bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Antiviral Mechanism of an Influenza A Virus Nucleoprotein-Specific Single-Domain Antibody Fragment
Authors: Hanke Leo , Knockenhauer Kevin E. , Brewer R. Camille , van Diest Eline , Schmidt Florian I. , Schwartz Thomas U. , Ploegh Hidde L. 
Published: December 2016

ABSTRACTAlpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, αNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of αNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/αNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies.IMPORTANCEInfluenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and provide a well-characterized tool to further study them.
Functional Characterization of Pneumocystis carinii Inositol Transporter 1
Authors: Cushion Melanie T. , Collins Margaret S. , Sesterhenn Thomas , Porollo Aleksey , Vadukoot Anish Kizhakkekkara , Merino Edward J. 
Published: December 2016

ABSTRACT

Fungi in the genus
Pneumocystis
live in the lungs of mammals, where they can cause a fatal pneumonia (PCP [

P
neumo
c
ystis

p
neumonia]) in hosts with compromised immune systems. The absence of a continuous
in vitro
culture system for any species of
Pneumocystis
has led to limited understanding of these fungi, especially for the discovery of new therapies. We recently reported that
Pneumocystis carinii
,
Pneumocystis murina
, and most significantly,
Pneumocystis jirovecii
lack both enzymes necessary for
myo-
inositol biosynthesis but contain genes with homologies to fungal
myo
-inositol transporters. Since
myo
-inositol is essential for eukaryotic viability, the primary transporter, ITR1, was functionally and structurally characterized in
P. carinii
. The predicted structure of
P. carinii
ITR1 (PcITR1) contained 12 transmembrane alpha-helices with intracellular C and N termini, consistent with other inositol transporters. The apparent
K

m

was 0.94 ± 0.08 (mean ± standard deviation), suggesting that
myo-
inositol transport in
P. carinii
is likely through a low-affinity, highly selective transport system, as no other sugars or inositol stereoisomers were significant competitive inhibitors. Glucose transport was shown to use a different transport system. The
myo
-inositol transport was distinct from mammalian transporters, as it was not sodium dependent and was cytochalasin B resistant. Inositol transport in these fungi offers an attractive new drug target because of the reliance of the fungi on its transport, clear differences between the mammalian and fungal transporters, and the ability of the host to both synthesize and transport this critical nutrient, predicting low toxicity of potential inhibitors to the fungal transporter.

IMPORTANCE
myo
-Inositol is a sugarlike nutrient that is essential for life in most organisms. Humans and microbes alike can obtain it by making it, which involves only 2 enzymes, by taking it from the environment by a transport process, or by recycling it from other cellular constituents. Inspection of the genomes of the pathogenic fungi of the genus
Pneumocystis
showed that these pneumonia-causing parasites could not make
myo
-inositol, as they lacked the 2 enzymes. Instead, we found evidence of inositol transporters, which would import the sugar from the lungs where the fungi reside. In the present report, we characterized the transport of
myo
-inositol in the fungus and found that the transporter was highly selective for
myo
-inositol and did not transport any other molecules. The transport was distinct from that in mammalian cells, and since mammals can both make and transport
myo
-inositol, while
Pneumocystis
fungi must transport it, this process offers a potential new drug target.
Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
Authors: Tam Kayan , Schultz Megan , Reyes-Robles Tamara , Vanwalscappel Bénédicte , Horton Joshua , Alonzo Francis , Wu Beili , Landau Nathaniel R. , Torres Victor J. 
Published: December 2016

ABSTRACT

Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by
Staphylococcus aureus
that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5.

IMPORTANCE
The bicomponent pore-forming toxins are thought to play a vital role in the success of
Staphylococcus aureus
as a mammalian pathogen. One of the leukocidins, LukED, is necessary and sufficient for lethality in mice. At the molecular level, LukED causes cell lysis through binding to specific cellular receptors. CCR5 is one of the receptors targeted by LukED and is the major coreceptor for CCR5-tropic HIV-1. While the molecular interaction of CCR5 and HIV-1 is well characterized, the means by which LukED interacts with CCR5 is less clear. In this study, we demonstrated that receptor specificity is conferred through unique interactions between key domains on CCR5 and LukE. Although HIV-1 and LukED target the same receptor, our data demonstrated that they interact with CCR5 differently, highlighting the molecular complexity of host-pathogen interactions.
Is frequent attendance of longer duration related to less transient episodes of care? A retrospective analysis of transient and chronic episodes of care
Authors: Smits Frans T , Brouwer Henk J , Schene Aart H , van Weert Henk C P M , ter Riet Gerben 
Published: December 2016

ObjectivesFrequent attenders (FAs) suffer more and consult general practitioners (GPs) more often forchronicphysical and psychiatric illnesses, social difficulties and distress than non-FAs. However, it is unclear to what extent FAs presenttransientepisodes of care (TECs) compared with non-FAs.DesignRetrospective analysis of all episodes of care (ECs) in 15 116 consultations in 1 year. Reasons for encounter (RFEs) linked to patients’ problem lists were defined as chronic ECs (CECs), other episodes as TECs.Setting1 Dutch urban primary healthcare centre served by 5 GPs.ParticipantsAll 5712 adult patients were enlisted between 2007 and 2009. FAs were patients whose attendance rate ranked within the top decile of their sex and age group in at least one of the years between 2007 and 2009.Outcome measuresNumber of RFEs linked to TECs/CECs for non-FAs and 1-year (1yFAs), 2-year (2yFAs) and 3-year FAs (3yFAs), and the adjusted effect of frequent attendance of different duration on the number of TECs.ResultsThe average number of RFEs linked to TECs (non-FAs 1.4; 3yFAs 7.3) and to CECs (non-FAs 0.9; 3yFAs 6.2) increased substantially with the duration of frequent attendance. The ratio of TECs to all ECs differed little for FAs (52–54%) and non-FAs (64%). Compared with non-FAs, the adjusted additional number of TECs was 3.4 (95% CI 3.2 to 3.7, 1yFAs), 6.6 (95% CI 6.1 to 7.0, 2yFAs) and 9.4 (95% CI 8.8 to 10.1, 3yFAs).ConclusionsFAs present more TECs and CECs with longer duration of frequent attendance. The constant ratio of TECs might be a sign of a low threshold for FAs to consult their GP. The large numbers of TECs in FAs might be associated with their high level of anxiety and low mastery. The consultation pattern of FAs may best be characterised by describing both TECs and CECs.
Assessment of a web-based Guided Self-Determination intervention for adults with type 2 diabetes in general practice: a study protocol
Authors: Karlsen Bjørg , Oftedal Bjørg , Stangeland Lie Silje , Rokne Berit , Peyrot Mark , Zoffmann Vibeke , Graue Marit 
Published: December 2016

IntroductionSelf-management is deemed the cornerstone in overall diabetes management. Web-based self-management interventions have potential to support adults with type 2 diabetes (T2DM) in managing their disease. Owing to somewhat ambiguous results of such interventions, interventions should be theory-based and incorporate well-defined counselling methods and techniques for behavioural change. This study is designed to assess the effectiveness of a theory-driven web-based Guided Self-Determination (GSD) intervention among adults with T2DM in general practice to improve diabetes self-management behaviours and glycosylated haemoglobin (HbA1c).Methods and analysisA complex intervention design based on the framework of the UK Medical Research Council is employed as a guide for developing the intervention, assessing its feasibility and evaluating its effectiveness. The study consists of three phases: (1) the modelling phase adapting the original GSD programme for adults with T2DM, using a qualitative design, (2) feasibility assessment of the adapted intervention on the web, employing qualitative and quantitative methods and (3) evaluating the effectiveness of the intervention on diabetes self-management behaviours and HbA1c, using a quasi-experimental design. The first phase, which is completed, and the second phase, which is underway, will provide important information about the development of the intervention and its acceptability, whereas the third phase will assess the effectiveness of this systematically developed intervention.Ethics and disseminationThe Norwegian Regional Committee for Medical and Health Research Ethics (REK west number 2015/60) has approved the study design. Patients recruited in the different phases will fill out an informed consent form prior to inclusion and will be guaranteed anonymity and the right to withdraw from the study at any time. The results of the study will be published in peer-reviewed journals, electronically and in print, and presented at research conferences.Trial registration number:NCT02575599.
Retrospective cohort study of usage patterns of epidural injections for spinal pain in the US fee-for-service Medicare population from 2000 to 2014
Authors: Manchikanti Laxmaiah , Pampati Vidyasagar , Hirsch Joshua A 
Published: December 2016

ObjectiveTo assess the usage patterns of epidural injections for chronic spinal pain in the fee-for-service (FFS) Medicare population from 2000 to 2014 in the USA.DesignA retrospective cohort.MethodsThe descriptive analysis of the administrative database from Centers for Medicare and Medicaid Services (CMS) Physician/Supplier Procedure Summary (PSPS) master data from 2000 to 2014 was performed. The guidance from Strengthening the Reporting of Observational studies in Epidemiology (STROBE) was applied. Analysis included multiple variables based on the procedures, specialties and geography.ResultsOverall epidural injections increased 99% per 100 000 Medicare beneficiaries with an annual increase of 5% from 2000 to 2014. Lumbar interlaminar and caudal epidural injections constituted 36.2% of all epidural injections, with an overall decrease of 2% and an annual decrease of 0.2% per 100 000 Medicare beneficiaries. However, lumbosacral transforaminal epidural injections increased 609% with an annual increase of 15% from 2000 to 2014 per 100 000 Medicare population.ConclusionsUsage of epidural injections increased from 2000 to 2014, with a decline thereafter. However, an escalating growth has been seen for lumbosacral transforaminal epidural injections despite numerous reports of complications and regulations to curb the usage of transforaminal epidural injections.
Traditional Chinese acupuncture versus minimal acupuncture for mild-to-moderate knee osteoarthritis: a protocol for a randomised, controlled pilot trial
Authors: Sun Ning , Shi Guang-Xia , Tu Jian-Feng , Li Yong-Ting , Zhang Li-Wen , Cao Yan , Du Yi , Zhao Jing-Jie , Xiong Da-Chang , Hou Hai-Kun , Liu Cun-Zhi 
Published: December 2016

IntroductionKnee osteoarthritis (KOA) is one of the most common musculoskeletal disorders. Acupuncture is a popular form of complementary medicine for musculoskeletal conditions, although the evidence is inconclusive. Our objective is to evaluate the efficacy of traditional Chinese acupuncture for pain relief and function improvement in mild-to-moderate knee osteoarthritis (TCAKOA) participants.Methods/analysis42 patients will be recruited who have been diagnosed with mild-to-moderate KOA and randomly allocated in equal proportions to traditional Chinese acupuncture or minimal acupuncture. They will receive acupuncture for 24 sessions over 8 weeks. The primary end point is success rate, which will be calculated according to a change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain and function scores at 8 weeks. Secondary end points include pain and function measurement, global change, the quality of life and the use of non-steroidal anti-inflammatory drugs (Celebrex, Pfizer) at 8, 16 and 26 weeks.Ethics and disseminationEthical approval of this study has been granted by the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University (permission number: 2016BL-010-02). Written informed consent will be obtained from all participants. Outcomes of the trial will be disseminated through peer-reviewed publications.Trial registration numberISRCTN14016893; Pre-results.
Inbox Messaging: an effective tool for minimizing non-urgent paging related interruptions in hospital medicine provider workflow
Authors: Ferguson Alice , Aaronson Barry , Anuradhika Anuradhika 
Published: December 2016

Communication is one of the foundations on which safe, high quality care is built.1, 3, 6, 17, 20The nature of hospital medicine requires that nurses and providers be efficient and effective in communicating with multiple disciplines.17This need for timely communication must continually be balanced with the need to minimize interruptions in workflow.1,2 3,4,6,7,9,13,15,17,18Interruptions not only lead to distraction, they also add inefficiency to the care process and have been shown to contribute to an increased risk of medical error.2,3,4,7,17,18A major source of interruptions are pagers that emit an audible tone with each message received.3,9,10,17,18This interruptive nature makes pagers a less-than-ideal tool for communicating non-urgent (address within one hour) messages received.3,9,10,17,18In addition to increasing interruptions, pagers do not facilitate closed loop communication, another feature that has been shown to improve safety.14,17,25Inbox Messaging is intended to provide a less disruptive closed-loop method of communication for non-urgent messages.Inbox Messaging is an interface within the electronic health record (EHR) that functions similarly to e-mail. A multi-disciplinary communication workgroup identified this interface as having potential to not only decrease interruptions, but to also facilitate closed-loop communication. Inbox is currently utilized between the hours of 0700 and 1800 for non-urgent nurse-provider communication about patients on the hospital medicine service. The number of RN non-urgent pages per day was 103 (SD=19, n=97) prior to the Inbox intervention, with a significant decrease (p<.001) during follow-up to 38 (SD=14, n=354) pages per day. At the same time, the number of messages per day increased from 0 to 80 (SD=20, n=354) messages during follow-up. As desired, the mean number of RN urgent pages was unchanged from 13 per day to 13 per day (p=.52).Cerner Inbox Messaging decreases the frequency of non-urgent pager-related interruptions in workflow.
Interventional management of high-flow craniofacial vascular malformations: a database analysis and review of the literature
Authors: Dabus Guilherme , Linfante Italo , Benenati James , Perlyn Chad A , Martínez-Galdámez Mario 
Published: December 2016

BackgroundHigh-flow craniofacial vascular malformations are uncommon, locally aggressive lesions that pose a therapeutic challenge.ObjectiveTo report our experience with the treatment of high-flow craniofacial vascular malformations.MethodsAfter institutional review board approval was obtained, the neurointerventional databases of two institutions were retrospectively reviewed for vascular malformations from October 2010 to June 2015. All patients who had been treated for a high-flow craniofacial vascular malformation were included in the analysis. Clinical presentation, location, type, agent and techniques used, procedural complications, and clinical and imaging follow-up were included in the analysis.ResultsEighteen patients (12 female and 6 male) harboring 21 high-flow vascular malformations met the inclusion criteria in our study. All patients were symptomatic. One patient had two separated arteriovenous malformations (AVMs) (one nasal and the other forehead/scalp), and one patient had three separated scalp lesions. One patient with a nasal AVM had capillary malformation-AVM syndrome. Overall, 13 AVM and 8 arteriovenous fistuli were treated in 31 targeted embolization procedures (ranging from 1 procedure to 4 procedures, mean 1.7 procedures). Onyx was the predominant agent used in 25 procedures. In 31 procedures, 1 procedural complication (skin ulceration) occurred. At the end of the last treatment session 14 of the 21 lesions were cured. Symptomatic control was achieved in all cases, with resolution or significant improvement of the symptoms (mean follow-up of 10 months).ConclusionsHigh-flow craniofacial vascular malformations can be successfully managed with interventional techniques.
Interaction between gravity-driven listric normal fault linkage and their hanging-wall rollover development: a case study from the western Niger Delta, Nigeria
Authors: Fazlikhani Hamed , Back Stefan , Kukla Peter A. , Fossen Haakon 
Published: December 2016

Abstract
Rollover is the folding of the hanging-wall sedimentary record in response to slip on listric normal faults, and is a common feature of sediment-rich, gravity-driven tectonic provinces. Rollovers have been extensively studied by means of geometrical reconstruction, and numerical and analogue modelling. However, the detailed interaction between the kinematics of bounding listric normal faults and their hanging-wall deformation is not yet fully understood. In this study, we use 3D seismic-reflection data from the Forcados-Yokri area, western Niger Delta, Nigeria, to study the lateral linkage and landwards backstepping history of an array of listric normal faults, particularly focusing on their influence on the development and evolution of hanging-wall rollovers. Five individual, partly overlapping rollover structures have been studied with respect to their relative initiation and decay time, their spatial distribution, and their relationship to the tectonic history of their respective bounding faults. We demonstrate that the studied rollovers are highly dependent on the development of their bounding faults in terms of initiation time, lateral linkage, internal structural development and decay. Fault–rollover interaction is dynamic and changes through time depending on the temporal evolution of listric faults. Four genetic types of fault–rollover interaction were identified in this study: (1) the rotation of a rollover–crestal-collapse system, controlled by a changing lateral bounding-fault orientation during fault growth; (2) a stepwise shift of rollover–crestal-collapse systems associated with rollover abandonment, controlled by the initiation of a new fault in the footwall of an older structure; (3) a gradual shift of successive rollovers controlled by branching main faults; and (4) a general landwards and upwards migration of crestal-collapse faults within a rollover above stationary listric main faults.
Desynchronization does not contribute to intracortical inhibition and facilitation: a paired-pulse paradigm study combined with TST
Authors: Caranzano L. , Stephan M. A. , Herrmann F. R. , Benninger D. H. 
Published: December 2016

The paired-pulse (PP) transcranial magnetic stimulation (TMS) paradigms allow the exploration of the motor cortex physiology. The triple stimulation technique (TST) improves conventional TMS by reducing effects of desynchronization of motor neuron discharges allowing a precise evaluation of the corticospinal conduction. The objective of our study was to explore PP TMS paradigms combined with the TST to study whether the desynchronization contributes to these phenomena and whether the combined TMS-TST protocol could improve the consistency of responses. We investigated the PP paradigms of short intracortical inhibition (SICI) with 2 ms interstimulus interval (ISI) and of intracortical facilitation (ICF) with 10 ms ISI in 22 healthy subjects applying either conventional TMS alone or combined with the TST protocol. The results of the PP paradigms combined with the TST of SICI and ICF do not differ from those with conventional TMS. However, combining the PP paradigm with the TST reduces their variability. These results speak against a contribution of the desynchronization of motor neuron discharges to the PP paradigms of SICI and ICF. Combining the PP TMS paradigm with the TST may improve their consistency, but the interindividual variability remains such that it precludes their utility for clinical practice. NEW & NOTEWORTHY Combining the triple stimulation technique with the paired-pulse stimulation paradigm improves the consistency of short intracortical inhibition and facilitation and could be useful in research, but the interindividual variability precludes their utility for clinical practice. Our findings do not suggest that desynchronization of descending discharges following transcranial magnetic stimulation contributes to short intracortical inhibition or intracortical facilitation.