bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of transfusion‐transmitted malaria
Authors: Owusu‐Ofori S. , Allain J.‐P. , Owusu‐Ofori A.
Published: December 2016

Transfusion‐transmitted malaria (TTM) occurs when the Plasmodium found in the transfusion recipient and corresponding blood donor are genotypically identical. All five species of Plasmodium are known to cause TTM. Transfusion transmission of Plasmodium has been estimated between 14 and 28 per cent in regions, where about a quarter to half of the population carries the parasite. The presentation and clinical severity of transfusion‐transmitted malaria may differ between malaria‐endemic and non‐endemic countries. Elements critical to outcomes in recipients include parasite load transfused, patient anti‐Plasmodium titre pretransfusion, per cent clearance of parasites and level of anti‐Plasmodium humoural immune response. Several strategies to prevent TTM include donor deferral, screening, prophylaxis and presumptive treatment and now pathogen reduction. Malaria testing is recommended for endemic countries, but there are no practical, affordable and suitably sensitive screening tests. Microscopy has limited sensitivity, whilst PCR though efficient is cost‐inhibiting. Donor screening in countries facing perennial blood shortages would drastically reduce blood availability. Practice across sub‐Saharan Africa shows no uniformity with screening. WHO advocates for presumptive antimalarial treatment of transfusion recipients in endemic countries, whilst guidelines for malaria programs require parasitological confirmation before medication. Improving safety of blood units without compromising supply in high disease burden areas may be achieved with pathogen reduction technologies applicable to whole blood and red cell concentrates. Countries with high risk for TTM inadvertently have high transfusion rates amongst young children and women and may benefit from applying such technologies to minimize the residual risk of transfusion‐transmissible agents, including malaria.
Screw migration in a 14-year-old boy with hip osteotomy; a rare cause of upper thigh hematoma
Authors: Ünal Emre
Published: December 2016

Soft tissue injury due to orthopedic hardware migration is an uncommon complication. However particularly patients who have routine physical therapy sessions for extremity contractures are at risk for vascular injury in the setting of migrated screws. Ultrasound is an efficient modality to evaluate migrated screws and adjacent soft tissue structures. As a consequence of repetitive trauma a migrated screw would eventually result in injury. Herein a case of upper thigh hematoma due to screw migration in a patient with hip osteotomy is reported.
A rare retrovesical hydatid cyst and value of transrectal ultrasonography in diagnosis: a case report and review of the literature
Authors: Unal Emre , Keles Meryem , Yazgan Sibel , Karcaaltincaba Musturay
Published: December 2016

We present a large hydatid cyst located midline and posterior to prostatic gland and seminal vesicles in an asymptomatic patient. Computed tomography (CT) scan revealed a large retrovesical mass and the transrectal ultrasonography idetified a degenerated hydatid cyst with “ball of wool’’ appearance. Although extremely rare, hydatid disease should be kept in mind in the differential diagnosis of pelvic particularly retrovesical midline masses.
Understanding the Demographic Differences in Neighborhood Walking Supports
Authors: Carlson Susan A. , Watson Kathleen B. , Paul Prabasaj , Schmid Thomas L. , Fulton Janet E.
Published: December 2016

Background:

Information about how presence and usefulness of neighborhood supports for walking differs by demographic characteristics can help guide community strategies to promote walking.

Methods:

Reported presence and usefulness of neighborhood supports (shops, transit stops, sidewalks, parks, interesting things to look at, well-lit at night, low crime rate, and cars following speed limit) were examined in 3973 U.S. adults who completed the 2014 SummerStyles survey.

Results:

Percentage reporting neighborhood supports as present ranged from 25.3% (SE = 0.8) for interesting things to 55.8% (SE = 1.0) for low crime rate. Percentage who reported a support as useful ranged from 24.6% (SE = 1.4) for transit stops to 79.0% (SE = 1.1) for sidewalks among those with the support. This percentage ranged from 13.4% (SE = 0.8) for transit stops to 52.8% (SE = 1.1) for shops among those without the support. One or more demographic differences were observed for the presence of each support, and the presence of all supports differed by education and metro status. Demographic patterns were less clear when examining usefulness and patterns often differed by support type and presence.

Conclusions:

Presence and usefulness of neighborhood supports for walking can differ by type and demographic characteristics. Recognizing these difference can help communities plan and implement strategies to promote walking.
Active Classrooms: A Cluster Randomized Controlled Trial Evaluating the Effects of a Movement Integration Intervention on the Physical Activity Levels of Primary School Children
Authors: Martin Rosemarie , Murtagh Elaine
Published: December 2016

Background:

A cluster randomized controlled trial was conducted to assess the effectiveness of the Active Classrooms intervention, which integrates movement into academic lessons, on the moderate-to-vigorous physical activity levels (MVPA) of primary school children during class-time and throughout the school day.

Methods:

Ten classroom teachers and their students aged 8 to 12 years were recruited and randomized into the Active Classrooms intervention group (n = 131students, n = 5teachers) or a delayed-treatment controlled group (n = 117students, n = 5teachers). The intervention group participated in active academic lessons taught by the classroom teacher over an 8 week period. Accelerometers were used to gather physical activity data at baseline, postintervention and at 4 months follow-up. Teachers completed a questionnaire to evaluate the program.

Results:

A significant difference for change in daily class time MVPA levels was identified between the treatment (n = 95) and control (n = 91) groups from pre- to postintervention (P < .001) and this difference was maintained at follow-up (P < .001). No significant difference emerged between the treatment and control groups for change in school day MVPA levels from pre- to postintervention (P = .52) or follow-up (P = .09). Teachers reported that they were highly satisfied with the program.

Conclusions:

Movement integration has the potential to improve physical activity levels of primary school children in the classroom.
The Thin Line: A Phenomenological Study of Mental Toughness and Decision Making in Elite High-Altitude Mountaineers
Authors: Crust Lee , Swann Christian , Allen-Collinson Jacquelyn
Published: December 2016

Mental toughness (MT) is a key psychological variable related to achievement in performance domains and perseverance in challenging circumstances. We sought to understand the lived experiences of mentally tough high-altitude mountaineers, focusing primarily upon decisions to persevere or abort summit attempts. Phenomenological interviews were conducted with 14 mountaineers including guides, expedition leaders, and doctors (Mage = 44 years). A content analysis was employed to identify key themes in the data. Participants emphasized the importance of MT in extreme environments and described rational, flexible, and vigilant decision-making. Turning around without summiting was the toughest decision reported, with recognition of the thin line between persevering and overstretching. In contrast to much MT literature, mountaineers accepted limits, demonstrated restraint, and sacrificed personal goals to aid others. Costly perseverance was also reported with some mountaineers described as “too tough”: overcompetitive, goal-obsessed, and biased decision-makers. These findings revealed both benefits and dangers of MT in mountaineering.
In Vitro
Activity of Posaconazole against Talaromyces marneffei by Broth Microdilution and Etest Methods and Comparison to Itraconazole, Voriconazole, and Anidulafungin
Authors: Lau Susanna K. P. , Lo George C. S. , Lam Clare S. K. , Chow Wang-Ngai , Ngan Antonio H. Y. , Wu Alan K. L. , Tsang Dominic N. C. , Tse Cindy W. S. , Que Tak-Lun , Tang Bone S. F. , Woo Patrick C. Y.
Published: December 2016

We determined the susceptibilities of 57
Talaromyces marneffei
strains to anidulafungin, itraconazole, voriconazole, and posaconazole with MICs of 2 to 8, 0.002 to 0.004, 0.016 to 0.063, and 0.001 to 0.002 μg/ml by broth microdilution and >32, ≤0.002 to 0.008, ≤0.002 to 0.008, and ≤0.002 μg/ml by Etest, respectively, at yeast phase; MICs at mycelial phase for anidulafungin and posaconazole were 1 to 2 and 0.004 to 0.063 μg/ml, respectively. The results suggest promising activities of posaconazole. Etest can be used for testing of azoles against
T. marneffei
.
Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model
Authors: Lin Yu-Wei , Zhou Qi Tony , Cheah Soon-Ee , Zhao Jinxin , Chen Ke , Wang Jiping , Chan Hak-Kim , Li Jian
Published: December 2016

Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR)
Pseudomonas aeruginosa
. However, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against three
P. aeruginosa
strains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (
f
AUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection (
R
2
= 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). The
f
AUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDR
P. aeruginosa
lung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy.
Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne
bla
KPC-3
Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections
Authors: Shields Ryan K. , Chen Liang , Cheng Shaoji , Chavda Kalyan D. , Press Ellen G. , Snyder Avin , Pandey Ruchi , Doi Yohei , Kreiswirth Barry N. , Nguyen M. Hong , Clancy Cornelius J.
Published: December 2016

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant
Enterobacteriaceae
(CRE) that produce
Klebsiella pneumoniae
carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant
K. pneumoniae
emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant
K. pneumoniae
isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne
bla
KPC-3
, which were not present in baseline isolates.
bla
KPC-3
mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in
K. pneumoniae
, plasmid transfer, and
bla
KPC
cloning into competent
Escherichia coli
. In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ≥4-fold from baseline, restoring susceptibility in
K. pneumoniae
from two patients. Cefepime and ceftriaxone MICs were also reduced ≥4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of
bla
KPC-3
encoding D179Y/T243M and D179Y variants was diminished compared to
bla
KPC-3
expression in baseline isolates. In conclusion, the development of resistance-conferring
bla
KPC-3
mutations in
K. pneumoniae
within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.
Low Frequency of Ceftazidime-Avibactam Resistance among Enterobacteriaceae Isolates Carrying
bla
KPC
Collected in U.S. Hospitals from 2012 to 2015
Authors: Castanheira Mariana , Mendes Rodrigo E. , Sader Helio S.
Published: December 2016

Klebsiella pneumoniae
carbapenemase (KPC)-producing
Enterobacteriaceae
isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456
Enterobacteriaceae
isolates carrying
bla
KPC
collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC
50/90
, 0.5/2 μg/ml; 99.3% susceptible) and tigecycline (MIC
50/90
, 0.5/1 μg/ml; 98.9% susceptible at ≤2 μg/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (
K. pneumoniae
; MICs, ≥16 μg/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-β-lactamase genes,
bla
NDM-1
or
bla
VIM-4
, among other β-lactam resistance mechanisms, and one displayed a premature stop codon in
ompK35
and decreased expression of
ompK36
. Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carrying
bla
KPC-3
(
n
= 221) and
bla
KPC-2
(
n
= 145), respectively. Isolates carrying
bla
KPC
were more commonly recovered from pneumonia (
n
= 155), urinary tract (
n
= 93), and skin/soft tissue (
n
= 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites.
K. pneumoniae
(83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidime-avibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidime-avibactam was active against this large collection of isolates carrying
bla
KPC
and represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producing
Enterobacteriaceae
.
Interaction between SWP9 and Polar Tube Proteins of the Microsporidian Nosema bombycis and Function of SWP9 as a Scaffolding Protein Contribute to Polar Tube Tethering to the Spore Wall
Authors: Yang Donglin , Pan Lixia , Peng Pai , Dang Xiaoqun , Li Chunfeng , Li Tian , Long Mengxian , Chen Jie , Wu Yujiao , Du Huihui , Luo Bo , Song Yue , Tian Rui , Luo Jie , Zhou Zeyang , Pan Guoqing
Published: December 2016

All microsporidia possess a unique, highly specialized invasion mechanism that involves the polar tube and spore wall. The interaction between spore wall proteins (SWPs) and polar tube proteins (PTPs) in the formation, arrangement, orderly orientation, and function of the polar tube and spore wall remains to be determined. This study was undertaken to examine the protein interactions ofNosema bombycisSWP7 (NbSWP7), NbSWP9, and PTPs. Coimmunoprecipitation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and yeast two-hybrid data demonstrated that NbSWP9, but not NbSWP7, interacts with NbPTP1 and NbPTP2. Furthermore, immunoelectron microscopy (IEM) showed that NbSWP9 was localized mainly in the developing polar tube of sporoblasts, while NbSWP7 was found randomly in the cytoplasm. However, both NbSWP9 and NbSWP7 were located in the polar tube and spore wall ofN. bombycismature spores. The reason why NbSWP7 was localized to the polar tube may be due to the interaction between NbSWP9 and NbSWP7. Interestingly, the majority of NbSWP9, but not NbSWP7, accumulated in the beginning part of the extruded polar tube and the ruptured spore wall called the anchoring disk (AD) when the mature spores germinated under weak-alkaline environmental stimulation. Additionally, anti-NbSWP9 antibody reduced spore germination in a dose-dependent manner. In conclusion, our study further confirmed that NbSWP9 is a scaffolding protein that not only anchors and holds the polar tube but also tethers the polar tube to the spore wall.
Diversification of the AlpB Outer Membrane Protein of Helicobacter pylori Affects Biofilm Formation and Cellular Adhesion
Authors: Yonezawa Hideo , Osaki Takako , Fukutomi Toshiyuki , Hanawa Tomoko , Kurata Satoshi , Zaman Cynthia , Hojo Fuhito , Kamiya Shigeru
Published: December 2016

Helicobacter pylori
is one of the most common causes of bacterial infection in humans, and it forms biofilms on human gastric mucosal epithelium as well as on
in vitro
abiotic surfaces. Bacterial biofilm is critical not only for environmental survival but also for successful infection. We previously demonstrated that strain TK1402, which was isolated from a Japanese patient with duodenal and gastric ulcers, has high biofilm-forming ability
in vitro
relative to other strains. In addition, we showed that outer membrane vesicles (OMV) play an important role in biofilm formation. The aim of this study was to analyze which protein(s) in the OMV contributes to biofilm formation in TK1402. We obtained a spontaneous mutant strain derived from TK1402 lacking biofilm-forming ability. The protein profiles of the OMV were compared between this mutant strain and the wild type, and it was found that AlpB, an outer membrane protein in the OMV of the mutant strain, was markedly decreased compared to that of the wild type. Restoration of TK1402
alpB
to the mutant strain fully recovered the ability to form biofilm. However, restoration with
alpB
from other strains demonstrated incomplete recovery of biofilm-forming ability. We therefore inferred that the variable region of AlpB (amino acid positions 121 to 146) was involved in TK1402 biofilm formation. In addition, diversification of the AlpB sequence was shown to affect the ability to adhere to AGS cells. These results demonstrate a new insight into the molecular mechanisms of host colonization by
H. pylori
.

IMPORTANCE
Bacterial biofilm is critical not only for environmental survival but also for successful infection. The mechanism of
Helicobacter pylori
adherence to host cells mediated by cell surface adhesins has been the focus of many studies, but little is known regarding factors involved in
H. pylori
biofilm formation. Our study demonstrated that AlpB plays an important role in biofilm formation and that this property depends upon the specific sequence of
alpB
. This in turn was shown to be important in the ability to adhere to gastric cells. We anticipate that these results will provide new insight into the molecular mechanisms of
H. pylori
colonization.
Comparison of Phenotypic Tests and an Immunochromatographic Assay and Development of a New Algorithm for Detection of OXA-48-like Carbapenemases
Authors: Koroska Florian , Göttig Stephan , Kaase Martin , Steinmann Jörg , Gatermann Sören , Sommer Julian , Wille Thorsten , Plum Georg , Hamprecht Axel
Published: December 2016

OXA-48 is the most prevalent carbapenemase in
Enterobacteriaceae
in Europe and the Middle East, but it is frequently missed because many isolates display low MICs for carbapenems. Furthermore, in contrast to metallo-β-lactamases or
Klebsiella pneumoniae
carbapenemases (KPC), no specific inhibitor is available for the phenotypic detection of OXA-48. Molecular detection of
bla
OXA-48
is the “gold standard” but is not available in many laboratories. A few phenotypic assays have been described but have not been independently evaluated. The aim of this study was the systematic comparison of phenotypic tests and an immunochromatographic assay (ICT) for the detection of OXA-48/OXA-48-like carbapenemases and the development of an algorithm for reliable phenotypic detection of OXA-48. Four phenotypic tests (temocillin disk test, faropenem disk test, OXA-48 disk test, and high-inoculum [HI] OXA-48 disk test) and a new ICT (OXA-48
K
-SeT) were compared by using a set of 166
Enterobacteriaceae
isolates, including isolates producing OXA-48/OXA-48-like carbapenemases (
n =
84) or Ambler class A and B carbapenemases (
n =
41) and carbapenemase-negative isolates (
n =
41). The sensitivity and specificity for the different assays were 100% and 43.9% for temocillin, 57.1% and 98.8% for faropenem, 53.6% and 100% for the OXA-48 disk test, 98.8% and 97.6% for the HI OXA-48 disk test, and 100% and 100% for the ICT, respectively. The ICT displayed the highest sensitivity and specificity and was the most rapid assay, but it is more costly than phenotypic assays. Based on these results, a new algorithm incorporating temocillin, faropenem, and ICT which allows cost-effective detection of OXA-48 with 100% sensitivity and specificity was developed.
Implementation of Rapid Molecular Infectious Disease Diagnostics: the Role of Diagnostic and Antimicrobial Stewardship
Authors: Messacar Kevin , Parker Sarah K. , Todd James K. , Dominguez Samuel R.
Published: December 2016

New rapid molecular diagnostic technologies for infectious diseases enable expedited accurate microbiological diagnoses. However, diagnostic stewardship and antimicrobial stewardship are necessary to ensure that these technologies conserve, rather than consume, additional health care resources and optimally affect patient care. Diagnostic stewardship is needed to implement appropriate tests for the clinical setting and to direct testing toward appropriate patients. Antimicrobial stewardship is needed to ensure prompt appropriate clinical action to translate faster diagnostic test results in the laboratory into improved outcomes at the bedside. This minireview outlines the roles of diagnostic stewardship and antimicrobial stewardship in the implementation of rapid molecular infectious disease diagnostics.
The Autographa californica Multiple Nucleopolyhedrovirus
ac83
Gene Contains a
cis
-Acting Element That Is Essential for Nucleocapsid Assembly
Authors: Huang Zhihong , Pan Mengjia , Zhu Silei , Zhang Hao , Wu Wenbi , Yuan Meijin , Yang Kai
Published: December 2016

Baculoviridae
is a family of insect-specific viruses that have a circular double-stranded DNA genome packaged within a rod-shaped capsid. The mechanism of baculovirus nucleocapsid assembly remains unclear. Previous studies have shown that deletion of the
ac83
gene of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) blocks viral nucleocapsid assembly. Interestingly, the
ac83
-encoded protein Ac83 is not a component of the nucleocapsid, implying a particular role for
ac83
in nucleocapsid assembly that may be independent of its protein product. To examine this possibility, Ac83 synthesis was disrupted by insertion of a chloramphenicol resistance gene into its coding sequence or by deleting its promoter and translation start codon. Both mutants produced progeny viruses normally, indicating that the Ac83 protein is not required for nucleocapsid assembly. Subsequently, complementation assays showed that the production of progeny viruses required the presence of
ac83
in the AcMNPV genome instead of its presence in
trans
. Therefore, we reasoned that
ac83
is involved in nucleocapsid assembly via an internal
cis
-acting element, which we named the nucleocapsid assembly-essential element (NAE). The NAE was identified to lie within nucleotides 1651 to 1850 of
ac83
and had 8 conserved A/T-rich regions. Sequences homologous to the NAE were found only in alphabaculoviruses and have a conserved positional relationship with another essential
cis
-acting element that was recently identified. The identification of the NAE may help to connect the data of viral
cis
-acting elements and related proteins in the baculovirus nucleocapsid assembly, which is important for elucidating DNA-protein interaction events during this process.

IMPORTANCE
Virus nucleocapsid assembly usually requires specific
cis
-acting elements in the viral genome for various processes, such as the selection of the viral genome from the cellular nucleic acids, the cleavage of concatemeric viral genome replication intermediates, and the encapsidation of the viral genome into procapsids. In linear DNA viruses, such elements generally locate at the ends of the viral genome; however, most of these elements remain unidentified in circular DNA viruses (including baculovirus) due to their circular genomic conformation. Here, we identified a nucleocapsid assembly-essential element in the AcMNPV (the archetype of baculovirus) genome. This finding provides an important reference for studies of nucleocapsid assembly-related elements in baculoviruses and other circular DNA viruses. Moreover, as most of the previous studies of baculovirus nucleocapsid assembly have been focused on viral proteins, our study provides a novel entry point to investigate this mechanism via
cis
-acting elements in the viral genome.
Barriers to Infection of Human Cells by Feline Leukemia Virus: Insights into Resistance to Zoonosis
Authors: Terry Anne , Kilbey Anna , Naseer Asif , Levy Laura S. , Ahmad Shamim , Watts Ciorsdaidh , Mackay Nancy , Cameron Ewan , Wilson Sam , Neil James C.
Published: December 2016

The human genome displays a rich fossil record of past gammaretrovirus infections, yet no current epidemic is evident, despite environmental exposure to viruses that infect human cells
in vitro
. Feline leukemia viruses (FeLVs) rank high on this list, but neither domestic nor workplace exposure has been associated with detectable serological responses. Nonspecific inactivation of gammaretroviruses by serum factors appears insufficient to explain these observations. To investigate further, we explored the susceptibilities of primary and established human cell lines to FeLV-B, the most likely zoonotic variant. Fully permissive infection was common in cancer-derived cell lines but was also a feature of nontransformed keratinocytes and lung fibroblasts. Cells of hematopoietic origin were generally less permissive and formed discrete groups on the basis of high or low intracellular protein expression and virion release. Potent repression was observed in primary human blood mononuclear cells and a subset of leukemia cell lines. However, the early steps of reverse transcription and integration appear to be unimpaired in nonpermissive cells. FeLV-B was subject to G→A hypermutation with a predominant APOBEC3G signature in partially permissive cells but was not mutated in permissive cells or in nonpermissive cells that block secondary viral spread. Distinct cellular barriers that protect primary human blood cells are likely to be important in protection against zoonotic infection with FeLV.

IMPORTANCE
Domestic exposure to gammaretroviruses such as feline leukemia viruses (FeLVs) occurs worldwide, but the basis of human resistance to infection remains incompletely understood. The potential threat is evident from the human genome sequence, which reveals many past epidemics of gammaretrovirus infection, and from recent cross-species jumps of gammaretroviruses from rodents to primates and marsupials. This study examined resistance to infection at the cellular level with the most prevalent human cell-tropic FeLV variant, FeLV-B. We found that blood cells are uniquely resistant to infection with FeLV-B due to the activity of cellular enzymes that mutate the viral genome. A second block, which appears to suppress viral gene expression after the viral genome has integrated into the host cell genome, was identified. Since cells derived from other normal human cell types are fully supportive of FeLV replication, innate resistance of blood cells could be critical in protecting against cross-species infection.
Binding of the Methyl Donor
S
-Adenosyl-
l
-Methionine to Middle East Respiratory Syndrome Coronavirus 2′-
O
-Methyltransferase nsp16 Promotes Recruitment of the Allosteric Activator nsp10
Authors: Aouadi Wahiba , Blanjoie Alexandre , Vasseur Jean-Jacques , Debart Françoise , Canard Bruno , Decroly Etienne
Published: December 2016

The Middle East respiratory syndrome coronavirus (MERS-CoV) nonstructural protein 16 (nsp16) is an
S
-adenosyl-
l
-methionine (SAM)-dependent 2′-
O
-methyltransferase (2′-O-MTase) that is thought to methylate the ribose 2′-OH of the first transcribed nucleotide (N
1
) of viral RNA cap structures. This 2′-O-MTase activity is regulated by nsp10. The 2′-
O
methylation prevents virus detection by cell innate immunity mechanisms and viral translation inhibition by the interferon-stimulated IFIT-1 protein. To unravel the regulation of nsp10/nsp16 2′-O-MTase activity, we used purified MERS-CoV nsp16 and nsp10. First, we showed that nsp16 recruited N7-methylated capped RNA and SAM. The SAM binding promotes the assembly of the enzymatically active nsp10/nsp16 complex that converted
7m
GpppG (cap-0) into
7m
GpppG
2′Om
(cap-1) RNA by 2′-OH methylation of N
1
in a SAM-dependent manner. The subsequent release of SAH speeds up nsp10/nsp16 dissociation that stimulates the reaction turnover. Alanine mutagenesis and RNA binding assays allowed the identification of the nsp16 residues involved in RNA recognition forming the RNA binding groove (K46, K170, E203, D133, R38, Y47, and Y181) and the cap-0 binding site (Y30, Y132, and H174). Finally, we found that nsp10/nsp16 2′-O-MTase activity is sensitive to known MTase inhibitors, such as sinefungin and cap analogues. This characterization of the MERS-CoV 2′-O-MTase is a preliminary step toward the development of molecules to inhibit cap 2′-O methylation and to restore the host antiviral response.

IMPORTANCE
MERS-CoV codes for a cap 2′-
O
-methyltransferase that converts cap-0 into cap-1 structure in order to prevent virus detection by cell innate immunity mechanisms. We report the biochemical properties of MERS-CoV 2′O-methyltransferase, which is stimulated by nsp10 acting as an allosteric activator of the nsp16 2′-
O
-methyltransferase possibly through enhanced RNA binding affinity. In addition, we show that SAM promotes the formation of the active nsp10/nsp16 complex. Conversely, after cap methylation, the reaction turnover is speeded up by cap-1 RNA release and nsp10/nsp16 complex dissociation, at the low intracellular SAH concentration. These results suggest that SAM/SAH balance is a regulator of the 2′-
O
-methyltransferase activity and raises the possibility that SAH hydrolase inhibitors might interfere with CoV replication cycle. The enzymatic and RNA binding assays developed in this work were also used to identify nsp16 residues involved in cap-0 RNA recognition and to understand the action mode of known methyltransferase inhibitors.
Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication
Authors: Campos-León Karen , Wijendra Kalpanee , Siddiqa Abida , Pentland Ieisha , Feeney Katherine M. , Knapman Alison , Davies Rachel , Androphy Elliot J. , Parish Joanna L.
Published: December 2016

Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G
2
/M phase and functions in radiation-induced G
2
checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication.

IMPORTANCE
HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification of infection. The recruitment of specific cellular protein complexes to these factories aids efficient and controlled viral replication. We have identified a novel HPV-host interaction that functions in the cellular response to DNA damage and cell cycle control. We show that the HPV E2 protein targets Rad50-interacting protein 1 (Rint1) to facilitate virus genome replication. These findings add to our understanding of how HPV replicates and the host cell pathways that are targeted by HPV to support virus replication. Understanding these pathways will allow further research into novel inhibitors of HPV genome replication.
Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance
Authors: Hove-Jensen Bjarne , Andersen Kasper R. , Kilstrup Mogens , Martinussen Jan , Switzer Robert L. , Willemoës Martin
Published: December 2016

Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species.
The Denture-Associated Oral Microbiome in Health and Stomatitis
Authors: Shi Baochen , Wu Tingxi , McLean Jeffrey , Edlund Anna , Young Youngik , He Xuesong , Lv Hongyang , Zhou Xuedong , Shi Wenyuan , Li Huiying , Lux Renate
Published: December 2016

Denture stomatitis is a prevalent inflammatory condition of the mucosal tissue in denture wearers that is triggered by microorganisms. WhileCandidahas been extensively studied for its role in stomatitis etiology, the bacterial component largely remains to be investigated. Our data show that certain types of bacteria are significantly associated with denture health and disease. Furthermore, the bacterial communities residing on the teeth and dentures of the same person are similar to each other independently of the surface, and thus, denture health could impact the maintenance of remaining teeth and vice versa.
Risks Posed by Reston, the Forgotten Ebolavirus
Authors: Cantoni Diego , Hamlet Arran , Michaelis Martin , Wass Mark N. , Rossman Jeremy S.
Published: December 2016

Out of the five members of the
Ebolavirus
family, four cause life-threatening disease, whereas the fifth, Reston virus (RESTV), is nonpathogenic in humans.
Decreasing Time to Pain Relief for Emergency Department Patients with Extremity Fractures
Authors: Heilman James A. , Tanski Mary , Burns Beech , Lin Amber , Ma John
Published: December 2016

Significant delays occur in providing adequate pain relief for patients who present to the emergency department (ED) with extremity fractures. The median time to pain medication administration for patients presenting to our ED with extremity fractures was 72.5 minutes. We used a multidisciplinary approach to implement three improvement cycles with the goal of reducing the median time to pain medication by 15% over an eight month time period. First, we redesigned nursing triage and treatment processes. Second, we improved nursing documentation standardization to ensure accurate tracking of patients who declined pain medication. Third, through consensus building within our physician group, we implemented a department-wide standard of care to provide early pain relief for extremity fractures. Median time to pain medication for patients with an extremity fracture reduced significantly between the pre-and post-intervention periods (p=0.009). The average monthly median time to medication was 72.5 minutes (95% CI: 57.1 to 88.0) before the intervention (Jan 2013-Oct 2014) and 49.8 minutes (95% CI: 42.7 to 56.9) after the intervention (November 2014 to June 2016). In other words, monthly median time was 31% faster (22.7 minute difference) in the post intervention period. Implementing three key interventions reduced the time to pain medication for patients with extremity injuries. Since June 2016 the reductions in median time to medication have continued to improve.
XYZ-like spectra from Laplace sum rule at N2LO in the chiral limit
Authors: Albuquerque R. , Narison S. , Fanomezana F. , Rabemananjara A. , Rabetiarivony D. , Randriamanatrika G.
Published: December 2016

We present new compact integrated expressions of QCD spectral functions of heavy-light molecules and four-quark [Formula: see text]-like states at lowest order (LO) of perturbative (PT) QCD and up to [Formula: see text] condensates of the Operator Product Expansion (OPE). Then, by including up to next-to-next leading order (N2LO) PT QCD corrections, which we have estimated by assuming the factorization of the four-quark spectral functions, we improve previous LO results from QCD spectral sum rules (QSSR), on the [Formula: see text]-like masses and decay constants which suffer from the ill-defined heavy quark mass. PT N3LO corrections are estimated using a geometric growth of the PT series and are included in the systematic errors. Our optimal results based on stability criteria are summarized in Tables 11–14 and compared, in Sec. 10, with experimental candidates and some LO QSSR results. We conclude that the masses of the [Formula: see text] observed states are compatible with (almost) pure [Formula: see text], [Formula: see text] molecule or/and four-quark states. The ones of the [Formula: see text], [Formula: see text] molecule/four-quark states are about 1.5 GeV above the [Formula: see text] mesons experimental candidates and hadronic thresholds. We also find that the couplings of these exotics to the associated interpolating currents are weaker than that of ordinary [Formula: see text] mesons [Formula: see text] and may behave numerically as [Formula: see text] (respectively [Formula: see text]) for the [Formula: see text], [Formula: see text] (respectively [Formula: see text], [Formula: see text]) states which can stimulate further theoretical studies of these decay constants.
Chaos, Fractals and Their Applications
Authors: Thompson J. Michael T.
Published: December 2016

This paper gives an up-to-date account of chaos and fractals, in a popular pictorial style for the general scientific reader. A brief historical account covers the development of the subject from Newton’s laws of motion to the astronomy of Poincaré and the weather forecasting of Lorenz. Emphasis is given to the important underlying concepts, embracing the fractal properties of coastlines and the logistics of population dynamics. A wide variety of applications include: NASA’s discovery and use of zero-fuel chaotic “superhighways” between the planets; erratic chaotic solutions generated by Euler’s method in mathematics; atomic force microscopy; spontaneous pattern formation in chemical and biological systems; impact mechanics in offshore engineering and the chatter of cutting tools; controlling chaotic heartbeats. Reference is made to a number of interactive simulations and movies accessible on the web.
Lagrangian Descriptors for Stochastic Differential Equations: A Tool for Revealing the Phase Portrait of Stochastic Dynamical Systems
Authors: Balibrea-Iniesta Francisco , Lopesino Carlos , Wiggins Stephen , Mancho Ana M.
Published: December 2016

In this paper, we introduce a new technique for depicting the phase portrait of stochastic differential equations. Following previous work for deterministic systems, we represent the phase space by means of a generalization of the method of Lagrangian descriptors to stochastic differential equations. Analogously to the deterministic differential equations setting, the Lagrangian descriptors graphically provide the distinguished trajectories and hyperbolic structures arising within the stochastic dynamics, such as random fixed points and their stable and unstable manifolds. We analyze the sense in which structures form barriers to transport in stochastic systems. We apply the method to several benchmark examples where the deterministic phase space structures are well-understood. In particular, we apply our method to the noisy saddle, the stochastically forced Duffing equation, and the stochastic double gyre model that is a benchmark for analyzing fluid transport.
The Relationship Between Chaotic Maps and Some Chaotic Systems with Hidden Attractors
Authors: Jafari Sajad , Pham Viet-Thanh , Golpayegani S. Mohammad Reza Hashemi , Moghtadaei Motahareh , Kingni Sifeu Takougang
Published: December 2016

In this note, hidden attractors in chaotic maps are investigated. Although there are many new researches on hidden attractors in chaotic flows, no investigation has been done on hidden attractors in maps based on our knowledge. In addition, a new interesting chaotic map with a bifurcation diagram starting from any desired period and then continuing with period doubling is introduced in this paper.
Generating Chaos from Two Three-Dimensional Rigorous Linear Systems via a Novel Switching Control Approach
Authors: Sun Changchun , Xu Qicheng
Published: December 2016

By constructing two three-dimensional (3D) rigorous linear systems, a novel switching control approach for generating chaos from two linear systems is presented. Two 3D linear systems without any constant term have only one common equilibrium point that is the origin. By employing an absolute-value switching law, chaos can be generated by switching between two linear systems. Basic dynamical behaviors of the systems are investigated in detail. Numerical examples illustrate the effectiveness of the presented approach.
Bi-Hamiltonian Structures of 3D Chaotic Dynamical Systems
Authors: Esen Oğul , Ghose Choudhury Anindya , Guha Partha
Published: December 2016

We study Hamiltonian structures of dynamical systems with three degrees of freedom which are known for their chaotic properties, namely Lü, modified Lü, Chen, [Formula: see text] and Qi systems. We show that all these flows admit bi-Hamiltonian structures depending on the values of their parameters.
Bursting and Synchronization in a Two-Compartment Model with Current-Feedback Control
Authors: Meng Pan , Ji Quanbao , Wang Haixia , Lu Qishao
Published: December 2016

Based on the fast–slow dynamics and bifurcation analysis, two different types of bursting, that is, the “subHopf/homoclinic” and the “circle/fold cycle” types of bursting, are presented and analyzed in a two-compartment neuron model with current feedback control due to totally different generation mechanisms. The synchronization transition process from burst synchronization to nearly complete synchronization is considered in two electrically coupled nonidentical neurons, and fast–slow analysis can be extended to explore the bursting behavior of nearly complete synchronization. The analysis of bursting types and multitime-scale synchronization transition may help us better understand the information encoding and transmission in neural systems.
Number of Critical Periods for Perturbed Rigidly Isochronous Centers
Authors: Lu Lianghaolong , Peng Linping , Feng Zhaosheng
Published: December 2016

This paper deals with the bifurcation of critical periods from a rigidly quartic isochronous center. It shows that under any small homogeneous perturbation of degree four, up to any order in [Formula: see text], there are at most two critical periods bifurcating from the periodic orbits of the unperturbed system, and the upper bound is sharp. In addition, we further prove that under any small polynomial perturbation of degree [Formula: see text], up to the first order in [Formula: see text], there are at most [Formula: see text] critical periods bifurcating from the periodic orbits of the unperturbed quartic system.