bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endosymbiotic Gene Transfer in Tertiary Plastid-Containing Dinoflagellates
Authors: Burki Fabien , Imanian Behzad , Hehenberger Elisabeth , Hirakawa Yoshihisa , Maruyama Shinichiro , Keeling Patrick J. 
Published: December 2013

ABSTRACTPlastid establishment involves the transfer of endosymbiotic genes to the host nucleus, a process known as endosymbiotic gene transfer (EGT). Large amounts of EGT have been shown in several photosynthetic lineages but also in present-day plastid-lacking organisms, supporting the notion that endosymbiotic genes leave a substantial genetic footprint in the host nucleus. Yet the extent of this genetic relocation remains debated, largely because the long period that has passed since most plastids originated has erased many of the clues to how this process unfolded. Among the dinoflagellates, however, the ancestral peridinin-containing plastid has been replaced by tertiary plastids on several more recent occasions, giving us a less ancient window to examine plastid origins. In this study, we evaluated the endosymbiotic contribution to the host genome in two dinoflagellate lineages with tertiary plastids. We generated the first nuclear transcriptome data sets for the “dinotoms,” which harbor diatom-derived plastids, and analyzed these data in combination with the available transcriptomes for kareniaceans, which harbor haptophyte-derived plastids. We found low level of detectable EGT in both dinoflagellate lineages, with only 9 genes and 90 genes of possible tertiary endosymbiotic origin in dinotoms and kareniaceans, respectively, suggesting that tertiary endosymbioses did not heavily impact the host dinoflagellate genomes.
Ght Protein of Neisseria meningitidis Is Involved in the Regulation of Lipopolysaccharide Biosynthesis
Authors: Putker Florian , Grutsch Andreas , Tommassen Jan , Bos Martine P. 
Published: December 2013

ABSTRACT

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and is responsible for the barrier function of this membrane. A
ght
mutant of
Neisseria meningitidis
that showed increased sensitivity to hydrophobic toxic compounds, suggesting a breach in this permeability barrier, was previously described. Here, we assessed whether this phenotype was possibly caused by a defect in LPS transport or synthesis. The total amount of LPS appeared to be drastically reduced in a
ght
mutant, but the residual LPS was still detected at the cell surface, suggesting that LPS transport was not impaired. The
ght
mutant was rapidly overgrown by pseudorevertants that produced normal levels of LPS. Genetic analysis of these pseudorevertants revealed that the
lpxC
gene, which encodes a key enzyme in LPS synthesis, was fused to the promoter of the upstream-located
pilE
gene, resulting in severe
lpxC
overexpression. Analysis of
phoA
and
lacZ
gene fusions indicated that Ght is an inner membrane protein with an N-terminal membrane anchor and its bulk located in the cytoplasm, where it could potentially interact with LpxC. Cell fractionation experiments indeed indicated that Ght tethers LpxC to the membrane. We suggest that Ght regulates LPS biosynthesis by affecting the activity of LpxC. Possibly, this mechanism acts in the previously observed feedback inhibition of LPS synthesis that occurs when LPS transport is hampered.
The MiaA tRNA Modification Enzyme Is Necessary for Robust RpoS Expression in Escherichia coli
Authors: Thompson Karl M. , Gottesman Susan 
Published: December 2013

ABSTRACT

The stationary phase/general stress response sigma factor RpoS (σ
S
) is necessary for adaptation and restoration of homeostasis in stationary phase. As a physiological consequence, its levels are tightly regulated at least at two levels. Multiple small regulatory RNA molecules modulate its translation, in a manner that is dependent on the RNA chaperone Hfq and the
rpoS
5′ untranslated region. ClpXP and the RssB adaptor protein degrade RpoS, unless it is protected by an anti-adaptor. We here find that, in addition to these posttranscriptional levels of regulation, tRNA modification also affects the steady-state levels of RpoS. We screened mutants of several RNA modification enzymes for an effect on RpoS expression and identified the
miaA
gene, encoding a tRNA isopentenyltransferase, as necessary for full expression of both an
rpoS750-lacZ
translational fusion and the RpoS protein. This effect is independent of
rpoS
, the regulatory RNAs, and RpoS degradation. RpoD steady-state levels were not significantly different in the absence of MiaA, suggesting that this is an RpoS-specific effect. The
rpoS
coding sequence is significantly enriched for
leu
codons that use MiaA-modified tRNAs, compared to
rpoD
and many other genes. Dependence on MiaA may therefore provide yet another way for RpoS levels to respond to growth conditions.
Is previous history a reliable predictor for acute mountain sickness susceptibility? A meta-analysis of diagnostic accuracy
Authors: MacInnis Martin J , Lohse Keith R , Strong Jenny K , Koehle Michael S 
Published: December 2013

PurposeThe goal of this meta-analysis was to determine the clinical utility of acute mountain sickness (AMS) history to predict future incidents of AMS.Method17 studies (n=7921 participants) were included following a systematic review of the literature. A bivariate random-effects model was used to calculate the summary sensitivity and specificity of the diagnostic test, and moderator variables were tested to explain the heterogeneity across studies. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) method was used to assess concerns for bias and applicability for the included studies.ResultsThe history of AMS had a low diagnostic accuracy for the prediction of future AMS incidents: the summary sensitivity was 0.50 (95% CI (0.40 to 0.59)) and the summary specificity was 0.72 (95% CI (0.66 to 0.78)). There was significant heterogeneity in the sensitivity and specificity across studies, which we modelled using moderator analysis. Studies that restricted the use of acetazolamide and dexamethasone had not only a higher sensitivity (0.66) relative to those that did not (0.44; p=0.03) but also an increased false-positive rate (0.39 vs 0.23, p=0.03). The QUADAS-2 analysis showed that AMS histories were insufficiently detailed, and few studies controlled for prophylactic medication use or recent altitude exposure, leading to high risks of bias and concerns for applicability.ConclusionsThe use of AMS history to guide prophylactic strategies for high-altitude ascent is not supported by the literature; however, the low sensitivity and specificity of this diagnostic test could reflect the quality of the available studies. Ensuring that the characteristics of the history and future ascents are similar may improve the clinical utility of AMS history.
Using accelerometers to measure physical activity in large-scale epidemiological studies: issues and challenges
Authors: Lee I-Min , Shiroma Eric J 
Published: December 2013

BackgroundThe current guidelines for aerobic activity require that adults carry out ≥150 min/week of moderate-intensity physical activity, with a large body of epidemiological evidence showing this level of activity to decrease the incidence of many chronic diseases. Less is known about whether light-intensity activities also have such benefits, and whether sedentary behaviour is an independent predictor of increased risks of these chronic diseases, as imprecise assessments of these behaviours and cross-sectional study designs have limited knowledge to date.MethodsRecent technological advances in assessment methods have made the use of movement sensors, such as the accelerometer, feasible for use in longitudinal, large-scale epidemiological studies. Several such studies are collecting sensor-assessed, objective measures of physical activity with the aim of relating these to the development of clinical endpoints. This is a relatively new area of research; thus, in this article, we use the Women's Health Study (WHS) as a case study to illustrate the challenges related to data collection, data processing and analyses of the vast amount of data collected.ResultsThe WHS plans to collect 7 days of accelerometer-assessed physical activity and sedentary behaviour in ∼18 000 women aged ≥62 years. Several logistical challenges exist in collecting data; nonetheless, as of 31 August 2013, 11 590 women have already provided some data. In addition, the WHS experience on data reduction and data analyses can help inform other similar large-scale epidemiological studies.ConclusionsImportant data on the health effects of light-intensity activity and sedentary behaviour will emerge from large-scale epidemiological studies collecting objective assessments of these behaviours.
Risk Factors for Early Childhood Infection of Human Herpesvirus-8 in Zambian Children: The Role of Early Childhood Feeding Practices
Authors: Crabtree Kay L. , Wojcicki Janet M. , Minhas Veenu , Smith David R. , Kankasa Chipepo , Mitchell Charles D. , Wood Charles 
Published: December 2013

AbstractBackground: Human herpesvirus-8 (HHV-8) infection in early childhood is common throughout sub-Saharan Africa with prevalence increasing throughout childhood. Specific routes of transmission have not been clearly delineated, though HHV-8 is present in high concentrations in saliva.Methods: To understand the horizontal transmission of HHV-8 within households to children, we enrolled for cross-sectional analysis, 251 households including 254 children, age two and under, in Lusaka, Zambia. For all children, plasma was screened for HHV-8 and HIV type I (HIV-1) and health and behavioral questionnaires were completed. Multilevel logistic regression analysis was conducted to assess independent factors for HHV-8 infection in children.Results: Risk factors for HHV-8 infection included increasing number of HHV-8–positive household members [OR = 2.5; 95% confidence interval (CI), 1.9–3.3; P &lt; 0.01] and having a primary caregiver who tested the temperature of food with their tongue before feeding the child (OR = 2.4; 95% CI, 1.93–3.30; P = 0.01). Breastfeeding was protective against infection with HHV-8 for children (OR = 0.3; 95% CI, 0.16–0.72; P &lt; 0.01).Conclusions: These results indicate that exposure to HHV-8 in the household increases risk for early childhood infection, with specific feeding behaviors likely playing a role in transmission.Impact: Interventions to protect children from infection should emphasize the possibility of infection through sharing of foods. Cancer Epidemiol Biomarkers Prev; 23(2); 300–8. ©2013 AACR.
Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients
Authors: Govindaraj Chindu , Tan Peter , Walker Patricia , Wei Andrew , Spencer Andrew , Plebanski Magdalena 
Published: December 2013

Abstract
Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)–expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2+ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2+ Tregs.
Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2+ Tregs were analyzed subsequently.
Results: We report that TNFR2+ Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2+ Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2+ Tregs were associated with increases in Interferon (IFN)-γ and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs.
Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2+ Tregs, resulting in clinical benefits within patients with AML. Clin Cancer Res; 20(3); 724–35. ©2013 AACR.
Acquired Resistance to Dasatinib in Lung Cancer Cell Lines Conferred byDDR2Gatekeeper Mutation andNF1Loss
Authors: Beauchamp Ellen M. , Woods Brittany A. , Dulak Austin M. , Tan Li , Xu Chunxiao , Gray Nathanael S. , Bass Adam J. , Wong Kwok-kin , Meyerson Matthew , Hammerman Peter S. 
Published: December 2013

AbstractThe treatment of non–small cell lung cancer has evolved dramatically over the past decade with the adoption of widespread use of effective targeted therapies in patients with distinct molecular alterations. In lung squamous cell carcinoma (lung SqCC), recent studies have suggested that DDR2 mutations are a biomarker for therapeutic response to dasatinib and clinical trials are underway testing this hypothesis. Although targeted therapeutics are typically quite effective as initial therapy for patients with lung cancer, nearly all patients develop resistance with long-term exposure to targeted drugs. Here, we use DDR2-dependent lung cancer cell lines to model acquired resistance to dasatinib therapy. We perform targeted exome sequencing to identify two distinct mechanisms of acquired resistance: acquisition of the T654I gatekeeper mutation in DDR2 and loss of NF1. We show that NF1 loss activates a bypass pathway, which confers ERK dependency downstream of RAS activation. These results indicate that acquired resistance to dasatinib can occur via both second-site mutations in DDR2 and by activation of bypass pathways. These data may help to anticipate mechanisms of resistance that may be identified in upcoming clinical trials of anti-DDR2 therapy in lung cancer and suggest strategies to overcome resistance. Mol Cancer Ther; 13(2); 475–82. ©2013 AACR.
Association of Heart Rate at Hospital Discharge With Mortality and Hospitalizations in Patients With Heart Failure
Authors: Habal Marlena V. , Liu Peter P. , Austin Peter C. , Ross Heather J. , Newton Gary E. , Wang Xuesong , Tu Jack V. , Lee Douglas S. 
Published: December 2013

Background—
Heart failure (HF) is associated with a high burden of morbidity and mortality. Hospital discharge is an opportunity for identification of modifiable prognostic factors in the transition to chronic HF.

Methods and Results—

We examined the association of discharge heart rate with 30-day and 1-year mortality and hospitalization outcomes in a cohort of 9097 patients with HF discharged from hospital. Discharge heart rate was categorized into predefined groups: 40 to 60 (n=1333), 61 to 70 (n=2170), 71 to 80 (n=2631), 81 to 90 (n=1700), and >90 bpm (n=1263). There was a significant increase in all-cause 30-day mortality with adjusted odds ratios of 1.59 (95% confidence interval [CI], 1.18–2.14;
P
=0.003) for discharge heart rates 81 to 90 bpm and 1.56 (95% CI, 1.13–2.16;
P
=0.007) for heart rates >90 bpm when compared with the reference group (heart rates, 61–70 bpm). Cardiovascular death risk at 30 days was also higher with adjusted odds ratio 1.59 (discharge heart rates, 81–90 bpm; 95% CI, 1.09–2.33;
P
=0.017) and 1.65 (discharge heart rates, >90 bpm; 95% CI, 1.09–2.48;
P
=0.017). One-year all-cause mortality (adjusted odds ratio, 1.41; 95% CI, 1.16–1.72;
P
<0.001) and cardiovascular death (adjusted odds ratio, 1.47; 95% CI, 1.12–1.92;
P
=0.005) were higher with discharge heart rates >90 bpm when compared with the reference group (heart rates, 40–60 bpm). Readmissions for HF (adjusted hazard ratio, 1.26; 95% CI, 1.04–1.54;
P
=0.021) and cardiovascular disease (adjusted hazard ratio, 1.29; 95% CI, 1.08–1.54;
P
=0.004) within 30 days were also higher with discharge heart rates >90 bpm.

Conclusions—
Higher discharge heart rates were associated with greater risk of all-cause and cardiovascular mortality ≤1-year follow-up and an elevated risk of 30-day readmission for HF and cardiovascular disease.
High Prevalence of Occult Pulmonary Venous Hypertension Revealed by Fluid Challenge in Pulmonary Hypertension
Authors: Robbins Ivan M. , Hemnes Anna R. , Pugh Meredith E. , Brittain Evan L. , Zhao David X. , Piana Robert N. , Fong Pete P. , Newman John H. 
Published: December 2013

Background—
Determining the cause for pulmonary hypertension is difficult in many patients. Pulmonary arterial hypertension (PAH) is differentiated from pulmonary venous hypertension (PVH) by a wedge pressure (PWP) >15 mm Hg in PVH. Patients undergoing right heart catheterization for evaluation of pulmonary hypertension may be dehydrated and have reduced intravascular volume, potentially leading to a falsely low measurement of PWP and an erroneous diagnosis of PAH. We hypothesized that a fluid challenge during right heart catheterization would identify occult pulmonary venous hypertension (OPVH).

Methods and Results—

We reviewed the results of patients undergoing fluid challenge in our pulmonary hypertension database from 2004 to 2011. Baseline hemodynamics were obtained and repeated after infusion of 0.5 L of normal saline for 5 to 10 minutes. Patients were categorized as OPVH if PWP increased to >15 mm Hg after fluid challenge. Baseline hemodynamics in 207 patients met criteria for PAH. After fluid challenge, 46 patients (22.2%) developed a PWP >15 mm Hg and were reclassified as OPVH. Patients with OPVH had a greater increase in PWP compared with patients with PAH,
P
<0.001, and their demographics and comorbid illnesses were similar to patients with PVH. There were no adverse events related to fluid challenge.

Conclusions—
Fluid challenge at the time of right heart catheterization is easily performed, safe, and identifies a large group of patients diagnosed initially with PAH, but for whom OPVH contributes to pulmonary hypertension. These results have implications for therapeutic trials in PAH and support the routine use of fluid challenge during right heart catheterization in patients with risk factors for PVH.
Increased Sarcolipin Expression and Adrenergic Drive in Humans With Preserved Left Ventricular Ejection Fraction and Chronic Isolated Mitral Regurgitation
Authors: Zheng Junying , Yancey Danielle M. , Ahmed Mustafa I. , Wei Chih-Chang , Powell Pamela C. , Shanmugam Mayilvahanan , Gupta Himanshu , Lloyd Steven G. , McGiffin David C. , Schiros Chun G. , Denney Thomas S. , Babu Gopal J. , Dell’Italia Louis J. 
Published: December 2013

Background—
There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into ingenuity pathway analysis in patients with isolated MR.

Methods and Results—

Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared with 13 normal controls. Cine-MRI was performed in 31 patients before surgery to measure LV function and volume from serial short-axis summation. LV end-diastolic volume was 2-fold (
P
=0.005) higher in MR patients than in normal controls, and LV ejection fraction was 64±7% (50%–79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in β-adrenergic, cAMP, and G-protein–coupled signaling, whereas there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR versus control left ventricles. However, mRNA and protein levels of the sarcoplasmic reticulum Ca
2+
ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold, respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal left ventricles and its marked upregulation in MR left ventricles.

Conclusions—
These results demonstrate alterations in multiple pathways associated with β-adrenergic signaling and sarcolipin in the left ventricles of patients with isolated MR and LV ejection fraction >50%, suggesting a beneficial role for β-adrenergic blockade in isolated MR.
Incidence, Determinants, and Prognostic Significance of Hyperkalemia and Worsening Renal Function in Patients With Heart Failure Receiving the Mineralocorticoid Receptor Antagonist Eplerenone or Placebo in Addition to Optimal Medical Therapy
Authors: Rossignol Patrick , Dobre Daniela , McMurray John J.V. , Swedberg Karl , Krum Henry , van Veldhuisen Dirk J. , Shi Harry , Messig Michael , Vincent John , Girerd Nicolas , Bakris George , Pitt Bertram , Zannad Faiez 
Published: December 2013

Background—
Mineralocorticoid receptor antagonists improve outcomes in patients with systolic heart failure but may induce worsening of renal function (WRF) and hyperkalemia (HK). We assessed the risk factors for mineralocorticoid receptor antagonist–related WRF and for HK, as well as the association between HK and WRF with clinical outcomes in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).

Methods and Results—
Serial changes in estimated glomerular filtration rate and in serum potassium were available in 2737 patients during a median 21-month follow-up. HK variably defined as serum K >4.5, 5, or 5.5 mmol/L occurred in 74.7%, 32.5%, and 8.9% patients enrolled in EMPHASIS-HF, respectively. WRF defined as a decrease in estimated glomerular filtration rate >20% or >30% from baseline occurred in 27% and 14% of patients, respectively. Patients assigned eplerenone displayed modest and early but significant and persistent (1) rise in serum potassium and (2) reduction in estimated glomerular filtration rate when compared with those assigned placebo. In multivariate analyses, eplerenone was associated with a higher incidence of WRF and HK, which were interrelated and also associated with baseline patient characteristics (eg, age ≥75 years, hypertension, diabetes mellitus, nonwhite race, ejection fraction <30%, and treatment with an antiarrythmics drug or loop diuretic). Eplerenone retained its survival benefits without any significant interaction with the association between HK >5.5 mmol/L only and WRF and worse outcomes.

Conclusions—
In patients with heart failure receiving optimal therapy, WRF and HK were more frequent when eplerenone was added, but their occurrence did not eliminate the survival benefit of eplerenone.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00232180.