bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial and temporal transcriptomics ofSchistosoma japonicum-induced hepatic granuloma formation reveals novel roles for neutrophils
Authors: Chuah Candy , Jones Malcolm K , Burke Melissa L , Owen Helen C , Anthony Barrie J , McManus Donald P , Ramm Grant A , Gobert Geoffrey N 
Published: May 2013

ABSTRACTThe severity of schistosome egg-induced hepatic granulomatous pathology depends markedly on the nature of the host immune responses. In this study, we used LMM and microarray analysis to compare gene expression profiles of histologically distinct zones within, and directly proximal to, hepatic granulomas that developed in C57BL/6 mice infected with Schistosoma japonicum. There was significant up-regulation of type-1, type-2, and type-17 immune-associated genes within the granuloma core (adjacent to eggs), followed by increased expression of type-2 and fibrotic genes at the outer zones of granulomas. Neutrophil-associated genes were also found to be expressed differentially in the core and at the peripheral zone of granulomas, present at 7 weeks p.i., demonstrating a significant role of neutrophils in S. japonicum granulomatous pathology. The release of NETs was observed microscopically in granulomas obtained from the livers of infected mice and when human neutrophils were incubated in vitro in the presence of S. japonicum eggs. These finding are the first to suggest a novel, dual role for neutrophils in the mediation of tissue damage and repair in S. japonicum egg-induced hepatic granulomatous lesions. Together, these results provide an overview of the local events occurring within the granuloma microenvironment.
Dysregulation of Ovarian Follicular Development in Female Rat: LH Decreases FSH Sensitivity During Preantral-Early Antral Transition
Authors: Orisaka Makoto , Hattori Katsushige , Fukuda Shin , Mizutani Tetsuya , Miyamoto Kaoru , Sato Takashi , Tsang Benjamin K , Kotsuji Fumikazu , Yoshida Yoshio 
Published: May 2013

AbstractSeveral clinical studies have shown a correlation of hypersecretion of LH and polycystic ovary syndrome (PCOS), infertility, and miscarriage in women, suggesting that chronically elevated LH impairs fertility. Growth arrest of small antral follicles in PCOS is also assumed to be associated with an abnormal endocrine environment involving increased LH stimulation, a hyperandrogenic milieu, and subsequent dysregulated FSH action in the ovarian follicles. In this study, we examined whether and how LH modulates follicular development and steroid production during preantral-early antral follicle transition by using a rat preantral follicle culture system. LH augments testosterone and estradiol production in preantral follicles via up-regulating mRNA abundance of CYP17A1 and CYP19A1. LH promotes rat preantral follicle growth, and the follicular size reaches that of early antral follicles in vitro, a response attenuated by the specific androgen receptor antagonist and a targeted disruption of androgen receptor gene. Sustained follicle stimulation by LH, but not by androgen, decreases FSH receptor mRNA levels and FSH receptor signaling and inhibits FSH-induced follicular growth. The data suggest that LH promotes preantral-early antral transition via the increased synthesis and growth-promoting action of androgen. However, chronic LH stimulation impairs FSH-dependent antral follicle growth by suppressing granulosa cell FSHR expression via the modulation of intraovarian regulators, including LH-induced thecal factors.
High-Fat Feeding-Induced Hyperinsulinemia Increases Cardiac Glucose Uptake and Mitochondrial Function Despite Peripheral Insulin Resistance
Authors: Gupte Anisha A. , Minze Laurie J. , Reyes Maricela , Ren Yuelan , Wang Xukui , Brunner Gerd , Ghosn Mohamad , Cordero-Reyes Andrea M. , Ding Karen , Pratico Domenico , Morrisett Joel , Shi Zheng-Zheng , Hamilton Dale J. , Lyon Christopher J. , Hsueh Willa A. 
Published: May 2013

AbstractIn obesity, reduced cardiac glucose uptake and mitochondrial abnormalities are putative causes of cardiac dysfunction. However, high-fat diet (HFD) does not consistently induce cardiac insulin resistance and mitochondrial damage, and recent studies suggest HFD may be cardioprotective. To determine cardiac responses to HFD, we investigated cardiac function, glucose uptake, and mitochondrial respiration in young (3-month-old) and middle-aged (MA) (12-month-old) male Ldlr−/− mice fed chow or 3 months HFD to induce obesity, systemic insulin resistance, and hyperinsulinemia. In MA Ldlr−/− mice, HFD induced accelerated atherosclerosis and nonalcoholic steatohepatitis, common complications of human obesity. Surprisingly, HFD-fed mice demonstrated increased cardiac glucose uptake, which was most prominent in MA mice, in the absence of cardiac contractile dysfunction or hypertrophy. Moreover, hearts of HFD-fed mice had enhanced mitochondrial oxidation of palmitoyl carnitine, glutamate, and succinate and greater basal insulin signaling compared with those of chow-fed mice, suggesting cardiac insulin sensitivity was maintained, despite systemic insulin resistance. Streptozotocin-induced ablation of insulin production markedly reduced cardiac glucose uptake and mitochondrial dysfunction in HFD-fed, but not in chow-fed, mice. Insulin injection reversed these effects, suggesting that insulin may protect cardiac mitochondria during HFD. These results have implications for cardiac metabolism and preservation of mitochondrial function in obesity.
Development of p21 Activated Kinase-Targeted Multikinase Inhibitors That Inhibit Thyroid Cancer Cell Migration
Authors: Ma Yihui , McCarty Samantha K. , Kapuriya Naval P. , Brendel Victoria J. , Wang Chaojie , Zhang Xiaoli , Jarjoura David , Saji Motoyasu , Chen Ching-Shih , Ringel Matthew D. 
Published: May 2013

Context:
The p21 activated kinases (PAKs) are a family of serine/threonine kinases that are downstream effectors of small GTPase Cdc42 and Rac. PAKs regulate cell motility, proliferation, and cytoskeletal rearrangement. PAK isoform expression and activity have been shown to be enhanced in cancer and to function as an oncogene in vivo. PAKs also have been implicated in cancer progression.

Objective:
In thyroid cancer, we have previously determined that PAK overactivation is common in the invasive fronts of aggressive tumors and that it is functionally involved in thyroid cancer cell motility using molecular inhibitors. We report the development of two new PAK-inhibiting compounds that were modified from the structure OSU-03012, a previously identified multikinase inhibitor that competitively blocks ATP binding of both phosphoinositide-dependent kinase 1 (PDK1) and PAK1.

Results:
Seventeen compounds were created by combinatorial chemistry predicted to inhibit PAK activity with reduced anti-PDK1 effect. Two lead compounds were identified based on the ability to inhibit PAK1 activity in an ATP-competitive manner without discernible in vivo PDK1 inhibitory activity in thyroid cancer cell lines. Both compounds reduced thyroid cancer cell viability. Although they are not PAK-specific on a multikinase screening assay, the antimigration activity effect of the compounds in thyroid cancer cells was rescued by overexpression of a constitutively active PAK1, suggesting this activity is involved in this biological effect.

Conclusions:
We have developed 2 new multikinase inhibitors with anti-PAK activity that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.
On fundamental cellular processes for emergence of collective epithelial movement
Authors: Hirashima Tsuyoshi , Hosokawa Yoichiroh , Iino Takanori , Nagayama Masaharu 
Published: May 2013

Summary
In all animals, collective cell movement is an essential process in many events, including wound healing and embryonic development. However, our understanding of what characterizes the emergence of multicellular collective behavior is still far from complete. In this article we showed the fundamental cellular processes that drive collective cell movement by means of integrated approaches, including precise quantification measurements and mathematical modeling of measured data. First, we observed the dependence of the collective behaviors of cultured human skin cells on Ca2+ concentrations. When the culturing area confined by a PDMS sheet was suddenly expanded by removing the sheet, the group of cells moved to the expanded area with higher collectivity at higher Ca2+ concentrations. Next, we quantitatively measured cellular responses to the Ca2+ treatments, such as cell growth, cell division, and the strength of intercellular adhesion. Using a femtosecond-laser-based assay, an original method for estimating intercellular adhesion, we found that the strength of intercellular adhesion has an approximately 13-fold range in our treatments. Incorporating the quantitative data into a mathematical model, we then confirmed that the model well reproduced the multicellular behaviors we observed, demonstrating that the strength of intercellular adhesion sufficiently determines the generation of collective cell movement. Finally, we performed extensive numerical experiments, and the results suggested that the emergence of collective cell movement is derived by an optimal balance between the strength of intercellular adhesion and the intensity of cell migration.
Requirement of LIM domains for the transient accumulation of paxillin at damaged stress fibres
Authors: Watanabe-Nakayama Takahiro , Saito Masakazu , Machida Shin'ichi , Kishimoto Kikuo , Afrin Rehana , Ikai Atsushi 
Published: May 2013

Summary
Cells recognize and respond to changes in intra- and extracellular mechanical conditions to maintain their mechanical homeostasis. Linear contractile bundles of actin filaments and myosin II known as stress fibres (SFs) mediate mechanical signals. Mechanical cues such as excessive stress driven by myosin II and/or external force may damage SFs and induce the local transient accumulation of SF-repair complexes (zyxin and VASP) at the damaged sites. Using an atomic force microscope mounted on a fluorescence microscope, we applied mechanical damage to cells expressing fluorescently tagged cytoskeletal proteins and recorded the subsequent mobilization of SF-repair complexes. We found that a LIM protein, paxillin, transiently accumulated at the damaged sites earlier than zyxin, while paxillin knockdown did not affect the kinetics of zyxin translocation. The C-terminal half of paxillin, comprising four-tandem LIM domains, can still translocate to damaged sites on SFs, suggesting that the LIM domain is essential for the mechanosensory function of paxillin. Our findings demonstrate a crucial role of the LIM domain in mechanosensing LIM proteins.
Targeting of vasoactive intestinal peptide receptor 2, VPAC2, a secretin family G-protein coupled receptor, to primary cilia
Authors: Soetedjo Livana , Glover De'Vona A. , Jin Hua 
Published: May 2013

Summary
Primary cilia protrude from the cell surface of many cell types in the human body and function as cellular antennae via ciliary membrane localized receptors. Neurons and glial cells in the brain possess primary cilia, and the malfunction of primary cilia may contribute to neurological deficits present in many cilia-associated disorders. Several rhodopsin family G-protein coupled receptors (GPCRs) are specifically localized to a subset of neuronal primary cilia. However, whether other family GPCRs target to neuronal cilia and whether glial primary cilia harbor any GPCRs are not known. We conducted a screening of GPCRs to determine their ability to target to primary cilia, and identified a secretin family member, Vasoactive Intestinal Receptor 2 (VPAC2), as a novel ciliary GPCR. Here, we show that endogenous VPAC2 targets to primary cilia in various brain regions, including the suprachiasmatic nuclei and the thalamus. Surprisingly, VPAC2 not only localizes to neuronal cilia but also to glial cilia. In addition, we show that VPAC2's C-terminus is both necessary and sufficient for its ciliary targeting and we define a novel ciliary targeting signal: the tetrapeptide RDYR motif in the C-terminus of VPAC2. Furthermore, we demonstrate that VPAC2 ciliary targeting is dependent on Tubby, the BBSome (a complex of Bardet–Biedl syndrome proteins) and the BBSome targeting factor, Arl6.
Foxc1 is required by pericytes during fetal brain angiogenesis
Authors: Siegenthaler Julie A. , Choe Youngshik , Patterson Katelin P. , Hsieh Ivy , Li Dan , Jaminet Shou-Ching , Daneman Richard , Kume Tsutomu , Huang Eric J. , Pleasure Samuel J. 
Published: May 2013

Summary
Brain pericytes play a critical role in blood vessel stability and blood–brain barrier maturation. Despite this, how brain pericytes function in these different capacities is only beginning to be understood. Here we show that the forkhead transcription factor Foxc1 is expressed by brain pericytes during development and is critical for pericyte regulation of vascular development in the fetal brain. Conditional deletion of Foxc1 from pericytes and vascular smooth muscle cells leads to late-gestation cerebral micro-hemorrhages as well as pericyte and endothelial cell hyperplasia due to increased proliferation of both cell types. Conditional Foxc1 mutants do not have widespread defects in BBB maturation, though focal breakdown of BBB integrity is observed in large, dysplastic vessels. qPCR profiling of brain microvessels isolated from conditional mutants showed alterations in pericyte-expressed proteoglycans while other genes previously implicated in pericyte–endothelial cell interactions were unchanged. Collectively these data point towards an important role for Foxc1 in certain brain pericyte functions (e.g. vessel morphogenesis) but not others (e.g. barriergenesis).
SLiM: Simulating Evolution with Selection and Linkage
Authors: Messer Philipp W 
Published: May 2013

AbstractSLiM is an efficient forward population genetic simulation designed for studying the effects of linkage and selection on a chromosome-wide scale. The program can incorporate complex scenarios of demography and population substructure, various models for selection and dominance of new mutations, arbitrary gene structure, and user-defined recombination maps.
Genome Engineering ofDrosophilawith the CRISPR RNA-Guided Cas9 Nuclease
Authors: Gratz Scott J , Cummings Alexander M , Nguyen Jennifer N , Hamm Danielle C , Donohue Laura K , Harrison Melissa M , Wildonger Jill , O’Connor-Giles Kate M 
Published: May 2013

AbstractWe have adapted a bacterial CRISPR RNA/Cas9 system to precisely engineer the Drosophila genome and report that Cas9-mediated genomic modifications are efficiently transmitted through the germline. This RNA-guided Cas9 system can be rapidly programmed to generate targeted alleles for probing gene function in Drosophila.
The NOMS Framework: Approach to the Treatment of Spinal Metastatic Tumors
Authors: Laufer Ilya , Rubin David G. , Lis Eric , Cox Brett W. , Stubblefield Michael D. , Yamada Yoshiya , Bilsky Mark H. 
Published: May 2013

Abstract

Background.
Spinal metastases frequently arise in patients with cancer. Modern oncology provides numerous treatment options that include effective systemic, radiation, and surgical options. We delineate and provide the evidence for the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which is used at Memorial Sloan-Kettering Cancer Center to determine the optimal therapy for patients with spine metastases.

Methods.
We provide a literature review of the integral publications that serve as the basis for the NOMS framework and report the results of systematic implementation of the NOMS-guided treatment.

Results.
The NOMS decision framework consists of the neurologic, oncologic, mechanical, and systemic considerations and incorporates the use of conventional external beam radiation, spinal stereotactic radiosurgery, and minimally invasive and open surgical interventions. Review of radiation oncology and surgical literature that examine the outcomes of treatment of spinal metastatic tumors provides support for the NOMS decision framework. Application of the NOMS paradigm integrates multimodality therapy to optimize local tumor control, pain relief, and restoration or preservation of neurologic function and minimizes morbidity in this often systemically ill patient population.

Conclusion.
NOMS paradigm provides a decision framework that incorporates sentinel decision points in the treatment of spinal metastases. Consideration of the tumor sensitivity to radiation in conjunction with the extent of epidural extension allows determination of the optimal radiation treatment and the need for surgical decompression. Mechanical stability of the spine and the systemic disease considerations further help determine the need and the feasibility of surgical intervention.
Ipilimumab, Vemurafenib, Dabrafenib, and Trametinib: Synergistic Competitors in the Clinical Management of BRAF Mutant Malignant Melanoma
Authors: Luke Jason J. , Hodi F. Stephen 
Published: May 2013

Abstract
There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T-lymphocyte antigen-4 blockade, with ipilimumab, and targeting of BRAFV600, with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. These advancements, however, reveal new clinical questions regarding combinations and optimal sequencing of these agents in patients with BRAF mutant disease. We review the development of these agents, putative biomarkers, and resistance mechanisms relevant to their use, and possibilities for sequencing and combining these agents.
Efficacy and Economic Value of Adjuvant Imatinib for Gastrointestinal Stromal Tumors
Authors: Rutkowski Piotr , Gronchi Alessandro 
Published: May 2013

Abstract

Objective.
This article presents the clinical effectiveness and cost-effectiveness of the use of adjuvant imatinib mesylate for treating patients with localized primary gastrointestinal stromal tumors (GISTs) and discusses the impact of prolonged treatment with adjuvant imatinib on health care costs.

Methods.
A systematic review of the medical literature was conducted to explore recently reported clinical trials demonstrating the clinical benefit of adjuvant imatinib in GISTs, along with analyses discussing the economic impact of adjuvant imatinib.

Results.
Two phase III trials have demonstrated a significant clinical benefit of adjuvant imatinib treatment in GIST patients at risk of recurrence after tumor resection. Guidelines now suggest adjuvant treatment for at least 3 years in patients at high risk of recurrence. Despite this clinical effectiveness, prolonged use of adjuvant imatinib can lead to an increase in the risk for adverse events and to increased costs for both patients and health care systems. However, the increased cost is partially offset by cost reductions associated with delayed or avoided GIST recurrences. Three years of adjuvant treatment in high-risk patients was concluded to be cost-effective. Therefore, the careful selection of patients who are most likely to benefit from treatment can lead to improved clinical outcomes and significant cost savings.

Conclusion.
Although introducing adjuvant imatinib has an economic impact on health plans, this effect seems to be limited. Several analyses have demonstrated that adjuvant imatinib is more cost-effective for treating localized primary GISTs than surgery alone. In addition, 3 years of adjuvant imatinib is more cost-effective than 1 year of adjuvant therapy.
A Complete Petrophysical-Evaluation Method for Tight Formations From Drill Cuttings Only in the Absence of Well Logs
Authors: Ortega Camilo , Aguilera Roberto 
Published: May 2013

Summary
The amount of tight-formation petrophysical work conducted at present in horizontal wells and the examples available in the literature are limited to only those wells that have complete data sets. This is very important. But the reality is that in the vast majority of horizontal wells, the data required for detailed analyses are quite scarce. Petrophysical evaluation in the absence of well logs and cores can now be considered owing to the possibility of measuring both the permeability and porosity of drill cuttings. This is essential because the application of the successive correlations used throughout the paper is based on porosity and permeability data.
To try to alleviate the data-scarcity problem, a new method is presented for complete petrophysical evaluation derived from information that can be extracted from drill cuttings in the absence of well logs. The cuttings data include porosity and permeability. The gamma ray and any other logs, if available, can help support the interpretation. However, the methodology is built strictly on data extracted from cuttings and can be used for horizontal, slanted, and vertical wells. The method is illustrated with the use of a tight gas formation in the Deep basin of the western Canada sedimentary basin (WCSB). However, it also has direct application in the case of liquids.
The method is shown to be a powerful petrophysical tool because it allows quantitative evaluation of water saturation, pore-throat aperture, capillary pressure, flow units, porosity (or cementation) exponent m, true-formation resistivity, and distance to a water table (if present). Also, the method allows one to distinguish the contributions from viscous and diffusion-like flow in tight gas formations. The method further allows the construction of Pickett plots without previous availability of well logs, and it assumes the existence of intervals at irreducible water saturation, which is the case of many tight formations currently under exploitation.
It is concluded that drill cuttings are a powerful direct source of information that allows complete and practical evaluation of tight reservoirs in which well logs are scarce. The uniqueness and practicality of this quantitative procedure originate from the fact that it starts only from the laboratory analysis of drill cuttings—something that has not been performed in the past.
An Estimate of the Near-Term Electricity-Generation Potential of Coproduced Water From Active Oil and Gas Wells
Authors: Augustine Chad , Falkenstern David 
Published: May 2013

Summary
This study estimates the near-term market electricity-generation potential of water produced as a byproduct from active oil and gas operations. A geographic information system (GIS) was developed to combine oil- and gas-well location, depth, and water-production information from 2.5 million wells (half a million of which were identified as active, producing wells) with geothermal-resource maps and to estimate the power-generation potential of the coproduction resource. The study found that the near-term market potential for the coproduction resource from active oil and gas wells is approximately 300 MW of electrical output (MWe), which is less than suggested in previous studies.