bluuebunny/crossref_metadata_2025 huggingface dataset:
Connecting undergraduate instruction to the 2017 solar eclipse
Authors: Lopez Ramon E. , Ambrose Bradley S. , Bailey Janelle M. , Cid Ximena C. , Vieyra Rebecca E. , Willoughby Shannon D.
Published: March 2017

Space science is perhaps the science topic that elicits the greatest interest in students in the United States and also worldwide. NASA has always endeavored to leverage that widespread interest to advance STEM education, not least because NASA requires a thriving STEM workforce for the future.
Time-domain Helmholtz-Kirchhoff integral for surface scattering in a refractive medium
Authors: Choo Youngmin , Song H. C. , Seong Woojae
Published: March 2017

The time-domain Helmholtz-Kirchhoff (H-K) integral for surface scattering is derived for a refractive medium, which can handle shadowing effects. The starting point is the H-K integral in the frequency domain. In the high-frequency limit, the Green's function can be calculated by ray theory, while the normal derivative of the incident pressure from a point source is formulated using the ray geometry and ray-based Green's function. For a corrugated pressure-release surface, a stationary phase approximation can be applied to the H-K integral, reducing the surface integral to a line integral. Finally, a computationally-efficient, time-domain H-K integral is derived using an inverse Fourier transform. A broadband signal scattered from a sinusoidal surface in an upwardly refracting medium is evaluated with and without geometric shadow corrections, and compared to the result from a conventional ray model.
Extension of the angular spectrum method to model the pressure field of a cylindrically curved array transducer
Authors: Ilyina Natalia , Hermans Jeroen , Van Den Abeele Koen , D'hooge Jan
Published: March 2017

An extension to the angular spectrum approach for modelling pressure fields of a cylindrically curved array transducer is described in this paper. The proposed technique is based on representing the curved transducer surface as a set of planar elements whose contributions are combined at a selected intermediate plane from which the field is further propagated using the conventional angular spectrum approach. The accuracy of the proposed technique is validated through comparison with Field II simulations.
A Cross-Sectional Study of Age Differences and Postural Control in Male Athletes Using the Stability Evaluation Test (SET)
Authors: Williams Richelle M. , Rice Trevor , Lam Kenneth , McLeod Tamara Valovich
Published: March 2017

Postural control is an integral part of sport participation and is often measured when assessing concussion and rehabilitating musculoskeletal injuries. The purpose of this study was to determine whether developmental differences in postural control, as measured by the Stability Evaluation Test protocol, exist between multiple male age groups (9–25-years-old). Significant differences were present across age groups, suggesting pediatric males demonstrated higher sway velocity scores than older males. We also found that preadolescent males showed increased postural sway when compared with older populations. Overall, it was found that age-related differences exist in postural control, with older males demonstrating less sway, and therefore better postural control.
Tri-Axial Accelerometry as an Injury Predictor Tool in Elite Soccer
Authors: Brown Wayne , Greig Matt
Published: March 2017

The epidemiology and etiology of ankle sprain injuries in soccer have been well described. Retrospective analysis of epidemiological data identified an English Premier League player sustaining a high lateral ankle sprain. GPS data collated during the training session in which the injury was sustained, and subsequent rehabilitation sessions, were analyzed to quantify uniaxial PlayerLoad metrics. The injured player revealed a 3:1 asymmetrical loading pattern in the mediolateral plane and multiaxial high loading events which might present the inciting event to injury. The high magnitude, asymmetrical and multiplanar loading is consistent with lateral ankle sprain etiology.
Qualitative Video Analysis of Track-Cycling Team Pursuit in World-Class Athletes
Authors: Sigrist Samuel , Maier Thomas , Faiss Raphael
Published: March 2017

Context: Track-cycling team pursuit (TP) is a highly technical effort involving 4 athletes completing 4 km from a standing start, often in less than 240 s. Transitions between athletes leading the team are obviously of utmost importance. Purpose: To perform qualitative video analyses of transitions of world-class athletes in TP competitions. Methods: Videos captured at 100 Hz were recorded for 77 races (including 96 different athletes) in 5 international track-cycling competitions (eg, UCI World Cups and World Championships) and analyzed for the 12 best teams in the UCI Track Cycling TP Olympic ranking. During TP, 1013 transitions were evaluated individually to extract quantitative (eg, average lead time, transition number, length, duration, height in the curve) and qualitative (quality of transition start, quality of return at the back of the team, distance between third and returning rider score) variables. Determination of correlation coefficients between extracted variables and end time allowed assessment of relationships between variables and relevance of the video analyses. Results: Overall quality of transitions and end time were significantly correlated (r = .35, P = .002). Similarly, transition distance (r = .26, P = .02) and duration (r = .35, P = .002) were positively correlated with end time. Conversely, no relationship was observed between transition number, average lead time, or height reached in the curve and end time. Conclusion: Video analysis of TP races highlights the importance of quality transitions between riders, with preferably swift and short relays rather than longer lead times for faster race times.
Accuracy and Reliability of Marker-Based Approaches to Scale the Pelvis, Thigh, and Shank Segments in Musculoskeletal Models
Authors: Kainz Hans , Hoang Hoa X. , Stockton Chris , Boyd Roslyn R. , Lloyd David G. , Carty Christopher P.
Published: March 2017

Gait analysis together with musculoskeletal modeling is widely used for research. In the absence of medical images, surface marker locations are used to scale a generic model to the individual’s anthropometry. Studies evaluating the accuracy and reliability of different scaling approaches in a pediatric and/or clinical population have not yet been conducted and, therefore, formed the aim of this study. Magnetic resonance images (MRI) and motion capture data were collected from 12 participants with cerebral palsy and 6 typically developed participants. Accuracy was assessed by comparing the scaled model’s segment measures to the corresponding MRI measures, whereas reliability was assessed by comparing the model’s segments scaled with the experimental marker locations from the first and second motion capture session. The inclusion of joint centers into the scaling process significantly increased the accuracy of thigh and shank segment length estimates compared to scaling with markers alone. Pelvis scaling approaches which included the pelvis depth measure led to the highest errors compared to the MRI measures. Reliability was similar between scaling approaches with mean ICC of 0.97. The pelvis should be scaled using pelvic width and height and the thigh and shank segment should be scaled using the proximal and distal joint centers.
Translation of Fit & Strong! for Use by Hispanics With Arthritis: A Feasibility Trial of ¡En Forma y Fuerte!
Authors: Der Ananian Cheryl , Smith-Ray Renae , Meacham Brad , Shah Amy , Hughes Susan
Published: March 2017

This study evaluated the feasibility and effectiveness of translating the evidence-based program, Fit & Strong!, into a Spanish program, ¡En Forma y Fuerte!. A single-group, quasi-experimental design (n = 34, mean age = 58.8 [8.1], 87.2% female, 87.2% reported speaking mostly Spanish) was used to assess implementation feasibility and the impact of ¡En Forma y Fuerte! on arthritis-related outcomes in Hispanics with arthritis. Significant improvements in lower-extremity strength, perceived physical function, and pain were observed from baseline to 8 weeks (p < .05); these improvements were maintained at 6 months. Significant improvements in aerobic endurance and stiffness were observed from baseline to 6 months (p < .05). No major program adaptations (other than language) were observed or reported. However, the instructors provided several suggestions for program improvements, including adjusting the literacy level and length of the program. Findings suggest ¡En Forma y Fuerte! is feasible and effective, potentially providing a much-needed program for older Hispanics with arthritis.
Crawling Experience Relates to Postural and Emotional Reactions to Optic Flow in a Virtual Moving Room
Authors: Ueno Moeko , Uchiyama Ichiro , Campos Joseph J. , Anderson David I. , He Minxuan , Dahl Audun
Published: March 2017

Infants show a dramatic shift in postural and emotional responsiveness to peripheral lamellar optic flow (PLOF) following crawling onset. The present study used a novel virtual moving room to assess postural compensation of the shoulders backward and upward and heart rate acceleration to PLOF specifying a sudden horizontal forward translation and a sudden descent down a steep slope in an infinitely long virtual tunnel. No motion control conditions were also included. Participants were 53 8.5-month-old infants: 25 prelocomotors and 28 hands-and-knees crawlers. The primary findings were that crawling infants showed directionally appropriate postural compensation in the two tunnel motion conditions, whereas prelocomotor infants were minimally responsive in both conditions. Similarly, prelocomotor infants showed nonsignificant changes in heart rate acceleration in the tunnel motion conditions, whereas crawling infants showed significantly higher heart rate acceleration in the descent condition than in the descent control condition, and in the descent condition than in the horizontal translation condition. These findings highlight the important role played by locomotor experience in the development of the visual control of posture and in emotional reactions to a sudden optically specified drop. The virtual moving room is a promising paradigm for exploring the development of perception–action coupling.
Validation of a Noninvasive, Disposable Activity Monitor for Clinical Applications
Authors: Welk Greg , Kim Youngwon , Shook Robin P. , Ellingson Laura , Lobelo Roberto L.
Published: March 2017

Background:

The study evaluated the concurrent and criterion validity of a new, disposable activity monitor designed to provide objective data on physical activity and energy expenditure in clinical populations.

Methods:

A sample of healthy adults (n = 52) wore the disposable Metria IH1 along with the established Sensewear armband (SWA) monitor for a 1-week period. Concurrent validity was examined by evaluating the statistical equivalence of estimates from the Metria and the SWA. Criterion validity was examined by comparing the relative accuracy of the Metria IH1 and the SWA for assessing walking/running. The absolute validity of the 2 monitors was compared by computing correlations and mean absolute percent error (MAPE) relative to criterion data from a portable metabolic analyzer.

Results:

The output from 2 monitors was highly correlated (correlations > 0.90) and the summary measures yielded nearly identical allocations of time spent in physical activity and energy expenditure. The monitors yielded statistically equivalent estimates and had similar absolute validity relative to the criterion measure (12% to 15% error).

Conclusions:

The disposable nature of the adhesive Metria IH1 monitor offers promise for clinical evaluation of physical activity behavior in patients. Additional research is needed to test utility for counseling and behavior applications.
Subjective Responses to Interval and Continuous Exercise in Adults With Exercise-Induced Bronchoconstriction
Authors: O’Neill Carley , Dogra Shilpa
Published: March 2017

Background:

Exercise triggers asthma symptoms among adults with exercise induced bronchoconstriction (EIBC). This may lead to lower physical activity levels among this population. The purpose of this study was to assess perceived exertion (RPE), perceived breathlessness (RPD), affect (FS), and physical activity enjoyment during and following an acute bout of high intensity interval exercise (HIIE), moderate intensity interval (MIIE) and moderate intensity continuous exercise (MICE) in adults with EIBC.

Methods:

RPD, RPE, and FS were assessed each minute during the sessions and enjoyment was assessed following each session (n = 11).

Results:

RPE was lower during MIIE compared with MICE (P = .006). RPD was lowest during MIIE but was not different between HIIE and MICE. Affect was lower in MICE than HIIE in the last minute of exercise (P = .003) and overall was greatest during the MIIE (P = .022; P = .018). Enjoyment scores were similar between protocols.

Conclusions:

Interval exercise is associated with lower ratings of perceived exertion and dyspnea, an increase in in-task affect, and similar physical activity enjoyment when compared with continuous exercise.
Parental Physical Activity Associates With Offspring’s Physical Activity Until Middle Age: A 30-Year Study
Authors: Kaseva Kaisa , Hintsa Taina , Lipsanen Jari , Pulkki-Råback Laura , Hintsanen Mirka , Yang Xiaolin , Hirvensalo Mirja , Hutri-Kähönen Nina , Raitakari Olli , Keltikangas-Järvinen Liisa , Tammelin Tuija
Published: March 2017

Background:

Parents’ physical activity associates with their children’s physical activity. Prospective designs assessing this association are rare. This study examined how parents’ physical activity was associated with their children’s physical activity from childhood to middle adulthood in a 30-year prospective, population-based setting.

Methods:

Participants (n = 3596) were from the ongoing Cardiovascular Risk in Young Finns study started in 1980. Participants’ physical activity was self-reported at 8 phases from 1980 to 2011, and their parents’ physical activity at 1980. Analyses were adjusted for a set of health-related covariates assessed from 1980 to 2007.

Results:

High levels of mothers’ and fathers’ physical activity were systematically associated with increased levels of their children’s physical activity until offspring’s age of 24. Longitudinal analyses conducted from 1980 to 2011 showed that higher levels of parents’ physical activity were associated with increased levels of physical activity within their offspring until midlife, but the association between parents’ and their children’s physical activity weakened when participants aged (P < .05). Covariate adjustment did not attenuate the association.

Conclusions:

This study suggests that parents’ physical activity assessed in their offspring’s childhood contributes favorably to offspring’s physical activity from childhood to middle age.
A Systematic Review of Community-wide Media Physical Activity Campaigns: An Update From 2010
Authors: Yun Lira , Ori Elaine M. , Lee Younghan , Sivak Allison , Berry Tanya R.
Published: March 2017

Background:

Mass media campaign is an integral tool to influence physical activity participant behaviors. The purpose of the systematic review was to identify the effectiveness of mass media campaigns in promoting physical activity.

Methods:

Literature update from January 2010 to September 2016 was conducted in 13 databases. Full text articles of 128 were screened, and 23 articles (18 campaigns) were selected from the initial 1692 articles.

Results:

All campaigns involved mass media advertisements to promote physical activity to general individuals (n = 2), adults (8), children (4), older adults (2), and parents of children (n = 2). The campaign evaluation designs included clustered RCT (2), cohort (3), quasi-experimental (9), and cross-sectional (9). Eight articles demonstrated significant campaign impact on proximal, 6 on intermediate, 5 on distal outcomes, and 6 on distal change based on either proximal or intermediate outcome.

Conclusion:

The current review assessed the outcome evaluation of mass media physical activity campaigns that varied in their respective scope, target population and outcomes measured to identify individual changes at proximal, intermediate, and distal level. Results from formative and process evaluation as well as dose-response and cost-effective analysis are suggested to provide valuable evidence for campaign stakeholders and planners.
Effects of an Improvisation Intervention on Elite Figure Skaters’ Performance, Self Esteem, Creativity, and Mindfulness Skills
Authors: Richard Véronique , Halliwell Wayne , Tenenbaum Gershon
Published: March 2017

The study examined the effect of an improvisation intervention on figure skating performance, self-esteem, creativity, and mindfulness skills. Nine elite figure skaters participated in a 10-session program based on Cirque du Soleil artistic principles. A mixed methodology using questionnaires, competition scores, and interviews was used to test the program effects on these variables. Descriptive statistics revealed small but imperative increases in competition performance, perceived artistic performance, self-esteem, creativity, and mindfulness. Significant (p < .05) effect of time was revealed only for creativity and artistic performance variables. Qualitative data supported these results. Skaters described verbally that movements were performed more freely, attention was better focused on performance, and they overcame shyness. Quantitative and qualitative data are discussed interactively in relation to performance enhancement and personal growth.
Molecular mechanisms and therapeutic targets in pediatric brain tumors
Authors: Liu Kun-Wei , Pajtler Kristian W. , Worst Barbara C. , Pfister Stefan M. , Wechsler-Reya Robert J.
Published: March 2017

Molecular signatures hint at new opportunities for targeted and selective therapies for children with brain tumors.
Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes
Authors: Ostalecki Christian , Lee Jung-Hyun , Dindorf Jochen , Collenburg Lena , Schierer Stephan , Simon Beate , Schliep Stefan , Kremmer Elisabeth , Schuler Gerold , Baur Andreas S.
Published: March 2017

Systematic tissue antigen analysis reveals the stepwise changes in protein activity that drive melanoma.
Papers of note in
Nature
543
(7644)
Authors: VanHook Annalisa M.
Published: March 2017

This week’s articles highlight the role of autophagy in maintaining stem cells and a new player in the repair of double-strand DNA breaks.
Papers of note in
Science Translational Medicine
9
(380)
Authors: Ferrarelli Leslie K.
Published: March 2017

This week’s articles describe an antibody that inhibits two pathways that drive lung cancer and a new way to lessen colitis in Crohn’s disease.
Hypothermia-induced neuroprotection
Authors: VanHook Annalisa M.
Published: March 2017

A reticulon contributes to the neuroprotective effects of hypothermia.
An insulin-like message from mother
Authors: Mushegian Alexandra A.
Published: March 2017

Nematodes experiencing osmotic stress signal to the germ-line to prepare their offspring.
Substrate Recognition and Modification by a Pathogen-Associated Aminoglycoside Resistance 16S rRNA Methyltransferase
Authors: Vinal Kellie , Conn Graeme L.
Published: March 2017

The pathogen-associated 16S rRNA methyltransferase NpmA catalyzes m1A1408 modification to block the action of structurally diverse aminoglycoside antibiotics. Here, we describe the development of a fluorescence polarization binding assay and its use, together with complementary functional assays, to dissect the mechanism of NpmA substrate recognition. These studies reveal that electrostatic interactions made by the NpmA β2/3 linker collectively are critical for docking of NpmA on a conserved 16S rRNA tertiary surface. In contrast, other NpmA regions (β5/β6 and β6/β7 linkers) contain several residues critical for optimal positioning of A1408 but are largely dispensable for 30S binding. Our data support a model for NpmA action in which 30S binding and adoption of a catalytically competent state are distinct: docking on 16S rRNA via the β2/3 linker necessarily precedes functionally critical 30S substrate-driven conformational changes elsewhere in NpmA. This model is also consistent with catalysis being completely positional in nature, as the most significant effects on activity arise from changes that impact binding or stabilization of the flipped A1408 conformation. Our results provide a molecular framework for aminoglycoside resistance methyltransferase action that may serve as a functional paradigm for related enzymes and a starting point for development of inhibitors of these resistance determinants.
Age, Weight, and
CYP2D6
Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children
Authors: Gonçalves Bronner P. , Pett Helmi , Tiono Alfred B. , Murry Daryl , Sirima Sodiomon B. , Niemi Mikko , Bousema Teun , Drakeley Chris , ter Heine Rob
Published: March 2017

Low-dose primaquine is recommended to prevent
Plasmodium falciparum
malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and
CYP2D6
genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and
CYP2D6
genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine. (This study has been registered at ClinicalTrials.gov under registration no. NCT01935882.)
Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis
Authors: Alsultan Abdullah , Savic Rada , Dooley Kelly E. , Weiner Marc , Whitworth William , Mac Kenzie William R. , Peloquin Charles A. ,   the Tuberculosis Trials Consortium
Published: March 2017

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (
C
max
) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD])
C
max
was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC
0–24
) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (
V
/
F
) than men, and both clearance (CL/
F
) and
V
/
F
increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a
C
max
of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.
Downregulation of Autolysin-Encoding Genes by Phage-Derived Lytic Proteins Inhibits Biofilm Formation in Staphylococcus aureus
Authors: Fernández Lucía , González Silvia , Campelo Ana Belén , Martínez Beatriz , Rodríguez Ana , García Pilar
Published: March 2017

Phage-derived lytic proteins are a promising alternative to conventional antimicrobials. One of their most interesting properties is that they do not readily select for resistant strains, which is likely due to the fact that their targets are essential for the viability of the bacterial cell. Moreover, genetic engineering allows the design of new “tailor-made” proteins that may exhibit improved antibacterial properties. One example of this is the chimeric protein CHAPSH3b, which consists of a catalytic domain from the virion-associated peptidoglycan hydrolase of phage vB_SauS-phiIPLA88 (HydH5) and the cell wall binding domain of lysostaphin. CHAPSH3b had previously shown the ability to kill
Staphylococcus aureus
cells. Here, we demonstrate that this lytic protein also has potential for the control of biofilm-embedded
S. aureus
cells. Additionally, subinhibitory doses of CHAPSH3b can decrease biofilm formation by some
S. aureus
strains. Transcriptional analysis revealed that exposure of
S. aureus
cells to this enzyme leads to the downregulation of several genes coding for bacterial autolysins. One of these proteins, namely, the major autolysin AtlA, is known to participate in staphylococcal biofilm development. Interestingly, an
atl
mutant strain did not display inhibition of biofilm development when grown at subinhibitory concentrations of CHAPSH3b, contrary to the observations made for the parental and complemented strains. Also, deletion of
atl
led to low-level resistance to CHAPSH3b and the endolysin LysH5. Overall, our results reveal new aspects that should be considered when designing new phage-derived lytic proteins aimed for antimicrobial applications.
VraR Binding to the Promoter Region of
agr
Inhibits Its Function in Vancomycin-Intermediate Staphylococcus aureus (VISA) and Heterogeneous VISA
Authors: Dai Yuanyuan , Chang Wenjiao , Zhao Changcheng , Peng Jing , Xu Liangfei , Lu Huaiwei , Zhou Shusheng , Ma Xiaoling
Published: March 2017

Acquisition of vancomycin resistance in
Staphylococcus aureus
is often accompanied by a reduction in virulence, but the mechanisms underlying this change remain unclear. The present study was undertaken to investigate this process in a clinical heterogeneous vancomycin-intermediate
S. aureus
(hVISA) strain, 10827; an hVISA reference strain, Mu3; and a VISA reference strain, Mu50, along with their respective series of vancomycin-induced resistant strains. In these strains, increasing MICs of vancomycin were associated with increased expression of the vancomycin resistance-associated regulator gene (
vraR
) and decreased expression of virulence genes (
hla
,
hlb
, and
coa
) and virulence-regulated genes (RNAIII,
agrA
, and
saeR
). These results suggested that VraR might have a direct or indirect effect on virulence in
S. aureus
. In electrophoretic mobility shift assays, VraR did not bind to promoter sequences of
hla
,
hlb
, and
coa
genes, but it did bind to the
agr
promoter region. In DNase I footprinting assays, VraR protected a 15-nucleotide (nt) sequence in the intergenic region between the
agr
P2 and P3 promoters. These results indicated that when
S. aureus
is subject to induction by vancomycin, expression of
vraR
is upregulated, and VraR binding inhibits the function of the Agr quorum-sensing system, causing reductions in the virulence of VISA/hVISA strains. Our results suggested that VraR in
S. aureus
is involved not only in the regulation of vancomycin resistance but also in the regulation of virulence.
GFPuv-Expressing Recombinant Rickettsia typhi: a Useful Tool for the Study of Pathogenesis and CD8
+
T Cell Immunology in R. typhi Infection
Authors: Hauptmann Matthias , Burkhardt Nicole , Munderloh Ulrike , Kuehl Svenja , Richardt Ulricke , Krasemann Susanne , Hartmann Kristin , Krech Till , Fleischer Bernhard , Keller Christian , Osterloh Anke
Published: March 2017

Rickettsia typhi
is the causative agent of endemic typhus, a disease with increasing incidence worldwide that can be fatal. Because of its obligate intracellular life style, genetic manipulation of the pathogen is difficult. Nonetheless, in recent years, genetic manipulation tools have been successfully applied to rickettsiae. We describe here for the first time the transformation of
R. typhi
with the pRAM18dRGA plasmid that originally derives from
Rickettsia amblyommatis
and encodes the expression of GFPuv (green fluorescent protein with maximal fluorescence when excited by UV light). Transformed
R. typhi
(
R. typhi
GFPuv
) bacteria are viable, replicate with kinetics similar to those of wild-type
R. typhi
in cell culture, and stably maintain the plasmid and GFPuv expression under antibiotic treatment
in vitro
and
in vivo
during infection of mice. CB17 SCID mice infected with
R. typhi
GFPuv
succumb to the infection with kinetics similar to those for animals infected with wild-type
R. typhi
and develop comparable pathology and bacterial loads in the organs, demonstrating that the plasmid does not influence pathogenicity. In the spleen and liver of infected CB17 SCID mice, the bacteria are detectable by immunofluorescence microscopy in neutrophils and macrophages by histological staining. Finally, we show for the first time that transformed rickettsiae can be used for the detection of CD8
+
T cell responses. GFP-specific restimulation of spleen cells from
R. typhi
GFPuv
-infected BALB/c mice elicits gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 2 (IL-2) secretion by CD8
+
T cells. Thus,
R. typhi
GFPuv
bacteria are a novel, potent tool to study infection with the pathogen
in vitro
and
in vivo
and the immune response to these bacteria.
Interferon Regulatory Factor 6 Promotes Keratinocyte Differentiation in Response to Porphyromonas gingivalis
Authors: Huynh Jennifer , Scholz Glen M. , Aw Jiamin , Reynolds Eric C.
Published: March 2017

We recently demonstrated that the expression of the interferon regulatory factor 6 (IRF6) transcription factor in oral keratinocytes was stimulated by the periodontal pathogen
Porphyromonas gingivalis
. Here, we have established that IRF6 promotes the differentiation of oral keratinocytes in response to
P. gingivalis
. This was evidenced by the IRF6-dependent upregulation of specific markers of keratinocyte terminal differentiation (e.g., involucrin [IVL] and keratin 13 [KRT13]), together with additional transcriptional regulators of keratinocyte differentiation, including Grainyhead-like 3 (GRHL3) and Ovo-like zinc finger 1 (OVOL1). We have previously established that the transactivator function of IRF6 is activated by receptor-interacting protein kinase 4 (RIPK4). Consistently, the silencing of RIPK4 inhibited the stimulation of IVL, KRT13, GRHL3, and OVOL1 gene expression. IRF6 was shown to also regulate the stimulation of transglutaminase-1 (TGM1) gene expression by
P. gingivalis
, as well as that of small proline-rich proteins (e.g., SPRR1), which are covalently cross-linked by TGM1 to other proteins, including IVL, during cornification. The expression of the tight junction protein occludin (OCLN) was found to also be upregulated in an IRF6-dependent manner. IRF6 was demonstrated to be important for the barrier function of oral keratinocytes; specifically, silencing of IRF6 increased
P. gingivalis
-induced intercellular permeability and cell invasion. Taken together, our findings potentially position IRF6 as an important mediator of barrier defense against
P. gingivalis
.
The Small Protein SgrT Controls Transport Activity of the Glucose-Specific Phosphotransferase System
Authors: Lloyd Chelsea R. , Park Seongjin , Fei Jingyi , Vanderpool Carin K.
Published: March 2017

The bacterial small RNA (sRNA) SgrS has been a fruitful model for discovery of novel RNA-based regulatory mechanisms and new facets of bacterial physiology and metabolism. SgrS is one of only a few characterized dual-function sRNAs. SgrS can control gene expression posttranscriptionally via sRNA-mRNA base-pairing interactions. Its second function is coding for the small protein SgrT. Previous work demonstrated that both functions contribute to relief of growth inhibition caused by glucose-phosphate stress, a condition characterized by disrupted glycolytic flux and accumulation of sugar phosphates. The base-pairing activity of SgrS has been the subject of numerous studies, but the activity of SgrT is less well characterized. Here, we provide evidence that SgrT acts to specifically inhibit the transport activity of the major glucose permease PtsG. Superresolution microscopy demonstrated that SgrT localizes to the cell membrane in a PtsG-dependent manner. Mutational analysis determined that residues in the N-terminal domain of PtsG are important for conferring sensitivity to SgrT-mediated inhibition of transport activity. Growth assays support a model in which SgrT-mediated inhibition of PtsG transport activity reduces accumulation of nonmetabolizable sugar phosphates and promotes utilization of alternative carbon sources by modulating carbon catabolite repression. The results of this study expand our understanding of a basic and well-studied biological problem, namely, how cells coordinate carbohydrate transport and metabolism. Further, this work highlights the complex activities that can be carried out by sRNAs and small proteins in bacteria.

IMPORTANCE
Sequencing, annotation and investigation of hundreds of bacterial genomes have identified vast numbers of small RNAs and small proteins, the majority of which have no known function. In this study, we explore the function of a small protein that acts in tandem with a well-characterized small RNA during metabolic stress to help bacterial cells maintain balanced metabolism and continue growing. Our results indicate that this protein acts on the glucose transport system, inhibiting its activity under stress conditions in order to allow cells to utilize alternative carbon sources. This work sheds new light on a key biological problem: how cells coordinate carbohydrate transport and metabolism. The study also expands our understanding of the functional capacities of small proteins.
Timing of the decline in physical activity in childhood and adolescence: Gateshead Millennium Cohort Study
Authors: Farooq Mohammed Abdulaziz , Parkinson Kathryn N , Adamson Ashley J , Pearce Mark S , Reilly Jessica K , Hughes Adrienne R , Janssen Xanne , Basterfield Laura , Reilly John J
Published: March 2017

Background and aim

There is a widely held and influential view that physical activity begins to decline at adolescence. This study aimed to identify the timing of changes in physical activity during childhood and adolescence.

Methods

Longitudinal cohort study (Gateshead Millennium Study) with 8 years of follow-up, from North-East England. Cohort members comprise a socioeconomically representative sample studied at ages 7, 9, 12 and 15 years; 545 individuals provided physical activity data at two or more time points. Habitual total volume of physical activity and moderate-to-vigorous intensity physical activity (MVPA) were quantified objectively using the Actigraph accelerometer over 5–7 days at the four time points. Linear mixed models identified the timing of changes in physical activity across the 8-year period, and trajectory analysis was used to identify subgroups with distinct patterns of age-related changes.

Results

Four trajectories of change in total volume of physical activity were identified representing 100% of all participants: all trajectories declined from age 7 years. There was no evidence that physical activity decline began at adolescence, or that adolescent declines in physical activity were substantially greater than the declines during childhood, or greater in girls than boys. One group (19% of boys) had relatively high MVPA which remained stable between ages 7 and15 years.

Conclusions

Future policy and research efforts to promote physical activity should begin well before adolescence, and should include both boys and girls.
Exploiting social influence to magnify population-level behaviour change in maternal and child health: study protocol for a randomised controlled trial of network targeting algorithms in rural Honduras
Authors: Shakya Holly B , Stafford Derek , Hughes D Alex , Keegan Thomas , Negron Rennie , Broome Jai , McKnight Mark , Nicoll Liza , Nelson Jennifer , Iriarte Emma , Ordonez Maria , Airoldi Edo , Fowler James H , Christakis Nicholas A
Published: March 2017

Introduction

Despite global progress on many measures of child health, rates of neonatal mortality remain high in the developing world. Evidence suggests that substantial improvements can be achieved with simple, low-cost interventions within family and community settings, particularly those designed to change knowledge and behaviour at the community level. Using social network analysis to identify structurally influential community members and then targeting them for intervention shows promise for the implementation of sustainable community-wide behaviour change.

Methods and analysis

We will use a detailed understanding of social network structure and function to identify novel ways of targeting influential individuals to foster cascades of behavioural change at a population level. Our work will involve experimental and observational analyses. We will map face-to-face social networks of 30 000 people in 176 villages in Western Honduras, and then conduct a randomised controlled trial of a friendship-based network-targeting algorithm with a set of well-established care interventions. We will also test whether the proportion of the population targeted affects the degree to which the intervention spreads throughout the network. We will test scalable methods of network targeting that would not, in the future, require the actual mapping of social networks but would still offer the prospect of rapidly identifying influential targets for public health interventions.

Ethics and dissemination

The Yale IRB and the Honduran Ministry of Health approved all data collection procedures (Protocol number 1506016012) and all participants will provide informed consent before enrolment. We will publish our findings in peer-reviewed journals as well as engage non-governmental organisations and other actors through venues for exchanging practical methods for behavioural health interventions, such as global health conferences. We will also develop a ‘toolkit’ for practitioners to use in network-based intervention efforts, including public release of our network mapping software.

Trial registration number

NCT02694679; Pre-results.
Efficacy and safety of lapatinib and trastuzumab for HER2-positive breast cancer: a systematic review and meta-analysis of randomised controlled trials
Authors: Xu Zhi-qiao , Zhang Yan , Li Ning , Liu Pei-jie , Gao Ling , Gao Xin , Tie Xiao-jing
Published: March 2017

Objectives

The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour actively in models of HER2-positive breast cancer. However, the efficacy of trastuzumab in combination with lapatinib remains controversial. Therefore, we conducted this meta-analysis to compare combination treatment with lapatinib and trastuzumab to trastuzumab or lapatinib alone in the treatment of HER2-positive breast cancer.

Methods

Randomised controlled trials (RCTs), published in PubMed, Embase and Web of Science, were systematically reviewed to assess the survival benefits and toxicity profile of HER2-positive patients with breast cancer who were treated with lapatinib and trastuzumab. Outcomes included pathological complete response (pCR), event-free survival (EFS), overall survival (OS) and toxicities. Results were expressed as the risk ratio (RR) or HR with 95% CIs. Pooled estimates were calculated by using a fixed-effects model or a randomised-effects model.

Results

A total of 7 RCTs involving 2084 patients met the inclusion criteria and were included in this meta-analysis. The combination of lapatinib and trastuzumab significantly improved pCR (RR=1.43, 95% CI 1.23 to 1.67; p<0.001), EFS (HR=0.75, 95% CI 0.60 to 0.93; p=0.009) and OS (HR=0.72, 95% CI 0.56 to 0.93; p=0.011) in the treatment of HER2-positive breast cancer compared with trastuzumab or lapatinib alone. The combination treatment also increased the pCR irrespective of hormone receptor status and tumour size. More frequent grade 3 or 4 adverse events, including diarrhoea, rash or erythema, neutropenia and hepatic adverse events, were found in the combination group than in the trastuzumab or lapatinib group.

Conclusions

On the basis of the current evidence, our results reveal that the addition of lapatinib to trastuzumab can significantly improve pCR, EFS and OS with a tolerated toxicity in patients with HER2-positive breast cancer. Further well-conducted, large-scale trials are needed to validate these findings.
Knowledge and attitudes of UK university students in relation to ultraviolet radiation (UVR) exposure and their sun-related behaviours: a qualitative study
Authors: Kirk Lucy , Greenfield Sheila
Published: March 2017

Objectives

To explore whether knowledge about the harms of ultraviolet radiation (UVR) influences UK university students' sun-related behaviours and examine in depth their attitudes towards: sun protection, natural and artificial tanning behaviours.

Design

Qualitative methodology with 15 semistructured, individual interviews. Thematic analysis using the Framework Method with analyst triangulation and member validation.

Setting

One university in the West Midlands, UK.

Participants

15 Caucasian male (n=4) and female (n=11) students, aged 18–22 years, from a UK university. Participants were recruited using convenience sampling from the university's main campus followed by purposive sampling for: gender, course and sun-related behaviours.

Results

Five main themes emerged: (1)knowledge of UVR; (2) sun-protection practices; (3) attitudes towards tanning; (4) external influences and (5) internal influences. All students knew the associated skin cancer risks from the sun and sunbed use, but this did not appear an important influence in their sun-related behaviours. Body image strongly motivated sun-protection practices and the desire to tan naturally or artificially, across both genders. However, participants' final decision-making appeared to be influenced by their beliefs that practising known harmful sun-related behaviours would not affect them or the perceived susceptibility to sunburn. Beliefs about sunbathing and sunscreen use prompted improper use of sun protection and inadvertently caused more harmful practices. Participants' peers, family and the media had dual roles influencing the development of attitudes towards sun protection and tanning, which contributed to how participants behaved in the sun and their engagement in tanning methods.

Conclusions

Knowledge about the risk of skin cancer associated with UVR did not strongly influence sun-related behaviours, whereas body image appeared as a key motivator. Attitudes towards sun protection and tanning stemmed from the media, peers and family, and particularly from childhood habits. Public health strategies may benefit from appearance-related skin cancer prevention campaigns, encouraging safer parental sun-related habits and correcting sun-related misconceptions.
Paediatric early warning systems for detecting and responding to clinical deterioration in children: a systematic review
Authors: Lambert Veronica , Matthews Anne , MacDonell Rachel , Fitzsimons John
Published: March 2017

Objective

To systematically review the available evidence on paediatric early warning systems (PEWS) for use in acute paediatric healthcare settings for the detection of, and timely response to, clinical deterioration in children.

Method

The electronic databases PubMed, MEDLINE, CINAHL, EMBASE and Cochrane were searched systematically from inception up to August 2016. Eligible studies had to refer to PEWS, inclusive of rapid response systems and teams. Outcomes had to be specific to the identification of and/or response to clinical deterioration in children (including neonates) in paediatric hospital settings (including emergency departments). 2 review authors independently completed the screening and selection process, the quality appraisal of the retrieved evidence and data extraction; with a third reviewer resolving any discrepancies, as required. Results were narratively synthesised.

Results

From a total screening of 2742 papers, 90 papers, of varied designs, were identified as eligible for inclusion in the review. Findings revealed that PEWS are extensively used internationally in paediatric inpatient hospital settings. However, robust empirical evidence on which PEWS is most effective was limited. The studies examined did however highlight some evidence of positive directional trends in improving clinical and process-based outcomes for clinically deteriorating children. Favourable outcomes were also identified for enhanced multidisciplinary team work, communication and confidence in recognising, reporting and making decisions about child clinical deterioration.

Conclusions

Despite many studies reporting on the complexity and multifaceted nature of PEWS, no evidence was sourced which examined PEWS as a complex healthcare intervention. Future research needs to investigate PEWS as a complex multifaceted sociotechnical system that is embedded in a wider safety culture influenced by many organisational and human factors. PEWS should be embraced as a part of a larger multifaceted safety framework that will develop and grow over time with strong governance and leadership, targeted training, ongoing support and continuous improvement.