bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coxiella burnetii Effector Proteins That Localize to the Parasitophorous Vacuole Membrane Promote Intracellular Replication
Authors: Larson Charles L. , Beare Paul A. , Voth Daniel E. , Howe Dale , Cockrell Diane C. , Bastidas Robert J. , Valdivia Raphael H. , Heinzen Robert A. 
Published: November 2014

ABSTRACT

The intracellular bacterial pathogen
Coxiella burnetii
directs biogenesis of a parasitophorous vacuole (PV) that acquires host endolysosomal components. Formation of a PV that supports
C. burnetii
replication requires a Dot/Icm type 4B secretion system (T4BSS) that delivers bacterial effector proteins into the host cell cytosol. Thus, a subset of T4BSS effectors are presumed to direct PV biogenesis. Recently, the PV-localized effector protein CvpA was found to promote
C. burnetii
intracellular growth and PV expansion. We predict additional
C. burnetii
effectors localize to the PV membrane and regulate eukaryotic vesicle trafficking events that promote pathogen growth. To identify these vacuolar effector proteins, a list of predicted
C. burnetii
T4BSS substrates was compiled using bioinformatic criteria, such as the presence of eukaryote-like coiled-coil domains. Adenylate cyclase translocation assays revealed 13 proteins were secreted in a Dot/Icm-dependent fashion by
C. burnetii
during infection of human THP-1 macrophages. Four of the Dot/Icm substrates, termed

C
oxiella

v
acuolar
p
rotein B (CvpB), CvpC, CvpD, and CvpE, labeled the PV membrane and LAMP1-positive vesicles when ectopically expressed as fluorescently tagged fusion proteins.
C. burnetii
Δ
cvpB
, Δ
cvpC
, Δ
cvpD
, and Δ
cvpE
mutants exhibited significant defects in intracellular replication and PV formation. Genetic complementation of the Δ
cvpD
and Δ
cvpE
mutants rescued intracellular growth and PV generation, whereas the growth of
C. burnetii
Δ
cvpB
and Δ
cvpC
was rescued upon cohabitation with wild-type bacteria in a common PV. Collectively, these data indicate
C. burnetii
encodes multiple effector proteins that target the PV membrane and benefit pathogen replication in human macrophages.
Protection from Systemic Candida albicans Infection by Inactivation of the Sts Phosphatases
Authors: Naseem Shamoon , Frank David , Konopka James B. , Carpino Nick 
Published: November 2014

ABSTRACT

The human fungal pathogen
Candida albicans
causes invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. The
s
uppressor of
T
CR
s
ignaling 1 (Sts-1) and Sts-2 are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets. Functional inactivation of both Sts enzymes leads to profound resistance to systemic infection by
C. albicans
, such that greater than 80% of mice lacking Sts-1 and -2 survive a dose of
C. albicans
(2.5 × 10
5
CFU/mouse) that is uniformly lethal to wild-type mice within 10 days. Restriction of fungal growth within the kidney occurs by 24 h postinfection in the mutant mice. This occurs without induction of a hyperinflammatory response, as evidenced by the decreased presence of leukocytes and inflammatory cytokines that normally accompany the antifungal immune response. Instead, the absence of the Sts phosphatases leads to the rapid induction of a unique immunological environment within the kidney, as indicated by the early induction of a proinflammatory cytokine (CXL10). Mice lacking either Sts enzyme individually display an intermediate lethality phenotype. These observations identify an opportunity to optimize host immune responses toward a deadly fungal pathogen.
Clinical Implications of Oral Candidiasis: Host Tissue Damage and Disseminated Bacterial Disease
Authors: Kong Eric F. , Kucharíková Sona , Van Dijck Patrick , Peters Brian M. , Shirtliff Mark E. , Jabra-Rizk Mary Ann 
Published: November 2014

ABSTRACT

The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species
Candida albicans
and the bacterium
Staphylococcus aureus
are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV
+
and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to
S. aureus
resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive
C. albicans
hyphal invasion coupled with
S. aureus
deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of
C. albicans
. Further, in contrast to previous findings,
S. aureus
dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal
C. albicans
infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals.
Identification of Determinants of the Utilisation of Acupuncture Treatment Using Andersen's Behavioural Model
Authors: Lee Ye-Seul , Lee In-Seon , Kim Song-Yi , Lee Hyangsook , Park Hi-Joon , Lee Hyejung , Kim Sung-Hoon , Chae Younbyoung 
Published: November 2014

Objectives The utilisation of healthcare services is the result of a complex decision-making process with different determinants. This study aims to identify the determinants of the utilisation of acupuncture treatment using Andersen's behavioural model and quality of life. Methods In this study we reviewed Korean Health Panel data, a nationally representative set of data, and analysed the utilisation of outpatient acupuncture services during 2011. A two-part model, which included predisposing, enabling and need factors of Andersen's behavioural model in model 1 and the additional factor of health-related quality of life (HRQOL, EQ-5D Korean index) in model 2, was analysed by logistic analysis to identify determinants of acupuncture service usage among subjects who visited traditional Korean medical clinics. Results The higher frequency of acupuncture service usage among patients who visited traditional Korean medical clinics was associated with gender, age, number of chronic diseases, physical disabilities and HRQOL of the subjects. Conclusions This study shows that the important determinants of the frequency of acupuncture treatment utilisation are gender, age, number of chronic diseases and the presence of physical disabilities. Our findings contribute to understanding the characteristics of patients who use acupuncture treatment and may be used as a basic resource for related policy making by government officials and medical professionals.
A systematic review of associations between environmental exposures and development of asthma in children aged up to 9 years
Authors: Dick S , Friend A , Dynes K , AlKandari F , Doust E , Cowie H , Ayres J G , Turner S W 
Published: November 2014

ObjectivesChildhood asthma is a complex condition where many environmental factors are implicated in causation. The aim of this study was to complete a systematic review of the literature describing associations between environmental exposures and the development of asthma in young children.SettingA systematic review of the literature up to November 2013 was conducted using key words agreed by the research team. Abstracts were screened and potentially eligible papers reviewed. Papers describing associations between exposures and exacerbation of pre-existing asthma were not included. Papers were placed into the following predefined categories: secondhand smoke (SHS), inhaled chemicals, damp housing/mould, inhaled allergens, air pollution, domestic combustion, dietary exposures, respiratory virus infection and medications.ParticipantsChildren aged up to 9 years.Primary outcomesDiagnosed asthma and wheeze.Results14 691 abstracts were identified, 207 papers reviewed and 135 included in the present review of which 15 were systematic reviews, 6 were meta-analyses and 14 were intervention studies. There was consistent evidence linking exposures to SHS, inhaled chemicals, mould, ambient air pollutants, some deficiencies in maternal diet and respiratory viruses to an increased risk for asthma (OR typically increased by 1.5–2.0). There was less consistent evidence linking exposures to pets, breast feeding and infant dietary exposures to asthma risk, and although there were consistent associations between exposures to antibiotics and paracetamol in early life, these associations might reflect reverse causation. There was good evidence that exposures to house dust mites (in isolation) was not associated with asthma risk. Evidence from observational and intervention studies suggest that interactions between exposures were important to asthma causation, where the effect size was typically 1.5–3.0.ConclusionsThere are many publications reporting associations between environmental exposures and modest changes in risk for asthma in young children, and this review highlights the complex interactions between exposures that further increase risk.
Driven to distraction: a prospective controlled study of a simulated ward round experience to improve patient safety teaching for medical students
Authors: Thomas Ian , Nicol Laura , Regan Luke , Cleland Jennifer , Maliepaard Drieka , Clark Lindsay , Walker Kenneth , Duncan John 
Published: November 2014

BackgroundDistraction and interruption are endemic in the clinical environment and contribute to error. This study assesses whether simulation-based training with targeted feedback can improve undergraduate management of distractions and interruptions to reduce error-making.DesignA prospective non-randomised controlled study.Methods28 final year medical students undertook a simulated baseline ward round. 14 students formed an intervention group and received immediate feedback on distractor management and error. 14 students in a control group received no feedback. After 4 weeks, students participated in a post-intervention ward round of comparable rigour. Changes in medical error and distractor management between simulations were assessed with Mann-Whitney U tests using SPSS V.21.ResultsAt baseline, error rates were high. The intervention group committed 72 total baseline errors (mean of 5.1 errors/student; median 5; range 3–7). The control group exhibited a comparable number of errors—with a total of 76 observed (mean of 5.4 errors/student; median 6; range 4–7). Many of these errors were life-threatening. At baseline distractions and interruptions were poorly managed by both groups. All forms of simulation training reduced error-making. In the intervention group the total number of errors post-intervention fell from 72 to 17 (mean 1.2 errors/student; median 1; range 0–3), representing a 76.4% fall (p<0.0001). In the control group the total number of errors also fell—from 76 to 44 (mean of 3.1 errors/student; median 3; range 1–5), representing a 42.1% reduction (p=0.0003).ConclusionsMedical students are not inherently equipped to manage common ward-based distractions to mitigate error. These skills can be taught—with simulation and feedback conferring the greatest benefit. Curricular integration of simulated ward round experiences is recommended.
Hypoxia-Induced SUMOylation of E3 Ligase HAF Determines Specific Activation of HIF2 in Clear-Cell Renal Cell Carcinoma
Authors: Koh Mei Yee , Nguyen Vuvi , Lemos Robert , Darnay Bryant G. , Kiriakova Galina , Abdelmelek Mena , Ho Thai H. , Karam Jose , Monzon Federico A. , Jonasch Eric , Powis Garth 
Published: November 2014

AbstractClear-cell renal cell cancer (CRCC) is initiated typically by loss of the tumor-suppressor VHL, driving constitutive activation of hypoxia-inducible factor-1 (HIF1) and HIF2. However, whereas HIF1 has a tumor-suppressor role, HIF2 plays a distinct role in driving CRCC. In this study, we show that the HIF1α E3 ligase hypoxia-associated factor (HAF) complexes with HIF2α at DNA to promote HIF2-dependent transcription through a mechanism relying upon HAF SUMOylation. HAF SUMOylation was induced by hypoxia, whereas HAF-mediated HIF1α degradation was SUMOylation independent. HAF overexpression in mice increased CRCC growth and metastasis. Clinically, HAF overexpression was associated with poor prognosis. Taken together, our results show that HAF is a specific mediator of HIF2 activation that is critical for CRCC development and morbidity. Cancer Res; 75(2); 316–29. ©2014 AACR.
KAP1 Promotes Proliferation and Metastatic Progression of Breast Cancer Cells
Authors: Addison Joseph B. , Koontz Colton , Fugett James H. , Creighton Chad J. , Chen Dongquan , Farrugia Mark K. , Padon Renata R. , Voronkova Maria A. , McLaughlin Sarah L. , Livengood Ryan H. , Lin Chen-Chung , Ruppert J. Michael , Pugacheva Elena N. , Ivanov Alexey V. 
Published: November 2014

Abstract
KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here, we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers. KAP1 silencing in breast cancer cells reduced proliferation and inhibited the growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. In cells where KAP1 was silenced, we identified multiple downregulated genes linked to tumor progression and metastasis, including EREG/epiregulin, PTGS2/COX2, MMP1, MMP2, and CD44, along with downregulation of multiple KRAB-ZNF proteins. KAP1-dependent stabilization of KRAB-ZNF required direct interactions with KAP1. Together, our results show that KAP1-mediated stimulation of multiple KRAB-ZNF contributes to the growth and metastasis of breast cancer. Cancer Res; 75(2); 344–55. ©2014 AACR.
Aberrant Myosin 1b Expression Promotes Cell Migration and Lymph Node Metastasis of HNSCC
Authors: Ohmura Gaku , Tsujikawa Takahiro , Yaguchi Tomonori , Kawamura Naoshi , Mikami Shuji , Sugiyama Juri , Nakamura Kenta , Kobayashi Asuka , Iwata Takashi , Nakano Hiroshi , Shimada Taketoshi , Hisa Yasuo , Kawakami Yutaka 
Published: November 2014

Abstract
Lymph node metastasis is the major clinicopathologic feature associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Here, web-based bioinformatics meta-analysis was performed to elucidate the molecular mechanism of lymph node metastasis of human HNSCC. Preferential upregulation of Myosin 1b (MYO1B) transcript in HNSCC datasets was identified. Myo1b mRNA was highly expressed in human HNSCC cells and patient tissue specimens compared with their normal counterparts as shown by quantitative PCR (qPCR) analyses. Immunohistochemistry (IHC)-detected Myo1b expression was significantly correlated with lymph node metastases in patients with oral cancer of the tongue. HNSCC with high expression of Myo1b and chemokine receptor 4 (CCR4), another metastasis-associated molecule, was strongly associated with lymph node metastasis. RNA interference (RNAi) of Myo1b in HNSCC cells, SAS and HSC4, significantly inhibited migratory and invasive abilities through decreased large protrusion formation of cell membranes. Finally, Myo1b knockdown in SAS cells significantly inhibited in vivo cervical lymph node metastases in a cervical lymph node metastatic mouse model system.
Implications: Myo1b is functionally involved in lymph node metastasis of human HNSCC through enhanced cancer cell motility and is an attractive target for new diagnostic and therapeutic strategies for patients with HNSCC. Mol Cancer Res; 13(4); 721–31. ©2014 AACR.
Re-Entry Using Anatomically Determined Isthmuses
Authors: Kapel Gijsbert F.L. , Reichlin Tobias , Wijnmaalen Adrianus P. , Piers Sebastiaan R.D. , Holman Eduard R. , Tedrow Usha B. , Schalij Martin J. , Stevenson William G. , Zeppenfeld Katja 
Published: November 2014

Background—
Ventricular tachycardia (VT) is an important cause of late morbidity and mortality in repaired congenital heart disease. The substrate often includes anatomic isthmuses that can be transected by radiofrequency catheter ablation similar to isthmus block for atrial flutter. This study evaluates the long-term efficacy of isthmus block for treatment of re-entry VT in adults with repaired congenital heart disease.

Methods and Results—
Thirty-four patients (49±13 years; 74% male) with repaired congenital heart disease who underwent radiofrequency catheter ablation of VT in 2 centers were included. Twenty-two (65%) had a preserved left and right ventricular function. Patients were inducible for 1 (interquartile range, 1–2) VT, median cycle length: 295 ms (interquartile range, 242–346). Ablation aimed to transect anatomic isthmuses containing VT re-entry circuit isthmuses. Procedural success was defined as noninducibility of any VT and transection of the anatomic isthmus and was achieved in 25 (74%) patients. During long-term follow-up (46±29 months), all patients with procedural success (18/25 with internal cardiac defibrillators) were free of VT recurrence but 7 of 18 experienced internal cardiac defibrillator-related complications. One patient with procedural success and depressed cardiac function received an internal cardiac defibrillator shock for ventricular fibrillation. None of the 18 patients (12/18 with internal cardiac defibrillators) with complete success and preserved cardiac function experienced any ventricular arrhythmia. In contrast, VT recurred in 4 of 9 patients without procedural success. Four patients died from nonarrhythmic causes.

Conclusions—
In patients with repaired congenital heart disease with preserved ventricular function and isthmus-dependent re-entry, VT isthmus ablation can be curative.
Bulk Hook Echo Raindrop Sizes Retrieved Using Mobile, Polarimetric Doppler Radar Observations
Authors: French Michael M. , Burgess Donald W. , Mansell Edward R. , Wicker Louis J. 
Published: November 2014

AbstractPolarimetric radar observations obtained by the NOAA/National Severe Storms Laboratory mobile, X-band, dual-polarization radar (NOXP) are used to investigate “hook echo” precipitation properties in several tornadic and nontornadic supercells. Hook echo drop size distributions (DSDs) were estimated using NOXP data obtained from 2009 to 2012, including during the second Verification of the Origins of Rotation in Tornadoes Experiment (VORTEX2). Differences between tornadic and nontornadic hook echo DSDs are explored, and comparisons are made with previous observations of estimated hook echo DSDs made from stationary S- and C-band Doppler radars. Tornadic hook echoes consistently contain radar gates that are characterized by small raindrops; nontornadic hook echoes are mixed between those that have some small-drop gates and those that have almost no small-drop gates. In addition, the spatial distribution of DSDs was estimated using the high-spatial-resolution data afforded by NOXP. A unique polarimetric signature, an area of relatively low values of differential radar reflectivity factor ZDR south and east of the tornado, is observed in many of the tornadic cases. Also, because most data were obtained using 2-min volumetric updates, the evolution of approximated hook echo precipitation properties was studied during parts of the life cycles of three tornadoes. In one case, there is a large decrease in the percentage of large-raindrop gates and an increase in the percentage of small-raindrop gates in the minutes leading up to tornado formation. The percentage of large-drop gates generally increases prior to and during tornado dissipation. Near-storm environmental data are used to put forth possible relationships between bulk hook echo DSDs and tornado production and life cycle.
Dynamical Adjustment of the Northern Hemisphere Surface Air Temperature Field: Methodology and Application to Observations*
Authors: Smoliak Brian V. , Wallace John M. , Lin Pu , Fu Qiang 
Published: November 2014

Abstract
The influence of atmospheric circulation changes reflected in spontaneously occurring sea level pressure (SLP) anomalies upon surface air temperature (SAT) variability and trends is investigated using partial least squares (PLS) regression, a statistical method that seeks to maximally explain covariance between a predictand time series or field and a predictor field. Applying PLS regression in any one of the three variants described in this study (pointwise, PC-wise, and fieldwise), the method yields a dynamical adjustment to the observed NH SAT field that accounts for approximately 50% of the variance in monthly mean, cold season data. It is shown that PLS regression provides a more parsimonious and statistically robust dynamical adjustment than an adjustment method based on the leading principal components of the extratropical SLP field. The usefulness of dynamical adjustment is demonstrated by applying it to the attribution of cold season SAT trends in two reference intervals: 1965–2000 and 1920–2011. The adjustment is shown to reconcile much of the spatial structure and seasonal differences in the observed SAT trends. The dynamically adjusted SAT fields obtained from this analysis provide datasets capable of being analyzed for residual variability and trends associated with thermodynamic and radiative processes.
Nonstationary Analysis of Annual Maximum Streamflow of Canada
Authors: Tan Xuezhi , Gan Thian Yew 
Published: November 2014

AbstractBoth natural climate change and anthropogenic impacts may cause nonstationarities in hydrological extremes. In this study, long-term annual maximum streamflow (AMS) records from 145 stations over Canada were used to investigate the nonstationary characteristics of AMS, which include abrupt changes and monotonic temporal trends. The nonparameteric Pettitt test was applied to detect abrupt changes, while temporal monotonic trend analysis in AMS series was conducted using the nonparameteric Mann–Kendall and Spearman tests, as well as a parametric Pearson test. Nonstationary frequency analysis of the AMS series was done using a group of nonstationary probability distributions. The nonstationary characteristics of Canadian AMS were further investigated in terms of the Hurst exponent (H), which represents the long-term persistence (LTP) of streamflow data. The results presented here indicate that for Canadian AMS data, abrupt changes are detected more frequently than monotonic trends, partly because many rivers began to be regulated in the twentieth century. Drainage basins that have experienced significant land-use changes are more likely to show temporal trends in AMS, compared to pristine basins with stable land-use conditions. The nonstationary characteristics of AMS were accounted for by fitting the data with probability distributions with time-varying parameters. Large H found in almost ⅔ of the Canadian AMS dataset indicates strong LTP, which may partly represent the presence of long-term memories in many Canadian river basins. Furthermore, H values of AMS data are positively correlated with the basin area of Canadian rivers. It seems that nonstationary frequency analysis, instead of the traditional stationary hydrologic frequency analysis, should be employed in the future.