bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progranulin is expressed within motor neurons and promotes neuronal cell survival
Authors: Ryan Cara L , Baranowski David C , Chitramuthu Babykumari P , Malik Suneil , Li Zhi , Cao Mingju , Minotti Sandra , Durham Heather D , Kay Denis G , Shaw Christopher A , Bennett Hugh PJ , Bateman Andrew 
Published: October 2009

Abstract

Background
Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival.

Results

In situ hybridisation and immunohistochemical techniques revealed that the progranulin gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human progranulin gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival.

Conclusion
Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.
An efficient drug delivery vehicle for botulism countermeasure
Authors: Zhang Peng , Ray Radharaman , Singh Bal Ram , Li Dan , Adler Michael , Ray Prabhati 
Published: October 2009

Abstract

Background
Botulinum neurotoxin (BoNT) is the most potent poison known to mankind. Currently no antidote is available to rescue poisoned synapses. An effective medical countermeasure strategy would require developing a drug that could rescue poisoned neuromuscular synapses and include its efficient delivery specifically to poisoned presynaptic nerve terminals. Here we report a drug delivery strategy that could directly deliver toxin inhibitors into the intoxicated nerve terminal cytosol.

Results
A targeted delivery vehicle was developed for intracellular transport of emerging botulinum neurotoxin antagonists. The drug delivery vehicle consisted of the non-toxic recombinant heavy chain of botulinum neurotoxin-A coupled to a 10-kDa amino dextran via the heterobifunctional linker 3-(2-pyridylthio)-propionyl hydrazide. The heavy chain served to target botulinum neurotoxin-sensitive cells and promote internalization of the complex, while the dextran served as a platform to deliver model therapeutic molecules to the targeted neurons. Our results indicated that the drug delivery vehicle entry into neurons was via BoNT-A receptor mediated endocytosis. Once internalized into neurons, the drug carrier component separated from the drug delivery vehicle in a fashion similar to the separation of the BoNT-A light chain from the holotoxin. This drug delivery vehicle could be used to deliver BoNT-A antidotes into BoNT-A intoxicated cultured mouse spinal cord cells.

Conclusion
An effective BoNT-based drug delivery vehicle can be used to directly deliver toxin inhibitors into intoxicated nerve terminal cytosol. This approach can potentially be utilized for targeted drug delivery to treat other neuronal and neuromuscular disorders. This report also provides new knowledge of endocytosis and exocytosis as well as of BoNT trafficking.
Remarkable sequence similarity between the dinoflagellate-infecting marine girus and the terrestrial pathogen African swine fever virus
Authors: Ogata Hiroyuki , Toyoda Kensuke , Tomaru Yuji , Nakayama Natsuko , Shirai Yoko , Claverie Jean-Michel , Nagasaki Keizo 
Published: October 2009

Abstract

Heterocapsa circularisquama DNA virus (HcDNAV; previously designated as HcV) is a giant virus (girus) with a ~356-kbp double-stranded DNA (dsDNA) genome. HcDNAV lytically infects the bivalve-killing marine dinoflagellate H. circularisquama, and currently represents the sole DNA virus isolated from dinoflagellates, one of the most abundant protists in marine ecosystems. Its morphological features, genome type, and host range previously suggested that HcDNAV might be a member of the family Phycodnaviridae of Nucleo-Cytoplasmic Large DNA Viruses (NCLDVs), though no supporting sequence data was available. NCLDVs currently include two families found in aquatic environments (Phycodnaviridae, Mimiviridae), one mostly infecting terrestrial animals (Poxviridae), another isolated from fish, amphibians and insects (Iridoviridae), and the last one (Asfarviridae) exclusively represented by the animal pathogen African swine fever virus (ASFV), the agent of a fatal hemorrhagic disease in domestic swine. In this study, we determined the complete sequence of the type B DNA polymerase (PolB) gene of HcDNAV. The viral PolB was transcribed at least from 6 h post inoculation (hpi), suggesting its crucial function for viral replication. Most unexpectedly, the HcDNAV PolB sequence was found to be closely related to the PolB sequence of ASFV. In addition, the amino acid sequence of HcDNAV PolB showed a rare amino acid substitution within a motif containing highly conserved motif: YS DTDS was found in HcDNAV PolB instead of YG DTDS in most dsDNA viruses. Together with the previous observation of ASFV-like sequences in the Sorcerer II Global Ocean Sampling metagenomic datasets, our results further reinforce the ideas that the terrestrial ASFV has its evolutionary origin in marine environments.
γ-Aminobutyric Acid and Glutamate Differentially Regulate Intracellular Calcium Concentrations in Mouse Gonadotropin-Releasing Hormone Neurons
Authors: Constantin Stephanie , Jasoni Christine L. , Wadas Brandon , Herbison Allan E. 
Published: October 2009

Abstract
Multiple factors regulate the activity of the GnRH neurons responsible for controlling fertility. Foremost among neuronal inputs to GnRH neurons are those using the amino acids glutamate and γ-aminobutyric acid (GABA). The present study used a GnRH-Pericam transgenic mouse line, enabling live cell imaging of intracellular calcium concentrations ([Ca2+]i) to evaluate the effects of glutamate and GABA signaling on [Ca2+]i in peripubertal and adult mouse GnRH neurons. Activation of GABAA, N-methyl-d-aspartate, or α-amino-3-hydroxyl-5-methyl-4-isoxazole propionate acid (AMPA) receptors was found to evoke an increase in [Ca2+]i, in subpopulations of GnRH neurons. Approximately 70% of GnRH neurons responded to GABA, regardless of postnatal age or sex. Many fewer (∼20%) GnRH neurons responded to N-methyl-d-aspartate, and this was not influenced by postnatal age or sex. In contrast, about 65% of adult male and female GnRH neurons responded to AMPA compared with about 14% of male and female peripubertal mice (P &lt; 0.05). The mechanisms underlying the ability of GABA and AMPA to increase [Ca2+]i in adult GnRH neurons were evaluated pharmacologically. Both GABA and AMPA were found to evoke [Ca2+]i increases through a calcium-induced calcium release mechanism involving internal calcium stores and inositol-1,4,5-trisphosphate receptors. For GABA, the initial increase in [Ca2+]i originated from GABAA receptor-mediated activation of L-type voltage-gated calcium channels, whereas for AMPA this appeared to involve direct calcium entry through the AMPA receptor. These observations show that all of the principal amino acid receptors are able to control [Ca2+]i in GnRH neurons but that they do so in a postnatal age- and intracellular pathway-specific manner.
Chatter prevention and improved finish of workpiece for a milling process
Authors: Tsai N-C , Chen D-C , Lee R-M 
Published: October 2009

This paper presents how real-time chatter prevention can be realized by feedback of an acoustic cutting signal. The efficacy of the proposed adaptive spindle speed tuning algorithm is verified by intensive experimental simulations. A pair of microphones, perpendicular to each other, is used to acquire the acoustic cutting signal resulting from milling chatter. A real-time feedback control loop is constructed for spindle speed compensation in such a way to ensure that the milling process is within the stability zone of the stability lobe diagram. The acoustic chatter signal index (ACSI) and the spindle speed compensation strategy (SSCS) are proposed to quantify the acoustic signal and actively to tune the spindle speed respectively. By converting the acoustic feedback signal into the ACSI, an appropriate spindle speed compensation rate (SSCR) can be determined by the SSCS based on a real-time chatter level or the ACSI. Accordingly, the compensation command, referred to as added-on voltage (AOV), is applied to increase/decrease the spindle motor speed. By employing the commercial software MATLAB/Simulink and the dSpace DS1104 interface module to implement the controller, the proposed chatter prevention algorithm is practically verified by intensive experiments. By inspection on the precision and quality of the workpiece surface after milling, the efficacy of the real-time chatter prevention strategy via acoustic signal feedback is further assured.
From multi-body to many-body dynamics
Authors: Theodossiades S , Teodorescu M , Rahnejat H 
Published: October 2009

This article provides a brief historical review of multi-body dynamics analysis, initiated by the Newtonian axioms through constrained ( removed degrees of freedom) Lagrangian dynamics or restrained ( resisted degrees of freedom) Newton—Euler formulation. It provides a generic formulation method, based on system dynamics in a reduced configuration space, which encompasses both the aforementioned methods and is applicable to any cluster of material points. A detailed example is provided to show the integration of other physical phenomena such as flexibility and acoustic wave propagation into multi-body dynamics analysis. It is shown that in the scale of minutiae, when the action potentials deviate from Newtonian laws, the forces are often described by empirical or stochastic functions of separation and the medium of interactions. These make for complex analyses and distinguish a host of many body problems from Newtonian laws of motion. A simple example is provided to demonstrate this. It is suggested that unification of many-body analysis with that of multi-body dynamics is incumbent on the fundamental understanding of interaction potentials at close separations.
Impaired osteoblast function in GPRC6A null mice
Authors: Pi Min , Zhang Lishu , Lei Shu-Feng , Huang Min-Zhao , Zhu Wenyu , Zhang Jianghong , Shen Hui , Deng Hong-Wen , Quarles L Darryl 
Published: October 2009

Abstract
GPRC6A is a widely expressed orphan G protein–coupled receptor that senses extracellular amino acids, osteocalcin, and divalent cations in vitro. GPRC6A null (GPRC6A−/−) mice exhibit multiple metabolic abnormalities including osteopenia. To investigate whether the osseous abnormalities are a direct function of GPRC6A in osteoblasts, we examined the function of primary osteoblasts and bone marrow stromal cell cultures (BMSCs) in GPRC6A−/− mice. We confirmed that GPRC6A−/− mice exhibited a decrease in bone mineral density (BMD) associated with reduced expression of osteocalcin, ALP, osteoprotegerin, and Runx2-II transcripts in bone. Osteoblasts and BMSCs derived from GPRC6A−/− mice exhibited an attenuated response to extracellular calcium-stimulated extracellular signal-related kinase (ERK) activation, diminished alkaline phosphatase (ALP) expression, and impaired mineralization ex vivo. In addition, siRNA-mediated knockdown of GPRC6A in MC3T3 osteoblasts also resulted in a reduction in extracellular calcium-stimulated ERK activity. To explore the potential relevance of GPRC6A function in humans, we looked for an association between GPRC6A gene polymorphisms and BMD in a sample of 1000 unrelated American Caucasians. We found that GPRC6A gene polymorphisms were significantly associated with human spine BMD. These data indicate that GRPC6A directly participates in the regulation of osteoblast-mediated bone mineralization and may mediate the anabolic effects of extracellular amino acids, osteocalcin, and divalent cations in bone. © 2010 American Society for Bone and Mineral Research
The Effect of Core and Carburized Surface Microstructural Stability on Residual Stress Evolution during Tempering
Authors: Vatavuk Jan , di Monte Mariana Zicari , Couto Antonio Augusto 
Published: October 2009

Abstract
It is a well-known fact that compressive residual stresses are developed during the quenching process of carburized parts. The main purpose of this work is related to the tempering effects on as-quenched compressive residual stresses of commercial carburized samples. The work was carried out by using SAE 4120 RH steel samples with different diameters (15 and 38 mm), which led to different cooling rates with a direct effect on the nucleus microstructure. The carburized surface microstructure was considered similar. The 15 mm bars nucleus microstructures were predominantly martensitic but bainitic in the larger samples. The as-quenched surface compressive residual stress was lower in the smaller diameter samples. The compressive residual stress reduction due to increasing tempering temperature was continuous for the larger diameter work piece. The smaller diameter samples had different behaviors in two regions; the compressive stress for lower tempering temperatures was reduced, while values were enhanced over higher temperatures.
Physics and Chemistry of Micro-Nanotribology
Authors: Wen Shizhu , Luo Jianbin , Hu Yuanzhong 
Published: October 2009

Description
This new ASTM monograph presents the principles and applications of tribology in micro- nano-scale and discusses some of the challenges faced by tribilogists since the development of new manufacturing techniques for electronic products. It covers a broad range of topics on micro-nanotribology, with emphasis on the physical and chemical aspects and on bridging fundamental studies and applications.
Topics include:
This is a valuable resource for tribologists, mechanical engineers, lubrication engineers, and material scientist and engineers.
The Utility of Comparative Genetics to Inform Breast Cancer Prevention Strategies
Authors: Gould Michael N 
Published: October 2009

Abstract
My research seeks to aid in developing approaches to prevent breast cancer. This research evolved from our early empirical studies for discovering natural compounds with anticancer activities, coupled with clinical evaluation to a genetics-driven approach to prevention. This centers on the use of comparative genomics to discover risk-modifying alleles that could help define population and individual risk and also serve as potential prevention drugable targets to mitigate risk. Here, we initially fine map mammary cancer loci in a rat carcinogenesis model and then evaluate their human homologs in breast cancer case-control association studies. This approach has yielded promising results, including the finding that the compound rat QTL Mcs5a's human homologous region was associated with breast cancer risk. These and related findings have the potential to yield advancements both in translation-prevention research and in basic molecular genetics.
Optimizing Recovery for Waterflooding Under Dynamic Induced Fracturing Conditions
Authors: van den Hoek P. J. , Al-Masfry R. A. , Zwarts D. , Jansen J. D. , Hustedt B. , van Schijndel L. 
Published: October 2009

Summary
It is well established within the industry that water injection mostly takes place under induced fracturing conditions. Particularly in low-mobility reservoirs, large fractures may be induced during the field life.
This paper presents a new modeling strategy that combines fluid flow and fracture growth (fully coupled) within the framework of an existing "standard" reservoir simulator.
We demonstrate the coupled simulator by applications to repeated five-spot pattern flood models, addressing various aspects that often play an important role in waterfloods: shortcut of injector and producer, fracture containment to the reservoir layer, and areal and vertical reservoir sweep. We also demonstrate how induced fracture dimensions (length, height) can be very sensitive to typical reservoir engineering parameters, such as fluid mobility, mobility ratio, 3D saturation distribution (in particular, shockfront position), 3D temperature distribution, positions of wells (producers, injectors), and geological details (e.g., layering and faulting). In particular, it is shown that lower overall (time-dependent) reservoir transmissibility will result in larger induced fractures. Finally, it is demonstrated how induced fractures can be taken into account to determine an optimum life-cycle injection rate strategy.
The results presented in this paper are expected to also apply to (part of) enhanced-oil-recovery operations (e.g., polymer flooding).
HIV/AIDS Awareness, Attitudes and Risk Behavior Among University Students in Wuhan, China
Authors: Albrektsson Madelene , Alm Louise , Tan Xiaodong , Andersson Rune 
Published: October 2009

Background:
In China, the estimated number of HIV positives in 2007 was 700,000 and the epidemic continues to expand. Because of their attitudes towards sexual behavior, young people are considered to be a group at high risk.

Methods:
Eight hundred sixty-eight undergraduate students at Wuhan University were selected through stratified cluster sampling, to answer a questionnaire. They were divided into three main groups: Chinese medical students, foreign medical students and Chinese students from other faculties. Fourteen interviews were conducted in addition.

Results:
Ninety-nine percent of the students had heard of HIV/AIDS and 76% of the students could distinguish HIV from AIDS. The main route of transmission was believed by the Chinese students to be blood transfusion and sexual intercourse by the foreign medical students. The female students knew more about the routes of transmission than the male students. Medical students had a higher level of knowledge than non-medical students, and among the medical students, the foreign students were more knowledgeable than the Chinese students. Only 8 % of the students were sexually active.

Conclusion:
The students had an accepting attitude towards people living with HIV and no extensive risk behavior. Overall, the knowledge level was found to be moderate.
Prediction of Coronary Heart Disease Risk in a General, Pre-Diabetic, and Diabetic Population During 10 Years of Follow-up: Accuracy of the Framingham, SCORE, and UKPDS Risk Functions
Authors: van der Heijden Amber A.W.A. , Ortegon Monica M. , Niessen Louis W. , Nijpels Giel , Dekker Jacqueline M. 
Published: October 2009

OBJECTIVE
To test the validity of the Framingham, Systematic Coronary Risk Evaluation (SCORE), and UK Prospective Diabetes Study (UKPDS) risk function in the prediction of risk of coronary heart disease (CHD) in populations with normal glucose tolerance (NGT), intermediate hyperglycemia, and type 2 diabetes.

RESEARCH DESIGN AND METHODS
Calibration and discrimination of the three prediction models were tested using prospective data for 1,482 Caucasian men and women, 50–75 years of age, who participated in the Hoorn Study. All analyses were stratified by glucose status.

RESULTS
During 10 years of follow-up, a total of 197 CHD events, of which 43 were fatal, were observed in this population, with the highest percentage of first CHD events in the diabetic group. The Framingham and UKPDS prediction models overestimated the risk of first CHD event in all glucose tolerance groups. Overall, the prediction models had a low to moderate discriminatory capacity. The SCORE risk function was the best predictor of fatal CHD events in the group with NGT (area under the receiver operating characteristic curve 0.79 [95% CI 0.70–0.87]), whereas the UKPDS performed better in the intermediate hyperglycemia group (0.84 [0.74–0.94]) in the estimation of fatal CHD risk. After exclusion of known diabetic patients, all prediction models had a higher discriminatory ability in the group with diabetes.

CONCLUSIONS
The use of the Framingham function for prediction of the first CHD event is likely to overestimate an individual's absolute CHD risk. In CHD prevention, application of the SCORE and UKPDS functions might be useful in the absence of a more valid tool.
Autologous Umbilical Cord Blood Transfusion in Very Young Children With Type 1 Diabetes
Authors: Haller Michael J. , Wasserfall Clive H. , McGrail Kieran M. , Cintron Miriam , Brusko Todd M. , Wingard John R. , Kelly Susan S. , Shuster Jonathan J. , Atkinson Mark A. , Schatz Desmond A. 
Published: October 2009

OBJECTIVE
Interest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord blood infusion to ameliorate type 1 diabetes.

RESEARCH DESIGN AND METHODS
Fifteen patients diagnosed with type 1 diabetes and for whom autologous umbilical cord blood was stored underwent a single intravenous infusion of autologous cells and completed 1 year of postinfusion follow-up. Intensive insulin regimens were used to optimize glycemic control. Metabolic and immunologic assessments were performed before infusion and at established time periods thereafter.

RESULTS
Median (interquartile range [IQR]) age at infusion was 5.25 (3.1–7.3) years, with a median postdiagnosis time to infusion of 17.7 (10.9–26.5) weeks. No infusion-related adverse events were observed. Metabolic indexes 1 year postinfusion were peak C-peptide median 0.50 ng/ml (IQR 0.26–1.30), P = 0.002; A1C 7.0% (IQR 6.5–7.7), P = 0.97; and insulin dose 0.67 units · kg−1 · day−1 (IQR 0.55–0.77), P = 0.009. One year postinfusion, no changes were observed in autoantibody titers, regulatory T-cell numbers, CD4-to-CD8 ratio, or other T-cell phenotypes.

CONCLUSIONS
Autologous umbilical cord blood transfusion in children with type 1 diabetes is safe but has yet to demonstrate efficacy in preserving C-peptide. Larger randomized studies as well as 2-year postinfusion follow-up of this cohort are needed to determine whether autologous cord blood–based approaches can be used to slow the decline of endogenous insulin production in children with type 1 diabetes.