bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urea retranslocation from senescing Arabidopsis leaves is promoted by DUR3‐mediated urea retrieval from leaf apoplast
Authors: Bohner Anne , Kojima Soichi , Hajirezaei Mohammad , Melzer Michael , von Wirén Nicolaus 
Published: December 2014

SummaryIn plants, urea derives either from root uptake or protein degradation. Although large quantities of urea are released during senescence, urea is mainly seen as a short‐lived nitrogen (N) catabolite serving urease‐mediated hydrolysis to ammonium. Here, we investigated the roles of DUR3 and of urea in N remobilization. During natural leaf senescence urea concentrations and DUR3 transcript levels showed a parallel increase with senescence markers like ORE1 in a plant age‐ and leaf age‐dependent manner. Deletion of DUR3 decreased urea accumulation in leaves, whereas the fraction of urea lost to the leaf apoplast was enhanced. Under natural and N deficiency‐induced senescence DUR3 promoter activity was highest in the vasculature, but was also found in surrounding bundle sheath and mesophyll cells. An analysis of petiole exudates from wild‐type leaves revealed that N from urea accounted for >13% of amino acid N. Urea export from senescent leaves further increased in ureG‐2 deletion mutants lacking urease activity. In the dur3 ureG double insertion line the absence of DUR3 reduced urea export from leaf petioles. These results indicate that urea can serve as an early metabolic marker for leaf senescence, and that DUR3‐mediated urea retrieval contributes to the retranslocation of N from urea during leaf senescence.
Effect of tiletamine–zolazepam on the intraocular pressure of the dog
Authors: Jang Min , Park Sangwan , Son Won‐gyun , Jo Sang‐min , Hwang Hyeshin , Seo Kangmoon , Lee Inhyung 
Published: November 2014

AbstractObjectiveTo determine the effect of tiletamine–zolazepam (TZ) on canine intraocular pressure (IOP).Animals studiedSix healthy dogs without ocular abnormalities were used in this study.ProceduresThe study was carried out as a crossover experimental trial with a 7‐day interval between treatments. TZ combination was administered intravenously (IV) at a dose of 5, 10, and 20 mg/kg (TZ5, TZ10, and TZ20, respectively). Following preanesthetic baseline readings of IOP, each dog received IV TZ and then the IOP values were measured every 10 min for 40 min in all treatments.ResultsThe baseline IOP values (mean ± standard deviation) for TZ5, TZ10, and TZ20 were 12.7 ± 0.8, 14.4 ± 1.2, and 15.3 ± 1.7 mmHg, and each IOP changed to 11.1 ± 1.1, 13.1 ± 1.4 and 13.5 ± 1.7 mmHg after intravenous administration of each TZ treatment, respectively. However, there were no statistical differences between baseline and post‐treatment values.ConclusionsThe TZ combination had no clinically significant effect on IOP of the dog. This could be an option for induction or surgical procedures in dogs with ophthalmic problems when an increase in IOP is undesirable.
Semiautomatic registration of 3D transabdominal ultrasound images for patient repositioning during postprostatectomy radiotherapy
Authors: Presles Benoît , Fargier‐Voiron Marie , Biston Marie‐Claude , Lynch Rod , Munoz Alexandre , Liebgott Hervé , Pommier Pascal , Rit Simon , Sarrut David 
Published: December 2014

Purpose:The aim of the present work is to propose and evaluate registration algorithms of three‐dimensional (3D) transabdominal (TA) ultrasound (US) images to setup postprostatectomy patients during radiation therapy.Methods:Three registration methods have been developed and evaluated to register a reference 3D‐TA‐US image acquired during the planning CT session and a 3D‐TA‐US image acquired before each treatment session. The first method (method A) uses only gray value information, whereas the second one (method B) uses only gradient information. The third one (method C) combines both sets of information. All methods restrict the comparison to a region of interest computed from the dilated reference positioning volume drawn on the reference image and use mutual information as a similarity measure. The considered geometric transformations are translations and have been optimized by using the adaptive stochastic gradient descent algorithm. Validation has been carried out using manual registration by three operators of the same set of image pairs as the algorithms. Sixty‐two treatment US images of seven patients irradiated after a prostatectomy have been registered to their corresponding reference US image. The reference registration has been defined as the average of the manual registration values. Registration error has been calculated by subtracting the reference registration from the algorithm result. For each session, the method has been considered a failure if the registration error was above both the interoperator variability of the session and a global threshold of 3.0 mm.Results:All proposed registration algorithms have no systematic bias. Method B leads to the best results with mean errors of −0.6, 0.7, and −0.2 mm in left–right (LR), superior–inferior (SI), and anterior–posterior (AP) directions, respectively. With this method, the standard deviations of the mean error are of 1.7, 2.4, and 2.6 mm in LR, SI, and AP directions, respectively. The latter are inferior to the interoperator registration variabilities which are of 2.5, 2.5, and 3.5 mm in LR, SI, and AP directions, respectively. Failures occur in 5%, 18%, and 10% of cases in LR, SI, and AP directions, respectively. 69% of the sessions have no failure.Conclusions:Results of the best proposed registration algorithm of 3D‐TA‐US images for postprostatectomy treatment have no bias and are in the same variability range as manual registration. As the algorithm requires a short computation time, it could be used in clinical practice provided that a visual review is performed.
If Exercise is Medicine, Where is Exercise in Medicine? Review of U.S. Medical Education Curricula for Physical Activity-Related Content
Authors: Cardinal Bradley J. , Park Eugene A. , Kim MooSong , Cardinal Marita K. 
Published: December 2014

Background:This study provides an update on the amount and type of physical activity education occurring in medical education in the United States in 2013. It is the first study to do so since 2002.Methods:Applying content analysis methodology, we reviewed all accessible accredited doctor of medicine and doctor of osteopathic medicine institutions’ websites for physical activity education related coursework (N = 118 fully accessible; 69.41%).Results:The majority of institutions did not offer any physical activity education–related courses. When offered, they were rarely required. Courses addressing sports medicine and exercise physiology were offered more than courses in other content domains. Most courses were taught using a clinical approach. No differences were observed between MD and DO institutions, or between private and public institutions.Conclusions:More than one-half of the physicians trained in the United States in 2013 received no formal education in physical activity and may, therefore, be ill-prepared to assist their patients in a manner consistent with Healthy People 2020, the National Physical Activity Plan, or the Exercise is Medicine initiative. The Bipartisan Policy Center, American College of Sports Medicine, and the Alliance for a Healthier Generation called for a reversal of this situation on June 23, 2014.
Synergistic Effect of Nitazoxanide with Neuraminidase Inhibitors against Influenza A Viruses
In Vitro
Authors: Belardo Giuseppe , Cenciarelli Orlando , La Frazia Simone , Rossignol Jean Francois , Santoro M. Gabriella 
Published: December 2014

ABSTRACT

The emergence of drug-resistant influenza A virus (IAV) strains represents a serious threat to global human health and underscores the need for novel approaches to anti-influenza chemotherapy. Combination therapy with drugs affecting different IAV targets represents an attractive option for influenza treatment. We have previously shown that the thiazolide anti-infective nitazoxanide (NTZ) inhibits H1N1 IAV replication by selectively blocking viral hemagglutinin maturation. Herein we investigate the anti-influenza activity of NTZ against a wide range of human and avian IAVs (H1N1, H3N2, H5N9, H7N1), including amantadine-resistant and oseltamivir-resistant strains,
in vitro
. We also investigate whether therapy with NTZ in combination with the neuraminidase inhibitors oseltamivir and zanamivir exerts synergistic, additive, or antagonistic antiviral effects against influenza viruses. NTZ was effective against all IAVs tested, with 50% inhibitory concentrations (IC
50
s) ranging from 0.9 to 3.2 μM, and selectivity indexes (SIs) ranging from >50 to >160, depending on the strain and the multiplicity of infection (MOI). Combination therapy studies were performed in cell culture-based assays using A/Puerto Rico/8/1934 (H1N1), A/WSN/1933 (H1N1), or avian A/chicken/Italy/9097/1997 (H5N9) IAVs; dose-effect analysis and synergism/antagonism quantification were performed using isobologram analysis according to the Chou-Talalay method. Combination index (CI) analysis indicated that NTZ and oseltamivir combination treatment was synergistic against A/Puerto Rico/8/1934 (H1N1) and A/WSN/1933 (H1N1) IAVs, with CI values ranging between 0.39 and 0.63, independently of the MOI used. Similar results were obtained when NTZ was administered in combination with zanamivir (CI = 0.3 to 0.48). NTZ-oseltamivir combination treatment was synergistic also against the avian A/chicken/Italy/9097/1997 (H5N9) IAV (CI = 0.18 to 0.31). Taken together, the results suggest that regimens that combine neuraminidase inhibitors and nitazoxanide exert synergistic anti-influenza effects.
Mechanism of Action for Respiratory Syncytial Virus Inhibitor RSV604
Authors: Challa SreeRupa , Scott Andrew D. , Yuzhakov Olga , Zhou Ying , Tiong-Yip Choi Lai , Gao Ning , Thresher Jason , Yu Qin 
Published: December 2014

ABSTRACT

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children and other high-risk populations. RSV nucleoprotein (N) is essential for virus assembly and replication as part of the viral ribonucleoprotein (RNP) complex. RSV604 was a putative N inhibitor in phase 2 clinical trials whose molecular mechanism of action (MoA) was not well understood. This study investigated the cell line-dependent potency of RSV604 and demonstrated its direct binding to the N protein
in vitro
, providing the first evidence of direct target engagement for this class of inhibitors reported to date. The affinity of RSV604 N binding was not affected by RSV604 resistance mutations in the N protein. RSV604 engaged in two different MoAs in HeLa cells, inhibiting both RSV RNA synthesis and the infectivity of released virus. The lack of inhibition of viral RNA synthesis in some cell lines explained the cell-type-dependent potency of the inhibitor. RSV604 did not inhibit viral RNA synthesis in the RSV subgenomic replicon cells or in the cell-free RNP assay, suggesting that it might act prior to viral replication complex formation. RSV604 did not alter N protein localization in the infected cells. Taken together, these results provide new insights leading to an understanding of the MoAs of RSV604 and other similar N inhibitors.
Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa
Authors: Winkler Marisa L. , Papp-Wallace Krisztina M. , Hujer Andrea M. , Domitrovic T. Nicholas , Hujer Kristine M. , Hurless Kelly N. , Tuohy Marion , Hall Geraldine , Bonomo Robert A. 
Published: December 2014

ABSTRACT

Pseudomonas aeruginosa
is a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. Investigating a collection of β-lactam-resistant
P. aeruginosa
clinical isolates from a decade ago, we uncovered resistance to ceftazidime-avibactam, a novel β-lactam/β-lactamase inhibitor combination. The isolates were systematically analyzed through a variety of genetic, biochemical, genomic, and microbiological methods to understand how resistance manifests to a unique drug combination that is not yet clinically released. We discovered that avibactam was able to inactivate different AmpC β-lactamase enzymes and that
bla
PDC
regulatory elements and penicillin-binding protein differences did not contribute in a major way to resistance. By using carefully selected combinations of antimicrobial agents, we deduced that the greatest barrier to ceftazidime-avibactam is membrane permeability and drug efflux. To overcome the constellation of resistance determinants, we show that a combination of antimicrobial agents (ceftazidime/avibactam/fosfomycin) targeting multiple cell wall synthetic pathways can restore susceptibility. In
P. aeruginosa
, efflux, as a general mechanism of resistance, may pose the greatest challenge to future antibiotic development. Our unexpected findings create concern that even the development of antimicrobial agents targeted for the treatment of multidrug-resistant bacteria may encounter clinically important resistance. Antibiotic therapy in the future must consider these factors.
Susceptibility Profiles of Amphotericin B and Posaconazole against Clinically Relevant Mucorales Species under Hypoxic Conditions
Authors: Maurer Elisabeth , Binder Ulrike , Sparber Manuela , Lackner Michaela , Caramalho Rita , Lass-Flörl Cornelia 
Published: December 2014

ABSTRACT

The effect of hypoxic conditions on the
in vitro
efficacy of amphotericin B and posaconazole against
Mucorales
was evaluated by defining MICs with Etest and broth microdilution and identifying minimal fungicidal concentrations (MFCs). With Etest, oxygen-dependent changes were detected, while the MIC and the MFC determined with broth microdilution remained unaltered with reduced oxygen levels. The observed differences depended on the method used.
Substrate-Induced Radical Formation in 4-Hydroxybutyryl Coenzyme A Dehydratase from Clostridium aminobutyricum
Authors: Zhang Jin , Friedrich Peter , Pierik Antonio J. , Martins Berta M. , Buckel Wolfgang 
Published: December 2014

ABSTRACT

4-Hydroxybutyryl-coenzyme A (CoA) dehydratase (4HBD) from
Clostridium aminobutyricum
catalyzes the reversible dehydration of 4-hydroxybutyryl-CoA to crotonyl-CoA and the irreversible isomerization of vinylacetyl-CoA to crotonyl-CoA. 4HBD is an oxygen-sensitive homotetrameric enzyme with one [4Fe-4S]
2+
cluster and one flavin adenine dinucleotide (FAD) in each subunit. Upon the addition of crotonyl-CoA or the analogues butyryl-CoA, acetyl-CoA, and CoA, UV-visible light and electron paramagnetic resonance (EPR) spectroscopy revealed an internal one-electron transfer to FAD and the [4Fe-4S]
2+
cluster prior to hydration. We describe an active recombinant 4HBD and variants produced in
Escherichia coli
. The variants of the cluster ligands (H292C [histidine at position 292 is replaced by cysteine], H292E, C99A, C103A, and C299A) had no measurable dehydratase activity and were composed of monomers, dimers, and tetramers. Variants of other potential catalytic residues were composed only of tetramers and exhibited either no measurable (E257Q, E455Q, and Y296W) hydratase activity or <1% (Y296F and T190V) dehydratase activity. The E455Q variant but not the Y296F or E257Q variant displayed the same spectral changes as the wild-type enzyme after the addition of crotonyl-CoA but at a much lower rate. The results suggest that upon the addition of a substrate, Y296 is deprotonated by E455 and reduces FAD to FADH·, aided by protonation from E257 via T190. In contrast to FADH·, the tyrosyl radical could not be detected by EPR spectroscopy. FADH· appears to initiate the radical dehydration via an allylic ketyl radical that was proposed 19 years ago. The mode of radical generation in 4HBD is without precedent in anaerobic radical chemistry. It differs largely from that in enzymes, which use coenzyme B
12
,
S
-adenosylmethionine, ATP-driven electron transfer, or flavin-based electron bifurcation for this purpose.
Recombinant Protein Truncation Strategy for Inducing Bactericidal Antibodies to the Macrophage Infectivity Potentiator Protein of Neisseria meningitidis and Circumventing Potential Cross-Reactivity with Human FK506-Binding Proteins
Authors: Bielecka Magdalena K. , Devos Nathalie , Gilbert Mélanie , Hung Miao-Chiu , Weynants Vincent , Heckels John E. , Christodoulides Myron 
Published: December 2014

ABSTRACT

A recombinant macrophage infectivity potentiator (rMIP) protein of
Neisseria meningitidis
induces significant serum bactericidal antibody production in mice and is a candidate meningococcal vaccine antigen. However, bioinformatics analysis of MIP showed some amino acid sequence similarity to human FK506-binding proteins (FKBPs) in residues 166 to 252 located in the globular domain of the protein. To circumvent the potential concern over generating antibodies that could recognize human proteins, we immunized mice with recombinant truncated type I rMIP proteins that lacked the globular domain and the signal leader peptide (LP) signal sequence (amino acids 1 to 22) and contained the His purification tag at either the N or C terminus (C-term). The immunogenicity of truncated rMIP proteins was compared to that of full (i.e., full-length) rMIP proteins (containing the globular domain) with either an N- or C-terminal His tag and with or without the LP sequence. By comparing the functional murine antibody responses to these various constructs, we determined that C-term His truncated rMIP (−LP) delivered in liposomes induced high levels of antibodies that bound to the surface of wild-type but not Δ
mip
mutant meningococci and showed bactericidal activity against homologous type I MIP (median titers of 128 to 256) and heterologous type II and III (median titers of 256 to 512) strains, thereby providing at least 82% serogroup B strain coverage. In contrast, in constructs lacking the LP, placement of the His tag at the N terminus appeared to abrogate bactericidal activity. The strategy used in this study would obviate any potential concerns regarding the use of MIP antigens for inclusion in bacterial vaccines.
CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection
Authors: Mahamed Deeqa A. , Toussaint Leon E. , Bynoe Margaret S. 
Published: December 2014

ABSTRACTAs an obligate intracellular pathogen, the apicomplexan parasiteToxoplasma gondiievades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ectoenzyme CD73, which generates adenosine in the extracellular matrix, were resistant to chronic toxoplasmosis after oral infection withT. gondii. Resistance in CD73 knockout mice was due to a delay in parasite differentiation in the central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine inT. gondiipathogenesis, we infected wild-type (WT) and CD73−/−mice withT. gondiicysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73−/−mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Administration of the broad-spectrum adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) protected CD73−/−mice againstT. gondii-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73−/−mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limitingT. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A2Awere more susceptible to immunopathology during intraperitoneal infection withT. gondiithan WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival.
Different Effects of Transcutaneous Electric Nerve Stimulation and Electroacupuncture at St36–st37 on the Cerebral Cortex
Authors: Kang Yu-Tien , Liao Yi-Sheng , Hsieh Ching-Liang 
Published: November 2014

Background The effects of transcutaneous electric nerve stimulation (TENS) and electroacupuncture (EA) on the cerebral cortex are largely unclear. The purpose of the present study was to investigate the effect of TENS and EA on the cerebral cortex by examining their effect on the median nerve-somatosensory evoked potentials (MN-SEPs). Methods Twenty volunteers were studied. The cortical and cervical spinal potentials were recorded by median nerve stimulation at the left wrist. Sham TENS, 2 Hz TENS and 2 Hz EA were applied to both ST36 and ST37. MN-SEPs were recorded during sham TENS, 2 Hz TENS and 2 Hz EA, with at least 1 week interval for each subject. One-way analysis of variance was used to determine the differences in latency and amplitude of the MN-SEPs observed in the stimulation and post-stimulation periods compared with baseline. Scheffe's post hoc correction was employed to identify pairwise differences. Results No differences in mean latency were found between the stimulation procedures during the stimulation and post-stimulation periods. 2 Hz EA but not sham TENS or 2 Hz TENS caused higher mean amplitudes in N20 and N30 during the stimulation and post-stimulation periods. Conclusions EA, but not TENS, induces changes in certain components of the signal.
The current provision of community-based teaching in UK medical schools: an online survey and systematic review
Authors: Lee Sandra W W , Clement Naomi , Tang Natalie , Atiomo William 
Published: December 2014

ObjectiveTo evaluate the current provision and outcome of community-based education (CBE) in UK medical schools.Design and data sourcesAn online survey of UK medical school websites and course prospectuses and a systematic review of articles from PubMed and Web of Science were conducted. Articles in the systematic review were assessed using Rossi, Lipsey and Freeman's approach to programme evaluation.Study selectionPublications from November 1998 to 2013 containing information related to community teaching in undergraduate medical courses were included.ResultsOut of the 32 undergraduate UK medical schools, one was excluded due to the lack of course specifications available online. Analysis of the remaining 31 medical schools showed that a variety of CBE models are utilised in medical schools across the UK. Twenty-eight medical schools (90.3%) provide CBE in some form by the end of the first year of undergraduate training, and 29 medical schools (93.5%) by the end of the second year. From the 1378 references identified, 29 papers met the inclusion criteria for assessment. It was found that CBE mostly provided advantages to students as well as other participants, including GP tutors and patients. However, there were a few concerns regarding the lack of GP tutors’ knowledge in specialty areas, the negative impact that CBE may have on the delivery of health service in education settings and the cost of CBE.ConclusionsDespite the wide variations in implementation, community teaching was found to be mostly beneficial. To ensure the relevance of CBE for ‘Tomorrow's Doctors’, a national framework should be established, and solutions sought to reduce the impact of the challenges within CBE.Strengths and limitations of this studyThis is the first study to review how community-based education is currently provided throughout Medical Schools in the UK. The use of Rossi, Lipsey and Freeman's method of programme evaluation means that the literature was analysed in a consistent and comprehensive way. However, a weakness is that data from the online survey was obtained from online medical school prospectuses. This means the data may be incomplete or out of date. Data in the literature review may also be skewed by publication bias.