bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats
Authors: Hoover Jennifer L. , Singley Christine M. , Elefante Philippa , DeMarsh Peter , Zalacain Magdalena , Rittenhouse Stephen 
Published: August 2017

ABSTRACT

Directly testing proposed clinical dosing regimens in nonclinical studies can reduce the risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated human exposures from phase I trials in pneumonia models with
Streptococcus pneumoniae
and
Haemophilus influenzae
and an abscess model with
Staphylococcus aureus
is presented. GSK1322322 was administered via continuous intravenous infusion to recreate 1,000- or 1,500-mg oral doses every 12 h in humans. Significant reductions (
P
≤ 0.05 for all comparisons) in bacterial numbers compared with those for the baseline controls were observed for
S. pneumoniae
and
H. influenzae
(mean log
10
reductions, 1.6 to ≥2.7 and 1.8 to 3.3 CFU/lungs, respectively) with the recreated 1,000-mg oral dose. This profile was also efficacious against
S. aureus
(mean log
10
reduction, 1.9 to 2.4 CFU/abscess). There was a nonsignificant trend for improved efficacy against
S. aureus
with the 1,500-mg oral dose (mean log
10
reduction, 2.4 to 3.1 CFU/abscess). These results demonstrate that the human oral 1,000- or 1,500-mg exposure profiles of GSK1322322 recreated in rats were effective against representative community-associated pathogens and supported selection of the 1,500-mg oral dose given every 12 h for a phase II clinical skin infection study. Furthermore, this work exemplifies how the testing of recreated human pharmacokinetic profiles can be incorporated into the development process and serve as an aid for selecting optimal dosing regimens prior to conducting large-scale clinical studies.
The
rph-1
-Encoded Truncated RNase PH Protein Inhibits RNase P Maturation of Pre-tRNAs with Short Leader Sequences in the Absence of RppH
Authors: Bowden Katherine E. , Wiese Nicholas S. , Perwez Tariq , Mohanty Bijoy K. , Kushner Sidney R. 
Published: August 2017

ABSTRACT

RNase PH, encoded by the
rph
gene, is a 3′→5′ exoribonuclease that in
E. coli
participates primarily in the 3′ maturation of pre-tRNAs and the degradation of rRNA in stationary-phase cells. Interestingly, the routinely used laboratory strains of MG1655 and W3110 have naturally acquired the
rph-1
allele, encoding a truncated catalytically inactive RNase PH protein which is widely assumed to be benign. Contrary to this assumption, we show that the
rph-1
-encoded Rph-1 protein inhibits RNase P-mediated 5′-end maturation of primary pre-tRNAs with leaders of <5 nucleotides in the absence of RppH, an RNA pyrophosphohydrolase. In contrast, RppH is not required for 5′-end maturation of endonucleolytically generated pre-tRNAs in the
rph-1
strain and for any tRNAs in Δ
rph
mutant or
rph

+

strains. We propose that the Rph-1 protein bound to the 3′ end of the substrate creates a steric hindrance that in the presence of a triphosphate at the 5′ end reduces the ability of RNase P to bind to the pre-tRNA.

IMPORTANCE
In this paper, we demonstrate that the
rph-1
mutation found in commonly used
E. coli
strains leads to the synthesis of a truncated functionally inactive RNase PH protein that interferes with the 5′-end maturation of specific tRNAs with short 5′ leaders by RNase P in the absence of RppH, an RNA pyrophosphohydrolase that converts primary 5′ triphosphates into 5′ monophosphates. The data presented indicate that the presence of the triphosphate interferes with RNase P binding to the pre-tRNA.
Early Mesozoic sinistral transpression along the Pai-Khoi–Novaya Zemlya fold–thrust belt, Russia
Authors: Curtis Michael L. , Lopez-Mir Berta , Scott Robert A. , Howard James P. 
Published: August 2017

Abstract
The NW–SE-trending Pai-Khoi fold–thrust belt links the Permian Uralian Orogen in the Polar Urals with the early Mesozoic fold belt on Novaya Zemlya. An interpretation of structural lineaments present in southern Novaya Zemlya suggests that the NW–SE-trending fold belt in southernmost Novaya Zemlya may have formed contemporaneously with parallel sinistral strike-slip faults. Analysis of regional-scale geological maps of the adjacent Pai-Khoi fold–thrust belt reveals large-scale structural relationships indicative of sinistral shear along the fold–thrust belt, including the presence of left-stepping en echelon folds within the Kara Shale Allochthon. This interpretation is corroborated by a field study of the allochthon-bounding Main Pai-Khoi Thrust, which reveals a consistently oblique tectonic stretching lineation, pitching 56° towards the east, suggesting tectonic displacement towards the west. It is therefore proposed that the Pai-Khoi fold–thrust belt is best described as a zone of sinistral inclined transpression. The interpretation of the Pai-Khoi fold–thrust belt as a zone of sinistral transpression has important implications for the interpretation of this tectonic boundary. This is reflected in a new structural cross-section through southernmost Novaya Zemlya, which is characterized by thick-skinned tectonics and steep strike-slip faults. These faults may link at depth with the Baidaratsky Fault.
Quantitative Whole Genome Sequencing of Circulating Tumor Cells Enables Personalized Combination Therapy of Metastatic Cancer
Authors: Gulbahce Natali , Magbanua Mark Jesus M. , Chin Robert , Agarwal Misha R. , Luo Xuhao , Liu Jia , Hayden Daniel M. , Mao Qing , Ciotlos Serban , Li Zhenyu , Chen Yanxiang , Chen Xingpeng , Li Yuxiang , Zhang Rebecca Yu , Lee Katharine , Tearle Rick , Park Emily , Drmanac Snezana , Rugo Hope S. , Park John W. , Drmanac Radoje , Peters Brock A. 
Published: August 2017

Abstract
Much effort has been dedicated to developing circulating tumor cells (CTC) as a noninvasive cancer biopsy, but with limited success as yet. In this study, we combine a method for isolation of highly pure CTCs using immunomagnetic enrichment/fluorescence-activated cell sorting with advanced whole genome sequencing (WGS), based on long fragment read technology, to illustrate the utility of an accurate, comprehensive, phased, and quantitative genomic analysis platform for CTCs. Whole genomes of 34 CTCs from a patient with metastatic breast cancer were analyzed as 3,072 barcoded subgenomic compartments of long DNA. WGS resulted in a read coverage of 23× per cell and an ensemble call rate of &gt;95%. These barcoded reads enabled accurate detection of somatic mutations present in as few as 12% of CTCs. We found in CTCs a total of 2,766 somatic single-nucleotide variants and 543 indels and multi-base substitutions, 23 of which altered amino acid sequences. Another 16,961 somatic single nucleotide variant and 8,408 indels and multi-base substitutions, 77 of which were nonsynonymous, were detected with varying degrees of prevalence across the 34 CTCs. On the basis of our whole genome data of mutations found in all CTCs, we identified driver mutations and the tissue of origin of these cells, suggesting personalized combination therapies beyond the scope of most gene panels. Taken together, our results show how advanced WGS of CTCs can lead to high-resolution analyses of cancers that can reliably guide personalized therapy. Cancer Res; 77(16); 4530–41. ©2017 AACR.
S100A4 Is a Biomarker and Regulator of Glioma Stem Cells That Is Critical for Mesenchymal Transition in Glioblastoma
Authors: Chow Kin-Hoe , Park Hee Jung , George Joshy , Yamamoto Keiko , Gallup Andrew D. , Graber Joel H. , Chen Yuanxin , Jiang Wen , Steindler Dennis A. , Neilson Eric G. , Kim Betty Y.S. , Yun Kyuson 
Published: August 2017

Abstract
Glioma stem cells (GSC) and epithelial–mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast with previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target. Cancer Res; 77(19); 5360–73. ©2017 AACR.
Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis
Authors: Dewar Laura J. , Alcaide Miguel , Fornika Daniel , D’Amato Luisa , Shafaatalab Sanam , Stevens Charles M. , Balachandra Thambirajah , Phillips Susan M. , Sanatani Shubhayan , Morin Ryan D. , Tibbits Glen F. 
Published: August 2017

Background—
Inherited arrhythmia syndromes are responsible for a significant portion of autopsy-negative sudden unexpected death (SUD) cases, but molecular autopsy used to identify potentially causal variants is not routinely included in SUD investigations. We collaborated with a medical examiner's office to assist in finding a diagnosis for their autopsy-negative child SUD cases.

Methods and Results—
191 child SUD cases (<5 years of age) were selected for analyses. Our next generation sequencing panel incorporated 38 inherited arrhythmia syndrome candidate genes and another 33 genes not previously investigated for variants that may underlie SUDY pathophysiology. Overall, we identified 11 potentially causal disease-associated variants in 12 cases, for an overall yield of 6.3%. We also identified 31 variants of uncertain significance in 36 cases and 16 novel variants predicted to be pathogenic in silico in 15 cases. The disease-associated variants were reported to the medical examiner to notify surviving relatives and recommend clinical assessment.

Conclusions—
We have identified variants that may assist in the diagnosis of at least 6.3% of autopsy-negative child SUD cases and reduce risk of future SUD in surviving relatives. We recommend a cautious approach to variant interpretation. We also suggest inclusion of cardiomyopathy genes as well as other candidate SUD genes in molecular autopsy analyses.
Calanthe wuxiensis (Orchidaceae: Epidendroideae), a new species from Chongqing, China
Authors: YU FENG-QIONG , DENG HONG-PING , WANG QIAN , YANG ZHI-MING 
Published: August 2017

Calanthe wuxiensis, a new species from Chongqing, China, is described and illustrated. The new species is morphologically reminiscent of C. ecarinata and C. tricarinata, from which it differs in having white lip, lateral lobes long rectangular, apex gradually expand, middle lobe disk with three dark yellow short-crests.
Sycidiphaga, a new genus of Sycophaginae Walker, 1975 (Hymenoptera, Chalcidoidea, Agaonidae) associated with Ficus subgenus Sycidium in southern China
Authors: LIU YANG , RASPLUS JEAN-YVES , NOORT SIMON VAN , LI ZI , HUANG DAWEI 
Published: August 2017

A new genus of Sycophaginae (Hymenoptera: Agaonidae), Sycidiphaga Liu, Rasplus & Huang n. gen., is described with a single new species, S. cyrtophyllae Liu, Rasplus & Huang n. sp. This species was discovered in Yun Nan and Gui Zhou, China and is associated with Ficus cyrtophylla (Moraceae, Ficus, subgenus Sycidium). The new taxon is readily distinguished from other genera of Sycophaginae by: 1) the presence of a conspicuous interantennal blade-like projection that extends well above the level of the toruli; 2) an inflated parastigma surrounded by a slight infuscation of the wing membrane; 3) the presence of a long and conspicuous median sulcus on the male pronotum; and 4) the presence of dense and long pilosity on the wings. Illustrations and a diagnosis and description of Sycidiphaga are provided, as is a key to the world genera of Sycophaginae. The phylogenetic position of Sycidiphaga was demonstrated through sequencing four gene regions of COI, Cyt b, 28s D3-D5 and EF-1α genes and conducting a phylogenetic analysis of available sequences for the subfamily. Sycidiphaga cannot be placed with confidence within Sycophaginae but several discussed characters suggest a close relationship with Idarnes Walker and Sycophaga Westwood. Interactive Lucid identification keys are available online at www.figweb.org.
On the Relationship between Regional Ocean Heat Content and Sea Surface Height
Authors: Fasullo John T. , Gent Peter R. 
Published: August 2017

Abstract
An accurate diagnosis of ocean heat content (OHC) is essential for interpreting climate variability and change, as evidenced for example by the broad range of hypotheses that exists for explaining the recent hiatus in global mean surface warming. Potential insights are explored here by examining relationships between OHC and sea surface height (SSH) in observations and two recently available large ensembles of climate model simulations from the mid-twentieth century to 2100. It is found that in decadal-length observations and a model control simulation with constant forcing, strong ties between OHC and SSH exist, with little temporal or spatial complexity. Agreement is particularly strong on monthly to interannual time scales. In contrast, in forced transient warming simulations, important dependencies in the relationship exist as a function of region and time scale. Near Antarctica, low-frequency SSH variability is driven mainly by changes in the circumpolar current associated with intensified surface winds, leading to correlations between OHC and SSH that are weak and sometimes negative. In subtropical regions, and near other coastal boundaries, negative correlations are also evident on long time scales and are associated with the accumulated effects of changes in the water cycle and ocean dynamics that underlie complexity in the OHC relationship to SSH. Low-frequency variability in observations is found to exhibit similar negative correlations. Combined with altimeter data, these results provide evidence that SSH increases in the Indian and western Pacific Oceans during the hiatus are suggestive of substantial OHC increases. Methods for developing the applicability of altimetry as a constraint on OHC more generally are also discussed.
18FDG PET/CT in Routine Surveillance of Asymptomatic Patients following Treatment of Sinonasal Neoplasms
Authors: Workman Alan D. , Glicksman Jordan T. , Parasher Arjun K. , Carey Ryan M. , Brooks Steven G. , Kennedy David W. , Nabavizadeh Seyed A. , Learned Kim O. , Palmer James N. , Adappa Nithin D. 
Published: August 2017

ObjectiveSinonasal neoplasms have a high rate of recurrence following treatment, and current guidelines support the use of a variety of surveillance techniques. Recent work demonstrates that performance parameters of surveillance modalities may differ with sinonasal tumors in particular when compared with head and neck tumors overall. This study aims to characterize the value of 18fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) as a screening tool in asymptomatic patients.Study DesignRetrospective cohort study.SettingHospital of the University of Pennsylvania and Pennsylvania hospital.MethodsRecords of asymptomatic patients without suspicious endoscopy or suspicious imaging other than PET during the first 3 years following definitive treatment for sinonasal malignancy were screened and analyzed for inclusion in the cohort. Disease recurrence was determined by biopsy following suspicious PET evaluation.ResultsPET/CT scans (n = 111) were performed for 45 disease‐free asymptomatic patients with no evidence of disease on endoscopy, and 6.3% were suspicious and prompted biopsy during this period, revealing 3 cases of disease recurrence. Overall specificity for PET/CT alone was 96.3% (95% CI, 90.7%‐99.0%), with a negative predictive value of 99% (95% CI, 94.8%‐100%). All recurrences were detected between 7 and 12 months, and all patients with true recurrence diagnosed by PET/CT had extrasinonasal involvement of tumor at the time of surgery.ConclusionWe examined performance parameters of 18FDG PET/CT in asymptomatic patients with no evidence of disease on endoscopy during the posttreatment period for sinonasal malignancy. The ability of PET/CT to detect recurrences that may be missed by structural imaging or endoscopy makes it a valuable tool for clinicians.
Measurement of the normal feline pituitary gland in brachycephalic and mesocephalic cats
Authors: Häußler Thomas Christian , von Pückler Kerstin Heike , Thiel Cetina , Enderlein Sylke , Failing Klaus , Ondreka Nele , Kramer Martin , Schmidt Martin Jürgen 
Published: August 2017

Objectives The purpose of this study was to determine differences in normal feline pituitary dimensions in brachycephalic and mesocephalic cats as a basis for establishing cryohypophysectomy in cats. Methods Measurements were performed on sagittal T2-weighted and transverse post-gadolinium T1-weighted or T1 3D fast field echo-weighted MRI images. A total of 32 brachycephalic and 27 mesocephalic cats were examined. Inter-observer reproducibility was assessed by t-test and Bland–Altman analysis. Results The cats were 0.6–15.9 years of age with a body weight range of 1.84–6.60 kg. For brachycephalic cats, the mean pituitary gland sagittal height was 2.15 ± 0.15 mm, pituitary gland transverse height was 2.42 ± 0.21 mm, pituitary gland transverse width was 4.44 ± 0.27 mm and pituitary gland sagittal length was 3.14 ± 0.30 mm. In mesocephalic cats, the pituitary gland dimensions were 2.94 ± 0.16 mm, 3.09 ± 0.26 mm, 4.73 ± 0.31 mm and 4.88 ± 0.30 mm for pituitary gland sagittal height, transverse height, transverse width and sagittal length, respectively. There was a highly significant correlation between brachycephalic and mesocephalic cats and pituitary gland height and length ( P <0.0001), respectively. Sex also had an effect on pituitary gland measurements. Neutering status had no significant effect on hypophyseal measurements. Age had a significant influence on pituitary gland height, width and length in the brachycephalic population. Inter-observer reproducibility was good to excellent. Conclusions and relevance The different pituitary measurements in brachycephalic and mesocephalic cats has to be considered if surgery comes into question. There are ranges in pituitary gland sizes, even among the mesocephalic cat population. Thus, exact measuring of the pituitary gland is crucial before any surgical intervention.
A Novel Lumbar Motion Segment Classification to Predict Changes in Segmental Sagittal Alignment After Lateral Interbody Fixation
Authors: Acosta Frank L. , Mehta Vivek A. , Arakelyan Anush , Drazin Doniel , Cortland Clarissa , Hsieh Patrick C. , Liu John C. , Pham Martin H. 
Published: August 2017

Study Design: Retrospective cohort study. Objectives: Lateral interbody fixation is being increasingly used for the correction of segmental sagittal parameters. One factor that affects postoperative correction is the resistance afforded by posterior hypertrophic facet joints in the degenerative lumbar spine. In this article, we describe a novel preoperative motion segment classification system to predict postoperative correction of segmental sagittal alignment after lateral lumbar interbody fusion. Methods: Preoperative computed tomography scans were analyzed for segmental facet osseous anatomy for all patients undergoing lateral lumbar interbody fusion at 3 institutions. Each facet was assigned a facet grade (min = 0, max = 2), and the sum of the bilateral facet grades was the final motion segment grade (MSG; min = 0, max = 4). Preoperative and postoperative segmental lordosis was measured on standing lateral radiographs. Postoperative segmental lordosis was also conveyed as a percentage of the implanted graft lordosis (%GL). Simple linear regression was conducted to predict the postoperative segmental %GL according to MSG. Results: A total of 36 patients with 59 operated levels were identified. There were 19 levels with MSG 0, 14 levels with MSG 1, 13 levels with MSG 2, 8 levels with MSG 3, and 5 levels with MSG 4. Mean %GL was 115%, 90%, 77%, 43%, and 5% for MSG 0 to 4, respectively. MSG significantly predicted postoperative %GL ( P < .01). Each increase in MSG was associated with a 28% decrease in %GL. Conclusions: We propose a novel facet-based motion segment classification system that significantly predicted postoperative segmental lordosis after lateral lumbar interbody fusion.
CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation
Authors: Bai Ming , Grieshaber-Bouyer Ricardo , Wang Junxia , Schmider Angela B. , Wilson Zachary S. , Zeng Liling , Halyabar Olha , Godin Matthew D. , Nguyen Hung N. , Levescot Anaïs , Cunin Pierre , Lefort Craig T. , Soberman Roy J. , Nigrovic Peter A. 
Published: August 2017

Key PointsLigation of CD177, a GPI-linked surface protein expressed selectively on neutrophils, blocks neutrophil migration independently of PECAM-1. Blockade reflects activation through β2 integrins, immobilizing cells via stronger integrin attachments and impaired chemokine signaling.
Evaluation of two cooling devices for construction workers by a thermal manikin
Authors: Miura Katsuhiro , Takagi Kenji , Ikematsu Kenji 
Published: August 2017

AbstractTwo kinds of wearable cooling devices were evaluated for their cooling effect by a thermal manikin. All measurements were conducted in a climatic chamber. The cooling fans worked almost 3 h. Their cooling effect was large at the head and had little effects on other parts of the manikin. They decreased the insulation of a typical clothing ensemble of outdoor workers in construction industries from 0.75 clo to 0.48 clo. The cooling vest for heat protective clothing mainly worked on the trunk. It did not have enough effect nor had steady cooling effect. But the vest worked as direct cooling device for the trunk. The effect of the fans to Standard Effective Temperature (SET) is evaluated by simulation. The difference of SETs between the case of the typical ensemble and the case with the cooling fans at 35 °C of the surrounding environment is 2.6 °C. The lower the surrounding temperature is, the larger the difference between SETs of different clothing insulation value is.