatsugu , Sozu Takashi , Machida Ryunosuke , Omasa Mitsugu , Menju Toshi , Aoyama Akihiro , Sato Toshihiko , Chen-Yoshikawa Toyofumi-Fengshi , Sonobe Makoto , Date Hiroshi 
Published: March 2018

Background Patients undergoing complete resection of thymoma occasionally develop a recurrence of thymoma; they are also at risk of developing a second malignancy. The objective of our study was to compare the incidence and mortality of a second malignancy versus a recurrence of thymoma during the postoperative follow-up period after complete resection of thymoma. Methods A retrospective chart review was performed on our prospectively maintained database to identify patients undergoing complete resection of thymoma at our institution between 1991 and 2016. The incidence and related mortality of a second malignancy or recurrence of thymoma were recorded. Results One hundred and sixty-four patients were identified. Follow-up ranged from 1 to 239 months (median 54 months). During follow-up, 12 patients had a recurrence of thymoma and 14 developed a second malignancy. The mean risk ratio of recurrence to second malignancy was 0.58 (95% confidence interval: 0.48–0.69) at 5 years, 0.58 (95% confidence interval: 0.49–0.68) at 10 years, and 0.51 (95% confidence interval: 0.43–0.60) at 15 years. The mean risk ratio of recurrence versus second malignancy for related death was 0.59 (95% confidence interval: 0.50–0.70) at 5 years and 0.61 (95% confidence interval: 0.52–0.72) at 10 years. Conclusion It appears that patients undergoing complete resection of thymoma have a higher incidence of a second malignancy and a greater related mortality rate than a recurrence of thymoma. A multiinstitutional database is required to more rigorously evaluate both risks and to confirm our results.
Patient, Treatment, and Health Care Utilization Variables Associated with Adherence to Metabolic Monitoring Practices in Children and Adolescents Taking Second-Generation Antipsychotics
Authors: Coughlin Mary , Goldie Catherine Lindsay , Tranmer Joan , Khalid-Khan Sarosh , Tregunno Deborah 
Published: March 2018

Objective: Children and adolescents with a range of psychiatric disorders are increasingly being prescribed atypical or second-generation antipsychotics (SGAs). While SGAs are effective at treating conduct and behavioural symptoms, they infer significant cardiometabolic risk. This study aims to explore what patient, treatment, and health care utilization variables are associated with adherence to Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) metabolic monitoring guidelines. Method: A retrospective chart review of 294 children and adolescents accessing a large outpatient psychiatry setting within a 2-year study period (2014-2016) was conducted. Baseline and follow-up metabolic monitoring, demographic, treatment, and health care utilization variables were then assessed over a 1-year period of interest. Results: Metabolic monitoring practices did not adhere to CAMESA guidelines and were very poor over the 1-year observation period. There were significant differences between children (ages 4-12 years, n = 99) and adolescents (ages 13-18 years, n = 195). In adolescents, factors associated with any baseline metabolic monitoring were a higher number of psychiatry visits (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.10 to 1.41), longer duration of contact (OR, 14; 95% CI, 2.31 to 82.4), and use of other non-SGA medications (OR, 3.2; 95% CI, 1.17 to 8.94). Among children, having an emergency room visit (OR, 3.4; 95% CI, 1.01 to 11.71) and taking aripiprazole (OR, 7.4; 95% CI, 2.02 to 27.45) increased the odds of receiving baseline metabolic monitoring. Conclusion: Findings from this study highlight the need for better metabolic monitoring for children and adolescents taking SGAs. Enhanced focus on opportunities for multidisciplinary collaboration is needed to improve the quality of care offered to this population.
Clinical Markers of Anxiety Subtypes in Parkinson Disease
Authors: Broen Martinus P. G. , Leentjens A. F. G. , Hinkle J. T. , Moonen A. J. H. , Kuijf M. L. , Fischer N. M. , Perepezko K. , Bakker A. , Pontone G. M. 
Published: March 2018

Objective: The aim of this work was to investigate marker profiles for proposed anxiety subtypes in Parkinson disease (PD). Methods: We used the persistent anxiety, episodic anxiety, and avoidance behavior subscales of the Parkinson Anxiety Scale as dependent variables in multivariable linear regression analyses using a cross-sectional data set of 311 patients with PD. Independent variables consisted of a range of demographic, psychiatric, and disease-specific markers. Results: In the most parsimonious model of persistent anxiety, higher Hamilton Depression Rating Scale scores, a history of anxiety, fewer years of education, lower Mini-Mental State Examination scores, lower Lawton Instrumental Activities of Daily Living scores, female sex, and complications of therapy (higher Unified Parkinson Disease Rating Scale part IV scores) were all associated with more severe persistent anxiety. Markers associated with more severe episodic anxiety included PD-specific disturbances of activities of daily living, complications of therapy, higher Hamilton Depression Rating Scale scores, female sex, and a history of anxiety. Finally, higher Hamilton Depression Rating Scale scores, a history of anxiety, complications of therapy, and longer disease duration were associated with avoidance behavior. After excluding clinically depressed patients with PD, disease severity and longer disease duration were significantly associated with episodic anxiety, but not with persistent anxiety. Conclusion: Persistent anxiety is mainly influenced by nonspecific markers, while episodic anxiety seems to be more PD-specific compared to persistent anxiety and may be more situational or contextual. These results provide support for possible distinct underlying constructs for anxiety subtypes in PD.
Outcome of Percutaneous Fixation of Acute Achilles Tendon Ruptures
Authors: Rozis Meletis , Benetos Ioannis S. , Karampinas Panagiotis , Polyzois Vasilios , Vlamis John , Pneumaticos Spyros G. 
Published: March 2018

Background: Conservative treatment of an acute Achilles rupture remains a viable and acceptable option as does surgical fixation, with open and percutaneous repair consisting the main operative techniques. The purpose of this study was to compare the outcomes and complication rates of open versus percutaneous surgical procedures. Methods: From 2009 to 2016, 131 patients were admitted to our department with clinically and radiologically confirmed acute Achilles tendon ruptures. Of those, 82 patients met our inclusion criteria and were randomized into 2 groups, group A (open repair) and group B (percutaneous suturing). Suture equipment was the same for both groups. All patients followed the same rehabilitation protocol. Functional evaluation was made using American Orthopaedic Ankle & Foot Society (AOFAS) hindfoot and Achilles tendon Total Rupture Score (ATRS) questionnaires at the 12-month follow-up. Ankle range of motion (ROM), return-to-work time, and complication rates were additionally measured. Results: Both techniques had similar results regarding complication rates and return-to-work time. The major complication in group A was superficial infection (7%) and skin necrosis (3%), whereas 3 patients in group B developed paresthesias due to sural nerve entrapment. Patients in group B had better AOFAS hindfoot (96/100) and ATRS (95/100) scores, but the difference was not significant. ROM was similar in both groups at the 12-month follow-up. Conclusion: Percutaneous suturing seems to be a safe and effective technique that offers good functional outcomes and low complication rates in patients with acute Achilles tendon ruptures who elect to have surgery. Level of Evidence: Level II, prospective case series.