bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of the Paramyxovirus Parainfluenza Virus 5 Nucleoprotein in Complex with an Amino-Terminal Peptide of the Phosphoprotein
Authors: Aggarwal Megha , Leser George P. , Kors Christopher A. , Lamb Robert A. 
Published: December 2017

ABSTRACT

Parainfluenza virus 5 (PIV5) belongs to the family
Paramyxoviridae
, which consists of enveloped viruses with a nonsegmented negative-strand RNA genome encapsidated by the nucleoprotein (N). Paramyxovirus replication is regulated by the phosphoprotein (P) through protein-protein interactions with N and the RNA polymerase (L). The chaperone activity of P is essential to maintain the unassembled RNA-free form of N in order to prevent nonspecific RNA binding and premature N oligomerization. Here, we determined the crystal structure of unassembled PIV5 N in complex with a P peptide (N
0
P) derived from the N terminus of P (P50) at 2.65 Å. The PIV5 N
0
P consists of two domains: an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a hinge region. The cleft at the hinge region of RNA-bound PIV5 N was previously shown to be an RNA binding site. The N
0
P structure shows that the P peptide binds to the CTD of N and extends toward the RNA binding site to inhibit N oligomerization and, hence, RNA binding. Binding of P peptide also keeps the PIV5 N in the open form. A molecular dynamics (MD) analysis of both the open and closed forms of N shows the flexibility of the CTD and the preference of the N protein to be in an open conformation. The gradual opening of the hinge region, to release the RNA, was also observed. Together, these results advance our knowledge of the conformational swapping of N required for the highly regulated paramyxovirus replication.

IMPORTANCE
Paramyxovirus replication is regulated by the interaction of P with N and L proteins. Here, we report the crystal structure of unassembled parainfluenza virus 5 (PIV5) N chaperoned with P peptide. Our results provide a detailed understanding of the binding of P to N. The conformational switching of N between closed and open forms during its initial interaction with P, as well as during RNA release, was analyzed. Our data also show the plasticity of the CTD and the importance of domain movement for conformational switching. The results improve our understanding of the mechanism of interchanging N conformations for RNA replication and release.
Prophages and Growth Dynamics Confound Experimental Results with Antibiotic-Tolerant Persister Cells
Authors: Harms Alexander , Fino Cinzia , Sørensen Michael A. , Semsey Szabolcs , Gerdes Kenn 
Published: December 2017

ABSTRACT

Bacterial persisters are phenotypic variants that survive antibiotic treatment in a dormant state and can be formed by multiple pathways. We recently proposed that the second messenger (p)ppGpp drives
Escherichia coli
persister formation through protease Lon and activation of toxin-antitoxin (TA) modules. This model found considerable support among researchers studying persisters but also generated controversy as part of recent debates in the field. In this study, we therefore used our previous work as a model to critically examine common experimental procedures to understand and overcome the inconsistencies often observed between results of different laboratories. Our results show that seemingly simple antibiotic killing assays are very sensitive to variations in culture conditions and bacterial growth phase. Additionally, we found that some assay conditions cause the killing of antibiotic-tolerant persisters via induction of cryptic prophages. Similarly, the inadvertent infection of mutant strains with bacteriophage ϕ80, a notorious laboratory contaminant, apparently caused several of the phenotypes that we reported in our previous studies. We therefore reconstructed all infected mutants and probed the validity of our model of persister formation in a refined assay setup that uses robust culture conditions and unravels the dynamics of persister cells through all bacterial growth stages. Our results confirm the importance of (p)ppGpp and Lon but no longer support a role of TA modules in
E. coli
persister formation under unstressed conditions. We anticipate that the results and approaches reported in our study will lay the ground for future work in the field.

IMPORTANCE
The recalcitrance of antibiotic-tolerant persister cells is thought to cause relapsing infections and antibiotic treatment failure in various clinical setups. Previous studies identified multiple genetic pathways involved in persister formation but also revealed reproducibility problems that sparked controversies about adequate tools to study persister cells. In this study, we unraveled how typical antibiotic killing assays often fail to capture the biology of persisters and instead give widely differing results based on poorly controlled experimental parameters and artifacts caused by cryptic as well as contaminant prophages. We therefore established a new, robust assay that enabled us to follow the dynamics of persister cells through all growth stages of bacterial cultures without distortions by bacteriophages. This system also favored adequate comparisons of mutant strains with aberrant growth phenotypes. We anticipate that our results will contribute to a robust, common basis for future studies on the formation and eradication of antibiotic-tolerant persisters.
Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B-Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population
Authors: Salo Perttu P. , Havulinna Aki S. , Tukiainen Taru , Raitakari Olli , Lehtimäki Terho , Kähönen Mika , Kettunen Johannes , Männikkö Minna , Eriksson Johan G. , Jula Antti , Blankenberg Stefan , Zeller Tanja , Salomaa Veikko , Kristiansson Kati , Perola Markus 
Published: December 2017

Background—
Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP.

Methods and Results—

We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide–associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (
NPPA-NPPB
and
POC1B-GALNT4
) and 1 novel locus (
PPP3CC
) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The
NPPA-NPPB
locus containing the adjacent genes encoding ANP and BNP harbored 4 independent
cis
variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene
PPP3CC
and the polypeptide N-acetylgalactosaminyltransferase 4 gene
GALNT4
associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (
P
=8.2×10
−
4
).

Conclusions—
Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure–lowering effect of ANP in the general population.
Plasma Proteomics for Epidemiology
Authors: Yin Xiaoke , Baig Ferheen , Haudebourg Eloi , Blankley Richard T. , Gandhi Tejas , Müller Sebastian , Reiter Lukas , Hinterwirth Helmut , Pechlaner Raimund , Tsimikas Sotirios , Santer Peter , Willeit Johann , Kiechl Stefan , Witztum Joseph L. , Sullivan Anthony , Mayr Manuel 
Published: December 2017

Background—
Mass spectrometry is selective and sensitive, permitting routine quantification of multiple plasma proteins. However, commonly used nanoflow liquid chromatography (LC) approaches hamper sample throughput, reproducibility, and robustness. For this reason, most publications using plasma proteomics to date are small in study size.

Methods and Results—
Here, we tested a standard-flow LC mass spectrometry (MS) method using multiple reaction monitoring for the application to large epidemiological cohorts. We have reduced the LC-MS run time to almost a third of the nanoflow LC-MS approach. On the basis of a comparison of the quantification of 100 plasma proteins in >1500 LC-MS runs, the SD range of the retention time during continuous operation was substantially lower with the standard-flow LC-MS (<0.05 minutes) compared with the nanoflow LC-MS method (0.26–0.44 minutes). In addition, the standard-flow LC method also offered less variation in protein measurements. However, 5× more sample volume was required to achieve similar sensitivity. Two different commercial multiple reaction monitoring kits and an antibody-based multiplexing kit were used to compare the apolipoprotein measurements in a subset of samples. In general, good agreement was observed between the 2 multiple reaction monitoring kits, but some of the multiple reaction monitoring–based measurements differed from antibody-based assays.

Conclusions—
The multiplexing capability of LC-MS combined with a standard-flow method increases throughput and reduces the costs of large-scale protein measurements in epidemiological cohorts, but protein rather than peptide standards will be required for defined absolute proteoform quantification.
Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease
Authors: Paludan-Müller Christian , Ahlberg Gustav , Ghouse Jonas , Svendsen Jesper H. , Haunsø Stig , Olesen Morten S. 
Published: December 2017

Background—
De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database.

Methods and results—
We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic.

Conclusions—
We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously.
Association of Atrial Fibrillation and Oral Anticoagulant Use With Perioperative Outcomes After Major Noncardiac Surgery
Authors: Ge Yin , Ha Andrew C. T. , Atzema Clare L. , Abdel‐Qadir Husam M. , Fang Jiming , Austin Peter C. , Wijeysundera Duminda N. , Lee Douglas S. 
Published: December 2017

Background
We examined the association of atrial fibrillation (AF) and oral anticoagulant use with perioperative death and bleeding among patients undergoing major noncardiac surgery.

Methods and Results
A population‐based study of patients aged 66 years and older who underwent elective (n=87 257) or urgent (n=35 930) noncardiac surgery in Ontario, Canada (April 2012 to March 2015) was performed. Outcomes were compared between AF groups using inverse probability of treatment weighting using the propensity score. Of 4612 urgent surgical patients with AF, treatments before surgery included warfarin (n=1619), a direct oral anticoagulant (DOAC) (n=729), and no anticoagulation (n=2264). After urgent surgery, the death rate within 30 days was significantly higher in patients with AF compared with patients with no AF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.12–1.45). In contrast, among 4769 elective surgical patients with AF treated with warfarin (n=1453), a DOAC (n=1165), or no anticoagulation (n=2151), prior AF was not associated with higher mortality. Comparing patients with AF who were or were not anticoagulated, there was no difference in 30‐day mortality after urgent (HR, 0.95; 95% CI, 0.79–1.14) or elective (HR, 0.65; 95% CI, 0.38–1.09) surgery. There was no difference in 30‐day mortality between patients with AF treated with a DOAC or warfarin after urgent (HR, 0.91; 95% CI, 0.70–1.18) or elective (HR, 1.64; 95% CI, 0.77–3.53) surgery. Bleeding and thromboembolic rates did not differ significantly among patients with AF prescribed a DOAC or warfarin.

Conclusions
Prior AF was associated with 30‐day mortality among patients undergoing urgent surgery. In patients with AF, neither the preoperative use of oral anticoagulants, nor the type of agent (either a DOAC or warfarin) were associated with the rate of 30‐day mortality.
Sex differences in the relationship between prolactin levels and impaired processing speed in early psychosis
Authors: Montalvo Itziar , Nadal Roser , Armario Antonio , Gutiérrez-Zotes Alfonso , Creus Marta , Cabezas Ángel , Solé Montse , Algora Maria José , Sánchez-Gistau Vanessa , Vilella Elisabet , Labad Javier 
Published: December 2017

Introduction: Hyperprolactinaemia is commonly observed in people with psychotic disorders due to D2 receptor blockade by antipsychotic drugs, although it may also exist in drug-naïve patients with first-episode psychosis. Recent studies suggest that hyperprolactinaemia may have a negative impact on cognitive function in people with early psychosis. We aimed to explore whether there are sex differences in the association between prolactin levels and cognitive performance in early psychosis patients. Methods: We studied 60 young patients with early psychosis (aged 18–35 years, 35% females) and a sex- and age-matched control group of 50 healthy subjects. Cognitive assessment was performed with the MATRICS Consensus Cognitive Battery. Prolactin, total cortisol, follicular-stimulating hormone, luteal hormone and sex steroids (testosterone in men, oestradiol and progesterone in women) were measured in plasma. Salivary cortisol was measured at different sampling times (awakening response, 10:00 and 23:00). Psychopathological status was assessed, and antipsychotic treatment was registered. Multiple linear regression analyses were used to explore the relationship between prolactin and cognitive tasks while adjusting for covariates. Results: Prolactin levels were associated with impaired processing speed in men, and this association was independent of cortisol and testosterone. In women, prolactin levels were not associated with processing speed tasks, although we observed a negative effect of prolactin on verbal learning and spatial working memory in female healthy subjects. The male-dependent effect maintained its significance after adjusting for education status, antipsychotic treatment and negative symptoms. Conclusion: Our study demonstrates that the previously reported association between high prolactin levels and impaired cognitive processes in early psychosis is restricted to men.
Altered cerebellar functional connectivity in remitted bipolar disorder: A resting-state functional magnetic resonance imaging study
Authors: Wang Ying , Zhong Shuming , Chen Guanmao , Liu Tao , Zhao Lianping , Sun Yao , Jia Yanbin , Huang Li 
Published: December 2017

Objectives: Several recent studies have reported a strong association between the cerebellar structural and functional abnormalities and psychiatric disorders. However, there are no studies to investigate possible changes in cerebellar functional connectivity in bipolar disorder. This study aimed to examine the whole-brain functional connectivity pattern of patients with remitted bipolar disorder II, in particular in the cerebellum. Methods: A total of 25 patients with remitted bipolar disorder II and 25 controls underwent resting-state functional magnetic resonance imaging and neuropsychological tests. Voxel-wise whole-brain connectivity was analyzed using a graph theory approach: functional connectivity strength. A seed-based resting-state functional connectivity analysis was further performed to investigate abnormal functional connectivity pattern of those regions with changed functional connectivity strength. Results: Remitted bipolar disorder II patients had significantly decreased functional connectivity strength in the bilateral posterior lobes of cerebellum (mainly lobules VIIb/VIIIa). The seed-based functional connectivity analyses revealed decreased functional connectivity between the right posterior cerebellum and the default mode network (i.e. right posterior cingulate cortex/precuneus and right superior temporal gyrus), bilateral hippocampus, right putamen, left paracentral lobule and bilateral posterior cerebellum and decreased functional connectivity between the left posterior cerebellum and the right inferior parietal lobule and bilateral posterior cerebellum in patients with remitted bipolar disorder II. Conclusion: Our results suggest that cerebellar dysconnectivity, in particular distributed cerebellar–cerebral functional connectivity, might be associated with the pathogenesis of bipolar disorder.
Adenotonsillectomy for Obstructive Sleep Apnea and Quality of Life: Systematic Review and Meta‐analysis
Authors: Todd Cameron A. , Bareiss Anna K. , McCoul Edward D. , Rodriguez Kimsey H. 
Published: December 2017

ObjectiveTo determine the impact of adenotonsillectomy on the quality of life of pediatric patients with obstructive sleep apnea (OSA) and to identify gaps in the current research.Data SourcesThe MEDLINE, EMBASE, and Cochrane databases were systematically searched via the Ovid portal on June 18, 2016, for English‐language articles.Review MethodsFull‐text articles were selected that studied boys and girls <18 years of age who underwent adenotonsillectomy for OSA or sleep‐disordered breathing and that recorded validated, quantitative quality‐of‐life outcomes. Studies that lacked such measures, performed adenotonsillectomy for indications other than OSA or sleep‐disordered breathing, or grouped adenotonsillectomy with other procedures were excluded.ResultsOf the 328 articles initially identified, 37 were included for qualitative analysis. The level of evidence was generally low. All studies involving short‐term follow‐up (≤6 months) showed improvement in quality‐of‐life scores after adenotonsillectomy as compared with preoperative values. Studies involving long‐term follow‐up (>6 months) showed mixed results. Modifications to and concurrent procedures with conventional adenotonsillectomy were also identified that showed quality‐of‐life improvements. Three studies were identified for meta‐analysis that compared pre‐ and postoperative Obstructive Sleep Apnea–18 scores. Short‐ and long‐term follow‐up versus preoperative scores showed significant improvement (P <. 001). Short‐ and long‐term scores showed no significant difference.ConclusionThis systematic review and meta‐analysis demonstrate adenotonsillectomy’s effectiveness in improving the quality of life of pediatric patients with OSA. This is well demonstrated in the short term and has strong indications in the long term.
‘The importance of planning for the future’: Burden and unmet needs of caregivers’ in advanced heart failure: A mixed methods study
Authors: McIlfatrick Sonja , Doherty Leanne C , Murphy Mary , Dixon Lana , Donnelly Patrick , McDonald Kenneth , Fitzsimons Donna 
Published: December 2017

Background: While studies have evaluated caregiver outcomes in heart failure, the burden and support needs when caring for someone with advanced heart failure at the end of life have yet to be outlined. Aim: To identify psychosocial factors associated with caregiver burden and evaluate the support needs of caregivers in advanced heart failure. Design: A sequential mixed methods study comprising two phases: (1) postal survey with advanced heart failure patients and their caregivers and (2) interviews with current and bereaved caregivers. Correlation, chi-square, t test, regression and thematic analysis were undertaken on the data. Participants: Advanced heart failure patients ( n = 112) and their caregivers ( n = 84) were recruited from secondary care settings across the United Kingdom and Ireland. For phase 2 interviews, current caregivers ( n = 20) were purposively recruited from phase 1, and bereaved caregivers ( n = 10) were purposively recruited via voluntary organisation, social media and email. Results: More than half the caregivers (53%) had levels of distress associated with depression (Zarit Burden score >24). Caregiver depression score, preparedness for caregiving and patients’ depression score predicted caregiver burden. Qualitative analysis identified an overarching theme of lack of future care planning and four subthemes: (1) seeking emotional support from someone who understands, (2) want information on prognostication, (3) lack of knowledge on how to and where to get support and (4) require knowledge on what to expect at the end of life. Conclusion: Caregivers have unmet needs and feel unprepared for the future. Implementation of future care planning by clinical teams should address patient and caregiver support needs and in turn alleviate caregiver burden.
Growing the IBCLC Workforce: A Florida Needs Assessment
Authors: Eden Aimee R. , Anstey Erica H. , Orriola Deidre 
Published: December 2017

Background: Florida has fewer International Board Certified Lactation Consultants (IBCLCs) per 1,000 live births than the national average. An important strategy to support breastfeeding entails creating opportunities to prepare and train IBCLCs from underrepresented groups. However, it can be difficult for individuals to access lactation education and gain clinical experience necessary to become an IBCLC. Research aim: The Building a Better Breastfeeding Network project was a needs assessment designed to assess the interest in an IBCLC training program in Florida and perceived barriers and facilitators to completing such a program. Methods: An online survey was distributed via email to non-IBCLC students and maternal and child healthcare workers in Florida. Microsoft Excel was used to complete descriptive analyses. Results: Surveys were initiated by 1,939 eligible individuals from diverse racial and ethnic backgrounds across the state, 86% of whom responded that they would be possibly to very interested in an IBCLC training program. For those interested, cost was perceived as a potential barrier to enrolling in a program, but flexible course schedules and scholarship or financial aid availability would further attract participants. More than half were interested in working with underserved populations or in low-resource settings, but Black and Hispanic participants were significantly more likely to express interest in working in those settings. Conclusion: Due to the high level of interest in an IBCLC training program in Florida, a formal lactation training program may be successful in attracting diverse students, particularly if funding and program flexibility needs are met.