bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Numbers Game: Ribosome Densities, Bacterial Growth, and Antibiotic-Mediated Stasis and Death
Authors: Levin Bruce R. , McCall Ingrid C. , Perrot Véronique , Weiss Howard , Ovesepian Armen , Baquero Fernando 
Published: February 2017

ABSTRACTWe postulate that the inhibition of growth and low rates of mortality of bacteria exposed to ribosome-binding antibiotics deemed bacteriostatic can be attributed almost uniquely to these drugs reducing the number of ribosomes contributing to protein synthesis, i.e., the number of effective ribosomes. We tested this hypothesis withEscherichia coliK-12 MG1655 and constructs that had been deleted for 1 to 6 of the 7 rRNA (rrn) operons. In the absence of antibiotics, constructs with fewerrrnoperons have lower maximum growth rates and longer lag phases than those with more ribosomal operons. In the presence of the ribosome-binding “bacteriostatic” antibiotics tetracycline, chloramphenicol, and azithromycin,E. colistrains with 1 and 2rrnoperons are killed at a substantially higher rate than those with morerrnoperons. This increase in the susceptibility ofE. coliwith fewerrrnoperons to killing by ribosome-targeting bacteriostatic antibiotics is not reflected in their greater sensitivity to killing by the bactericidal antibiotic ciprofloxacin, which does not target ribosomes, but also to killing by gentamicin, which does. Finally, when such strains are exposed to these ribosome-targeting bacteriostatic antibiotics, the time before these bacteria start to grow again when the drugs are removed, referred to as the post-antibiotic effect (PAE), is markedly greater for constructs with fewerrrnoperons than for those with morerrnoperons. We interpret the results of these other experiments reported here as support for the hypothesis that the reduction in the effective number of ribosomes due to binding to these structures provides a sufficient explanation for the action of bacteriostatic antibiotics that target these structures.IMPORTANCEChemotherapeutic agents, including antibiotics, have been used for more than a century; nevertheless, there are still major gaps in our understanding of how these drugs operate which limit future advances in antibacterial chemotherapy. Although the molecular mechanisms by which antibiotics bind to their target structures are largely known, fundamental questions about how these drugs actually kill and/or inhibit the replication of bacteria remain unanswered and subjects of controversy. We postulate that for the broad class of ribosome-binding bacteriostatic antibiotics, their reducing the number of active (functional) ribosomes per cell provides a sufficient explanation for the abatement of replication and the low rate of decline in densities of viable cells of bacteria exposed to these drugs. UsingE. coliK-12 constructs with deletions of from one to six of the seven ribosome-RNA operons and the ribosome-binding bacteriostatic antibiotics tetracycline, chloramphenicol, and azithromycin, we tested this hypothesis. The results of our experiments are consistent with this “numbers game” hypothesis.
A Novel Phosphoregulatory Switch Controls the Activity and Function of the Major Catalytic Subunit of Protein Kinase A in
Aspergillus fumigatus
Authors: Shwab E. Keats , Juvvadi Praveen R. , Waitt Greg , Soderblom Erik J. , Moseley M. Arthur , Nicely Nathan I. , Asfaw Yohannes G. , Steinbach William J. 
Published: February 2017

ABSTRACT

Invasive aspergillosis (IA), caused by the filamentous fungal pathogen
Aspergillus fumigatus
, is a major cause of death among immunocompromised patients. The cyclic AMP/protein kinase A (PKA) signaling pathway is essential for hyphal growth and virulence of
A. fumigatus
, but the mechanism of regulation of PKA remains largely unknown. Here, we discovered a novel mechanism for the regulation of PKA activity in
A. fumigatus
via phosphorylation of key residues within the major catalytic subunit, PkaC1. Phosphopeptide enrichment and tandem mass spectrometry revealed the phosphorylation of PkaC1 at four sites (S175, T331, T333, and T337) with implications for important and diverse roles in the regulation of
A. fumigatus
PKA. While the phosphorylation at one of the residues (T333) is conserved in other species, the identification of three other residues represents previously unknown PKA phosphoregulation in
A. fumigatus
. Site-directed mutagenesis of the phosphorylated residues to mimic or prevent phosphorylation revealed dramatic effects on kinase activity, growth, conidiation, cell wall stress response, and virulence in both invertebrate and murine infection models. Three-dimensional structural modeling of
A. fumigatus
PkaC1 substantiated the positive or negative regulatory roles for specific residues. Suppression of PKA activity also led to downregulation of PkaC1 protein levels in an apparent novel negative-feedback mechanism. Taken together, we propose a model in which PkaC1 phosphorylation both positively and negatively modulates its activity. These findings pave the way for future discovery of fungus-specific aspects of this key signaling network.

IMPORTANCE
Our understanding of signal transduction networks in pathogenic fungi is limited, despite the increase in invasive fungal infections and rising mortality rates in the immunosuppressed patient population. Because PKA is known to be essential for hyphal growth and virulence of
A. fumigatus
, we sought to identify fungus-specific regulatory mechanisms governing PKA activity. In this study, we identify, for the first time, a novel mechanism for the regulation of PKA signaling in which differential phosphorylation of the PkaC1 catalytic subunit can lead to either positive or negative regulation of activity. Furthermore, we show that inactivation of PKA signaling leads to downregulation of catalytic subunit protein levels in a negative-feedback mechanism distinct from expression patterns previously reported in the yeasts. Our findings represent a divergence in the regulation of PKA signaling in
A. fumigatus
, which could potentially be exploited as a target and also open the avenue for discovery of fungus-specific downstream effectors of PKA.
Atmospheric K-feldspar as a potential climate modulating agent through geologic time
Authors: Pankhurst Matthew J. 
Published: February 2017

Abstract
Clouds and aerosols have a large, yet highly uncertain, effect on changes in Earth’s climate. A factor of particular note is the role played by ice-nucleating particles, which remains poorly understood. The mineral K-feldspar (Kfs) has recently been shown by a number of independent studies to nucleate ice in mixed-phase cloud conditions far more efficiently than other common minerals. Here, global atmospheric Kfs flux through geologic time is estimated; constrained by records of secular continental crust and biosphere evolution, plate tectonics, volcanism, glaciation, and attendant trends in land surface stability. The analysis reveals that Kfs flux today is at neither extreme of the range estimated across geological time. The present-day Kfs flux, however, is likely to be among the most spatially and temporally variable due to land surface change. The concept of an ice-nucleation efficiency factor that can be calculated from rocks, and also eolian sediments and soils, is proposed. This allows the impact of paleo-atmospheric dust to be estimated through the rock record alongside meteorological and atmospheric composition considerations. With the reasonable assumption that the ice-nucleating properties of Kfs are themselves independent of the background climate state, a better understanding of Kfs flux across a range of spatial and temporal scales will advance understanding of climate processes and interactions.
Long-term glacier melt fluctuations over the past 2500 yr in monsoonal High Asia revealed by radiocarbon-dated lacustrine pollen concentrates
Authors: Zhang Ji-Feng , Xu Baiqing , Turner Falko , Zhou Liping , Gao Pan , Lü Xinmiao , Nesje Atle 
Published: February 2017

Abstract
Long-term records of glacier mass changes are important for improving our understanding of glacier dynamics and for predicting the response of glaciers to future climate change. In contrast to moraine sequences that only record isolated stages of glacier status, proglacial lake sediments may record long-term continuous glacier activities. The melt of old glacier ice releases old pollen that may affect the radiocarbon ages of pollen in proglacial lake sediments. We define the offset between the calibrated pollen 14C ages and the sediment depositional age as the “old pollen effect” (OPE). In small catchments dominated by glaciers, the OPE may record variations in glacier melt intensity and extent, even though complex processes (e.g., modern pollen flux to a glacier or a proglacial lake, glacier flow velocities) may also impact the OPE. Using the sediments of a small proglacial lake on the southern Tibetan Plateau, we found that over the past 2.5 k.y., a weakened OPE occurred during three historical cool periods that coincided with regional glacier advances defined by moraine ages. Thus, we interpret the OPE as a new indicator of glacier melt intensity and its fluctuations. Our reconstructed glacier variability agrees well with glacier fluctuations in the European Alps and the global average temperature record, suggesting that hemispheric-scale temperature variations and/or mid-latitude Westerlies may have controlled the late Holocene glacier variability in monsoonal High Asia. We also show that the 20th century glacier melt intensity has exceeded that of two historical warm periods and is unprecedented over the past 2.5 k.y. This implies that current anthropogenic warming poses a serious threat to the survival of glaciers in monsoonal High Asia.
Inequality trends in maternal health services for young Ghanaian women with childbirth history between 2003 and 2014
Authors: Asamoah Benedict Oppong , Agardh Anette 
Published: February 2017

ObjectiveTo achieve universal coverage of reproductive healthcare and drastic reduction in maternal mortality, adequate attention and resources should be given to young women. This study therefore aimed to examine the inequality trends in the use of antenatal care (ANC) services and skilled birth attendance (SBA) within a subgroup of Ghanaian women aged 15–24 years between 2003 and 2014.DesignThis is a cross-sectional study that used data from the Ghana Demographic and Health Surveys (DHS) 2003, 2008 and 2014. We applied regression-based total attributable fraction (TAF) as an index for measuring multiple dimensions of inequality in the use of ANC and SBA.SettingGhana.ParticipantsYoung women aged 15–24 years with at least one previous birth experience in the past 5 years prior to the surveys.Main outcome measuresANC visits and skilled attendance at birth.ResultsUrbanicity-related, education-related and wealth-related inequality in non-use of SBA declined between 2003 and 2008, but increased between 2008 and 2014. A consistent decline was observed in urbanicity-related inequality in non-use of four or more ANC visits from 2003 through 2008 to 2014. A similar reduction was observed for education-related inequality in relation to the same outcome. In contrast, wealth-related inequality in ANC usage increased over time.ConclusionsThe rise in urbanicity-related, education-related and wealth-related inequality in the usage of SBA between 2008 and 2014 threatens the sustainability of the general progress made in the usage of maternal health services in Ghana within the same period.
Comparisons of neurodegeneration over time between healthy ageing and Alzheimer's disease cohorts via Bayesian inference
Authors: Cespedes Marcela I , Fripp Jurgen , McGree James M , Drovandi Christopher C , Mengersen Kerrie , Doecke James D 
Published: February 2017

ObjectivesIn recent years, large-scale longitudinal neuroimaging studies have improved our understanding of healthy ageing and pathologies including Alzheimer's disease (AD). A particular focus of these studies is group differences and identification of participants at risk of deteriorating to a worse diagnosis. For this, statistical analysis using linear mixed-effects (LME) models are used to account for correlated observations from individuals measured over time. A Bayesian framework for LME models in AD is introduced in this paper to provide additional insight often not found in current LME volumetric analyses.Setting and participantsLongitudinal neuroimaging case study of ageing was analysed in this research on 260 participants diagnosed as either healthy controls (HC), mild cognitive impaired (MCI) or AD. Bayesian LME models for the ventricle and hippocampus regions were used to: (1) estimate how the volumes of these regions change over time by diagnosis, (2) identify high-risk non-AD individuals with AD like degeneration and (3) determine probabilistic trajectories of diagnosis groups over age.ResultsWe observed (1) large differences in the average rate of change of volume for the ventricle and hippocampus regions between diagnosis groups, (2) high-risk individuals who had progressed from HC to MCI and displayed similar rates of deterioration as AD counterparts, and (3) critical time points which indicate where deterioration of regions begins to diverge between the diagnosis groups.ConclusionsTo the best of our knowledge, this is the first application of Bayesian LME models to neuroimaging data which provides inference on a population and individual level in the AD field. The application of a Bayesian LME framework allows for additional information to be extracted from longitudinal studies. This provides health professionals with valuable information of neurodegeneration stages, and a potential to provide a better understanding of disease pathology.
Educator engagement and interaction and children's physical activity in early childhood education and care settings: an observational study protocol
Authors: Tonge Karen L , Jones Rachel A , Hagenbuchner Markus , Nguyen Tuc V , Okely Anthony D 
Published: February 2017

IntroductionThe benefits of regular physical activity for children are significant. Previous research has addressed the quantity and quality of children's physical activity while in early childhood education and care (ECEC) settings, yet little research has investigated the social and physical environmental influences on physical activity in these settings. The outcomes of this study will be to measure these social and physical environmental influences on children's physical activity using a combination of a real-time location system (RTLS) (a closed system that tracks the location of movement of participants via readers and tags), accelerometry and direct observation.Methods and analysisThis study is the first of its kind to combine RTLSs and accelerometer data in ECEC settings. It is a cross-sectional study involving ∼100 educators and 500 children from 11 ECEC settings in the Illawarra region of New South Wales, Australia. A RTLS and Actigraph GT3X+ accelerometers will be concurrently used to measure the level and location of the children's and educators' physical activity while in outside environments. Children and educators will wear accelerometers on their hip that record triaxial acceleration data at 100 Hz. Children and educators will also wear a tag watch on their wrist that transmits a signal to anchors of the RTLS and the triangulation of signals will identify their specific location. In addition to these, up to three random periods (10–25 min in length) will be used to collect observational data each day and assessed with the classroom assessment and scoring system to measure the quality of interactions. In conjunction with the real-time location system (RTLS) and accelerometers, these observations will measure the relationship between the quality of interactions and children's physical activity.Ethics and disseminationThe results of this study will be disseminated through peer-reviewed publications and presentations. Ethical approval was obtained through the University of Wollongong Human Research Ethics Committee (HE14/330).
Techniques to determine the kinematics of synsedimentary normal faults and implications for fault growth models
Authors: Jackson Christopher A.-L. , Bell Rebecca E. , Rotevatn Atle , Tvedt Anette B. M. 
Published: February 2017

Abstract
Normal faults grow via a sympathetic increase in their displacement and length (‘isolated model’) or by rapid establishment of their near-final length prior to significant displacement accumulation (‘constant-length model’). The isolated model has dominated the structural geology literature for >30 years, although some 3D seismic data-based studies support the constant-length model. Because they make different predictions regarding rift development, and earthquake size and recurrence intervals in areas of continental extension, it is critical to test these models with data from natural examples. Here we outline a range of techniques that constrain the kinematics of synsedimentary normal faults and thus test competing fault growth models. We then apply these techniques to three seismically imaged faults, showing that, in general, they grew in accordance with the constant-length model, although periods of relatively minor tip propagation and coeval displacement accumulation, characteristics more consistent with the isolated model, also occurred. We argue that analysis of growth strata represents the best way to test competing fault growth models; most studies utilizing this approach support the constant-length fault model, suggesting it may be more widely applicable than is currently assumed. It is plausible that the very early development of large faults is, however, characterized by the development of faults that, pre-linkage, grow in accordance with the isolated model; we may simply lack the data resolution, especially in the subsurface, to resolve this very early stage of fault growth.
CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study
Authors: Ng Chaan S. , Zhang Zheng , Lee Susanna I. , Marques Helga S. , Burgers Kyle , Su Feng , Bauza Joseph , Mannel Robert S. , Walker Joan L. , Huh Warner King , Rubin Stephen C. , DiSilvestro Paul , Martin Lainie P. , Chan John K. , Bookman Michael A. , Coleman Robert L. , Lee Ting-Yim 
Published: February 2017

Abstract
Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial.
Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons.
Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (P = 0.028), while BF achieves borderline significance (P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3–6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status (P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS.
Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684–91. ©2017 AACR.
Exposure–Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients
Authors: LaCerte Carl , Ivaturi Vijay , Gobburu Joga , Greer Jacqueline M. , Doyle L. Austin , Wright John J. , Karp Judith E. , Rudek Michelle A. 
Published: February 2017

Abstract
Purpose: To elucidate any differences in the exposure–response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.
Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure–response relationships using unbound flavopiridol AUC were explored using recursive partitioning.
Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).
Conclusions: Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592–600. ©2017 AACR.
Sensorless Control of a Fault Tolerant PMSM Drives in Case of Single-phase Open Circuit Fault
Authors: Saleh Kamel , Sumner Mark 
Published: February 2017

This paper introduces a sensorless-speed-controlled PMSM motor fed by a four-leg inverter in case of a single phase open circuit fault regardless in which phase is the fault. To minimize the system performance degradation due to a single phase open circuit fault, a fault tolerant control strategy that includes taking appropriate actions to control the two remaining healthy currents is used in addition to use the fourth leg of the inverter. Tracking the saliency is done through measuring the dynamic current responses of the healthy phases of the PMSM motor due the IGBT switching actions using the fundamental PWM method without introducing any modification to the operation of the fourth leg of the inverter. Simulation results are provided to verify the effectiveness of the proposed strategy for sensorless controlling of a PMSM motor driven by a fault-tolerant four-phase inverter over a wide speed ranges under the case of a single phase open circuit.