bluuebunny/crossref_metadata_2025 huggingface dataset:
Mandatory Reporting in the Context of Home Visitation Programs
Authors: Davidov Danielle M. , Jack Susan M. , Frost Stephanie S. , Coben Jeffrey H.
Published: August 2012

The mandatory reporting of intimate partner violence (IPV) is a controversial issue that is receiving increased attention. A related concern is whether children’s exposure to IPV constitutes child maltreatment, making it reportable to child protective services. These issues have been relatively unexplored within the context of home visitation programs. A secondary analysis of qualitative data collected from community stakeholders, clients, and home visiting nurses in the Nurse–Family Partnership program was carried out. Participants’ perceptions about mandatory reporting of IPV and reporting of children’s exposure to IPV are highlighted. Emergent themes and implications for research, practice, and policy are discussed.
Cohabitation Is No Longer Associated With Elevated Spousal Homicide Rates in the United States
Authors: James Bridie , Daly Martin
Published: August 2012

Margo Wilson and collaborators discovered that cohabiting couples had very much higher spousal homicide rates than those in registered marriages, and cross-national research has shown this difference to be widespread. We now find that homicide rates in the two sorts of unions have converged in the United States, such that the previously large difference had completely vanished by 2005. Distinct age patterns whereby registered marriages are most lethal in youth and cohabitation is most lethal in middle age have nevertheless persisted. While their homicide rates were converging between 1990 and 2005, married and cohabiting couples were not growing more similar in their basic demographic attributes: age distributions and unemployment rates remained distinct, and differences in education and income actually increased. Why homicide rates in the two classes of unions have ceased to differ remains unknown. We suggest some lines of research that may help provide answers.
Using the Child Behavior Checklist and the Teacher’s Report Form for identification of children with autism spectrum disorders
Authors: So Pety , Greaves-Lord Kirstin , van der Ende Jan , Verhulst Frank C , Rescorla Leslie , de Nijs Pieter FA
Published: August 2012

This study evaluated the ability of the Child Behavior Checklist and the Teacher’s Report Form to identify children with autism spectrum disorders (ASD), using a sample of children with ASD (n = 458), referred children without ASD (n = 1109) and children from the general population (n = 999). A ten items ASD scale was constructed using half of the sample and the ability of this scale to discriminate between children with ASD and the other children was tested for the CBCL and the TRF separately and together in the other half of the sample. Using a cut-off score of 8 the combined CBCL/TRF ASD scale demonstrated high predictive values (NPV 95%, PPV 73%) in identifying children with ASD and children in the general population sample. This might be an acceptable percentage of false positives in general screening, considering the chance that these children might have other behavioural, emotional, and developmental problems which also need psychiatric evaluation. In the referred population, using a cut-off of 13, PPV was 49% and NPV was 85%. The high NPV indicates that in a referred population the scale is especially good at identifying children who do not need evaluation with a more ASD-specific instrument.
Simultaneous improvement in both exhaust emissions and fuel consumption by means of Fischer–Tropsch diesel fuels
Authors: Uchida Noboru , Sakata Ichiro , Kitano Kouji , Okabe Nobuhiro , Sakamoto Yoriko
Published: August 2012

In recent years, paraffinic fuels have attracted attention because of their potential for reducing diesel exhaust emissions, mainly smoke or particulate matter emissions. One of the paraffinic fuels, a Fischer–Tropsch diesel fuel, was selected to demonstrate the lower exhaust emissions while improving fuel economy in this study. To examine the detailed effects of fuel specifications on diesel combustion and emissions, preliminarily tests for three Fischer–Tropsch fuels and a baseline diesel fuel were carried out with three diesel engines having different engine displacements. In addition, differences in combustion phenomena between Fischer–Tropsch fuels and the baseline diesel fuel were observed by means of a single-cylinder engine with optical access. From these findings, one of the tested engines was modified to improve both exhaust emissions and fuel consumption, simultaneously, dedicated to the use of neat Fischer–Tropsch fuels. The conversion efficiency of an oxides of nitrogen reduction catalyst has also been improved. The desirable properties of Fischer–Tropsch fuels for diesel combustion, namely high cetane number and absence of poly-aromatic hydrocarbon contents, have been fully utilized to enhance the conventional diesel combustion limits to show the possibility to achieve very low exhaust emissions with substantial improvement in fuel economy. The results of this study indicate not only the superior emission characteristics of the Fischer–Tropsch fuels, but also evidence that higher exhaust gas recirculation and lower excess air ratios will be a key concept of both engine and aftertreatment optimization for further fuel consumption improvement.
Mother, Shane, and Sonny
Authors: Denzin Norman K.
Published: August 2012

This article focuses on the intersection of two memories. Mother dressed as a cowgirl, and riding my horse, who is named Sunny. It is a warm, sunny, Sunday afternoon in 1951, and I am ten years old. Two years later I am watching Shane with my father. In four years he will disappear from my life. I waited, night after night for him to come back, as in “come back Shane.” Far away, on the edge of the dream, a faint image: Mother is riding into an orange and purple sunset, her red bandana whipping in the wind.
A Critical Review of the Science and Practice of Competency Modeling
Authors: Stevens Gregory W.
Published: August 2012

As an alternative to traditional job analysis, the practice of competency modeling may be appealing to scholars and practitioners of human resource development (HRD) to serve as the foundation for many HRD activities. Among some of its advantages are a more explicit focus on performance and development that is aligned with organizational strategy, fuller integration with human resource systems, and a focus on broad work roles and functions instead of discrete jobs. Unfortunately, the use of competency models is often hindered as a result of conceptual ambiguity, a lack of methodological rigor in the development of such systems, and psychometric issues. The current integrative literature review seeks to clarify the practice of competency modeling within the context of HRD through a critical analysis of its foundations, conceptual and definitional issues, and potential barriers to use while providing the current state of the science and best practices.
Using the Multilayer Stent as a Supplement to EVAR in Combined Abdominal Aortic Aneurysm and Iliac Artery Aneurysm With Inadequate Distal Landing Zone—A Case Report
Authors: Pieper Claus C. , Meyer Carsten , Verrel Frauke , Schild Hans H. , Wilhelm Kai E.
Published: August 2012

Combined abdominal aortic aneurysm (AAA) and iliac artery aneurysm (IAA) is a common condition. The recently approved Cardiatis Multilayer stent (Cardiatis, Isnes, Belgium) is an innovative stent system for peripheral aneurysm management that has been applied in several clinical cases. After deployment, the unique stent design reduces mean velocity and vorticity within the aneurysm sac, causing thrombus formation and thus exclusion of the aneurysm while the vessels branching from the aneurysm remain patent. We describe a case of combined AAA and IAA with successful endovascular aneurysm repair of the AAA and treatment of the internal iliac artery with the Cardiatis Multilayer stent at 12 months of follow-up.
Internal Carotid Artery Dissection After Inferior Alveolar Nerve Block for Third Molar Dental Care Presented as Hypoglossal Nerve Palsy
Authors: De Santis Francesco , Martini Guido , Thüringen Peter , Thaler Monika , Mani Gabriele , Steckholzer Karin
Published: August 2012

Cervicocephalic artery dissections occurring during dental care have exceptionally been reported. We describe a case of internal carotid artery dissection, presenting as hypoglossal nerve palsy, occurring immediately after difficult inferior alveolar nerve anesthetic block for third inferior molar dental care. Carotid dissection was successfully treated with anticoagulation therapy while hypoglossal nerve palsy recovered with carotid dissection shrinkage. The etiopathogenetic mechanisms of this singular form of internal carotid artery dissection are discussed. The possibility of internal carotid artery dissection development during oral or dental procedure, specifically in cases of possible trivial intraoperative internal carotid artery injury, severe local periodontal infection, or prolonged cervical hyperextension should be considered. Every possible prophylactic measure should be taken (eg, sedating the patient during oral or dental procedures, aggressive preoperative management of general and local periodontal chronic infections, avoiding prolonged perioperative neck hyperextention) to prevent this very rare but potentially life-threatening complication.
Predicting tensile strength of double side friction stir welded 6082-T6 aluminium alloy
Authors: Gopi S , Manonmani K
Published: August 2012

This work presents the formulation of a mathematical model with process parameters and tool geometry to predict the response, joint strength, of double side friction stir welded aluminium alloy 6082-T6. The welding was carried out on 8 mm aluminium alloy plates. The process parameters considered were tool rotational speed or spindle speed, welding speed and shoulder penetration, and the tool geometries considered were pin profile and shoulder profile. A five-factor, five-level central composite design was used to determine the number of experiments. The tensile strength of the welded specimens was tested, and its correlation with process parameters was assessed. A mathematical model had been developed to predict the tensile strength using response surface methodology at 95% confidence level, and it was validated using analysis of variance.
New technique of in situ rolling friction stir welding
Authors: Huang Y X , Wan L , Lv S X , Zhang Z , Liu H J
Published: August 2012

A new technique of in situ rolling friction stir welding (IRFSW) has been developed to reduce the residual stress and distortion. It can eliminate the weld flashes and improve corrosion resistance of the FSW seam. A new kind of FSW tool consisting of rolling balls was designed to achieve IRFSW. The residual stresses across the weld were measured by ultrasonic stress measurement experimental installation. The 3·5%NaCl solution was used to corrode the surface of welded joint, and corrosion current and potential were determined by an electrochemical analyser. The results shown that the residual tensile stress was reduced, the weld flashes were eliminated, and the corrosion resistance was improved. By applying IRFSW, the reduction of distortion was ∼34·4% compared with that of conventional FSW joint for aluminium plant with 3 mm in thickness and 300 mm in length.
Evaluation of the protection conferred by a naturally attenuated Neospora caninum isolate against congenital and cerebral neosporosis in mice
Authors: Rojo-Montejo Silvia , Collantes-Fernández Esther , López-Pérez Inmaculada , Risco-Castillo Verónica , Prenafeta Antoni , Ortega-Mora Luis Miguel
Published: August 2012

The parasite Neospora caninum is an important abortifacient agent in cattle worldwide. At present, the development of an effective and safe vaccine against bovine neosporosis is of great relevance. Recently, a new isolate of N. caninum (Nc-Spain 1 H) which was obtained from the brain of an asymptomatic congenitally infected calf, exhibited non-virulent behaviour in mouse and bovine infection models. The aim of this study was to determine the safety and efficacy of Nc-Spain 1 H when used as a vaccinal isolate in well-established BALB/c models of congenital and cerebral neosporosis. Mice were subcutaneously immunised twice at 3-week intervals and were challenged with 2 × 106 tachyzoites of the virulent Nc-Liv isolate. After immunisation with live Nc-Spain 1 H tachyzoites, no parasitic DNA was detected in the dams’ brains before challenge and microsatellite analysis performed in PCR-positive mice showed that the profiles corresponded to the challenge isolate Nc-Liv, indicating the Nc-Spain 1 H isolate to be a safe vaccine candidate. The efficacy of the live vaccine was evaluated in the first experiment after the immunisation of mice with 5 × 105 live Nc-Spain 1 H tachyzoites. This immunisation protocol significantly reduced the neonatal mortality to 2.4%, reduced the vertical transmission from 89.1% to 2.3% and completely limited the cerebral infection. These results were associated with a Th1-type immune response. In the second experiment, the effect of various immunising doses was established using ten-fold dilutions of the tachyzoites (from 5 × 105 to 5 × 10). In all the cases, congenital protection rates above 60% were observed, and the mice that were immunised with the lowest dose (5 × 10) presented the highest protection rate (86%). Moreover, low immunising doses of Nc-Spain 1 H induced an IgG2a response, and high parasitic doses induced an IgG1 response. These results evidence the safety and the efficient protection that was conferred by Nc-Spain 1 H against congenital neosporosis, even when the mice were immunised with low parasitic doses.
Screening of selective histone deacetylase inhibitors by proteochemometric modeling
Authors: Wu Dingfeng , Huang Qi , Zhang Yida , Zhang Qingchen , Liu Qi , Gao Jun , Cao Zhiwei , Zhu Ruixin
Published: August 2012

Background

Histone deacetylase (HDAC) is a novel target for the treatment of cancer and it can be classified into three classes, i.e., classes I, II, and IV. The inhibitors selectively targeting individual HDAC have been proved to be the better candidate antitumor drugs. To screen selective HDAC inhibitors, several proteochemometric (PCM) models based on different combinations of three kinds of protein descriptors, two kinds of ligand descriptors and multiplication cross-terms were constructed in our study.

Results

The results show that structure similarity descriptors are better than sequence similarity descriptors and geometry descriptors in the leftacterization of HDACs. Furthermore, the predictive ability was not improved by introducing the cross-terms in our models. Finally, a best PCM model based on protein structure similarity descriptors and 32-dimensional general descriptors was derived (R2 = 0.9897, Qtest
2 = 0.7542), which shows a powerful ability to screen selective HDAC inhibitors.

Conclusions

Our best model not only predict the activities of inhibitors for each HDAC isoform, but also screen and distinguish class-selective inhibitors and even more isoform-selective inhibitors, thus it provides a potential way to discover or design novel candidate antitumor drugs with reduced side effect.
Inhibition of osteoclastogenesis by RNA interference targeting RANK
Authors: Ma Ruofan , Xu Jie , Dong Bin , Kauther Max Daniel , Jäger Marcus , Wedemeyer Christian
Published: August 2012

Background

Osteoclasts and osteoblasts regulate bone resorption and formation to allow bone remodeling and homeostasis. The balance between bone resorption and formation is disturbed by abnormal recruitment of osteoclasts. Osteoclast differentiation is dependent on the receptor activator of nuclear factor NF-kappa B (RANK) ligand (RANKL) as well as the macrophage colony-stimulating factor (M-CSF). The RANKL/RANK system and RANK signaling induce osteoclast formation mediated by various cytokines. The RANK/RANKL pathway has been primarily implicated in metabolic, degenerative and neoplastic bone disorders or osteolysis. The central role of RANK/RANKL interaction in osteoclastogenesis makes RANK an attractive target for potential therapies in treatment of osteolysis. The purpose of this study was to assess the effect of inhibition of RANK expression in mouse bone marrow macrophages on osteoclast differentiation and bone resorption.

Methods

Three pairs of short hairpin RNAs (shRNA) targeting RANK were designed and synthesized. The optimal shRNA was selected among three pairs of shRNAs by RANK expression analyzed by Western blot and Real-time PCR. We investigated suppression of osteoclastogenesis of mouse bone marrow macrophages (BMMs) using the optimal shRNA by targeting RANK.

Results

Among the three shRANKs examined, shRANK-3 significantly suppressed [88.3%] the RANK expression (p < 0.01). shRANK-3 also brought about a marked inhibition of osteoclast formation and bone resorption as demonstrated by tartrate–resistant acid phosphatase (TRAP) staining and osteoclast resorption assay. The results of our study show that retrovirus-mediated shRANK-3 suppresses osteoclast differentiation and osteolysis of BMMs.

Conclusions

These findings suggest that retrovirus-mediated shRNA targeting RANK inhibits osteoclast differentiation and osteolysis. It may appear an attractive target for preventing osteolysis in humans with a potential clinical application.
In vitro evaluation of Pandanus amaryllifolius ethanol extract for induction of cell death on non-hormone dependent human breast adenocarcinoma MDA-MB-231 cell via apoptosis
Authors: Chong Hueh Zan , Yeap Swee Keong , Rahmat Asmah , Akim Abdah Md , Alitheen Noorjahan Banu , Othman Fauziah , Gwendoline-Ee Cheng Lian
Published: August 2012

Background

Our previous study had shown thatP. amaryllifoliuswas able to selectively inhibit cell proliferation of hormone independent breast cancer cell line MDA-MB-231. To understand the mode of killing and mechanism of action forP. amaryllifolius, the ethanol extract was evaluated for their alteration of cell cycle progression, PS externalization, DNA fragmentation and expression of anti/pro-apoptotic related protein.

Results

Cell cycle progression analysis, Annexin V and Tunel assays suggested that IC50ofP. amaryllifoliusethanol extract induced G0/G1 cell cycle arrest, PS externalization and DNA fragmentation. On the other hand, ELISA for cytochrome c, caspase-3/7, 8 and 9 indicated that apoptosis was contributed by mitochondrial cytochrome c release via induction of caspase 3/7, 9, and p53 was associated with the suppression of XIAP inP. amaryllifoliustreated MDA-MB-231 cells.

Conclusion

Our findings suggest thatP. amaryllifoliusethanol extract induced apoptosis on hormone independent breast cancer cell line MDA-MB-231.
Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells
Authors: Horibe Tomohisa , Torisawa Aya , Kohno Masayuki , Kawakami Koji
Published: August 2012

Background

Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo.

Results

In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition.

Conclusion

These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
Up-regulated oncoprotein P28GANK correlates with proliferation and poor prognosis of human glioma
Authors: Yang Yang , Zhang Chunli , Li Li , Gao Yusong , Luo Xinming , Zhang Yadong , Liu Weiping , Fei Zhou
Published: August 2012

Background

The significance of p28GANK in gliomas remains unknown. This study aims to clarify the clinical significance of p28GANK in human gliomas.

Methods

The expression of p28GANK in 138 gliomas and 50 matched para-cancerous tissues was detected by immunohistochemical staining, and statistical analyses were performed to test the correlation of p28GANK with clinical parameters. To investigate the effects of p28GANK down-regulation on the growth of cells both in vitro and in vivo, an siRNA targeting p28GANK was transfected into U251 cells.

Results

P28GANK expression was significantly higher in tumor specimens than in matched para-cancerous tissues. Over-expressed p28GANK significantly correlated with high karnofsky performance score (KPS), advanced WHO grade and poor overall survival of the patients. Univariate analysis showed that WHO grade and KPS also correlated with the survival of patients, and multivariate analysis suggested that KPS and p28GANK expression were two independent prognostic factors. Moreover, p28GANK gene silencing decreased the malignant growth of U251 cells both in vitro and in vivo.

Conclusions

Increased expression of p28GANK is correlated with poor clinical outcomes in glioma patients. The down-regulation of p28GANK significantly inhibited cell proliferation, indicating that p28GANK might be a potential therapeutic target for glioma treatment.
Computational simulation of the effects of oxygen on the electronic states of hydrogenated 3C-porous SiC
Authors: Trejo Alejandro , Calvino Marbella , Ramos Estrella , Cruz-Irisson Miguel
Published: August 2012

A computational study of the dependence of the electronic band structure and density of states on the chemical surface passivation of cubic porous silicon carbide (pSiC) was performed using ab initio density functional theory and the supercell method. The effects of the porosity and the surface chemistry composition on the energetic stability of pSiC were also investigated. The porous structures were modeled by removing atoms in the [001] direction to produce two different surface chemistries: one fully composed of silicon atoms and one composed of only carbon atoms. The changes in the electronic states of the porous structures as a function of the oxygen (O) content at the surface were studied. Specifically, the oxygen content was increased by replacing pairs of hydrogen (H) atoms on the pore surface with O atoms attached to the surface via either a double bond (X = O) or a bridge bond (X-O-X, X = Si or C). The calculations show that for the fully H-passivated surfaces, the forbidden energy band is larger for the C-rich phase than for the Si-rich phase. For the partially oxygenated Si-rich surfaces, the band gap behavior depends on the O bond type. The energy gap increases as the number of O atoms increases in the supercell if the O atoms are bridge-bonded, whereas the band gap energy does not exhibit a clear trend if O is double-bonded to the surface. In all cases, the gradual oxygenation decreases the band gap of the C-rich surface due to the presence of trap-like states.
A novel Rho-dependent pathway that drives interaction of fascin-1 with p-Lin-11/Isl-1/Mec-3 kinase (LIMK) 1/2 to promote fascin-1/actin binding and filopodia stability
Authors: Jayo Asier , Parsons Maddy , Adams Josephine C
Published: August 2012

Background

Fascin-1 is an actin crosslinking protein that is important for the assembly of cell protrusions in neurons, skeletal and smooth muscle, fibroblasts, and dendritic cells. Although absent from most normal adult epithelia, fascin-1 is upregulated in many human carcinomas, and is associated with poor prognosis because of its promotion of carcinoma cell migration, invasion, and metastasis. Rac and Cdc42 small guanine triphosphatases have been identified as upstream regulators of the association of fascin-1 with actin, but the possible role of Rho has remained obscure. Additionally, experiments have been hampered by the inability to measure the fascin-1/actin interaction directly in intact cells. We investigated the hypothesis that fascin-1 is a functional target of Rho in normal and carcinoma cells, using experimental approaches that included a novel fluorescence resonance energy transfer (FRET)/fluorescence lifetime imaging (FLIM) method to measure the interaction of fascin-1 with actin.

Results

Rho activity modulates the interaction of fascin-1 with actin, as detected by a novel FRET method, in skeletal myoblasts and human colon carcinoma cells. Mechanistically, Rho regulation depends on Rho kinase activity, is independent of the status of myosin II activity, and is not mediated by promotion of the fascin/PKC complex. The p-Lin-11/Isl-1/Mec-3 kinases (LIMK), LIMK1 and LIMK2, act downstream of Rho kinases as novel binding partners of fascin-1, and this complex regulates the stability of filopodia.

Conclusions

We have identified a novel activity of Rho in promoting a complex between fascin-1 and LIMK1/2 that modulates the interaction of fascin-1 with actin. These data provide new mechanistic insight into the intracellular coordination of contractile and protrusive actin-based structures. During the course of the study, we developed a novel FRET method for analysis of the fascin-1/actin interaction, with potential general applicability for analyzing the activities of actin-binding proteins in intact cells.
Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells
Authors: Guha Debjani , Nagilla Pruthvi , Redinger Carrie , Srinivasan Alagarsamy , Schatten Gerald P , Ayyavoo Velpandi
Published: August 2012

Background

Human immunodeficiency virus type 1 (HIV-1) induces neuronal dysfunction through host cellular factors and viral proteins including viral protein R (Vpr) released from infected macrophages/microglia. Vpr is important for infection of terminally differentiated cells such as macrophages. The objective of this study was to assess the effect of Vpr in the context of infectious virus particles on neuronal death through proinflammatory cytokines released from macrophages.

Methods

Monocyte-derived macrophages (MDM) were infected with either HIV-1 wild type (HIV-1wt), Vpr deleted mutant (HIV-1∆Vpr) or mock. Cell lysates and culture supernatants from MDMs were analyzed for the expression and release of proinflammatory cytokines by quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay respectively. Mitogen-activated protein kinases (MAPK) were analyzed in activated MDMs by western blots. Further, the effect of Vpr on neuronal apoptosis was examined using primary neurons exposed to culture supernatants from HIV-1wt, HIV-1∆Vpr or mock-infected MDMs by Annexin-V staining, MTT and Caspase - Glo® 3/7 assays. The role of interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)-α on neuronal apoptosis was also evaluated in the presence or absence of neutralizing antibodies against these cytokines.

Results

HIV-1∆Vpr-infected MDMs exhibited reduced infection over time and specifically a significant downregulation of IL-1β, IL-8 and TNF-α at the transcriptional and/or protein levels compared to HIV-1wt-infected cultures. This downregulation was due to impaired activation of p38 and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) in HIV-1∆Vpr-infected MDMs. The association of SAPK/JNK and p38 to IL-1β and IL-8 production was confirmed by blocking MAPKs that prevented the elevation of IL-1β and IL-8 in HIV-1wtmore than in HIV-1∆Vpr-infected cultures. Supernatants from HIV-1∆Vpr-infected MDMs containing lower concentrations of IL-1β, IL-8 and TNF-α as well as viral proteins showed a reduced neurotoxicity compared to HIV-1wt-infected MDM supernatants. Reduction of neuronal death in the presence of anti-IL-1β and anti-IL-8 antibodies only in HIV-1wt-infected culture implies that the effect of Vpr on neuronal death is in part mediated through released proinflammatory factors.

Conclusion

Collectively, these results demonstrate the ability of HIV-1∆Vpr to restrict neuronal apoptosis through dysregulation of multiple proinflammatory cytokines in the infected target cells either directly or indirectly by suppressing viral replication.
Genomic sequencing and analyses of HearMNPV—a new Multinucleocapsid nucleopolyhedrovirus isolated from Helicoverpa armigera
Authors: Tang Ping , Zhang Huan , Li Yinü , Han Bin , Wang Guozeng , Qin Qilian , Zhang Zhifang
Published: August 2012

Background

HearMNPV, a nucleopolyhedrovirus (NPV), which infects the cotton bollworm, Helicoverpa armigera, comprises multiple rod-shaped nucleocapsids in virion(as detected by electron microscopy). HearMNPV shows a different host range compared with H. armigera single-nucleocapsid NPV (HearSNPV). To better understand HearMNPV, the HearMNPV genome was sequenced and analyzed.

Methods

The morphology of HearMNPV was observed by electron microscope. The qPCR was used to determine the replication kinetics of HearMNPV infectious for H. armigera in vivo. A random genomic library of HearMNPV was constructed according to the “partial filling-in” method, the sequence and organization of the HearMNPV genome was analyzed and compared with sequence data from other baculoviruses.

Results

Real time qPCR showed that HearMNPV DNA replication included a decreasing phase, latent phase, exponential phase, and a stationary phase during infection of H. armigera. The HearMNPV genome consists of 154,196 base pairs, with a G + C content of 40.07%. 162 putative ORFs were detected in the HearMNPV genome, which represented 90.16% of the genome. The remaining 9.84% constitute four homologous regions and other non-coding regions. The gene content and gene arrangement in HearMNPV were most similar to those of Mamestra configurata NPV-B (MacoNPV-B), but was different to HearSNPV. Comparison of the genome of HearMNPV and MacoNPV-B suggested that HearMNPV has a deletion of a 5.4-kb fragment containing five ORFs. In addition, HearMNPV orf66, bro genes, and hrs are different to the corresponding parts of the MacoNPV-B genome.

Conclusions

HearMNPV can replicate in vivo in H. armigera and in vitro, and is a new NPV isolate distinguished from HearSNPV. HearMNPV is most closely related to MacoNPV-B, but has a distinct genomic structure, content, and organization.
Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice
Authors: Bruckbauer Antje , Zemel Michael B , Thorpe Teresa , Akula Murthy R , Stuckey Alan C , Osborne Dustin , Martin Emily B , Kennel Stephen , Wall Jonathan S
Published: August 2012

Background

Sirtuins are important regulators of glucose and fat metabolism, and sirtuin activation has been proposed as a therapeutic target for insulin resistance and diabetes. We have shown leucine to increase mitochondrial biogenesis and fat oxidation via Sirt1 dependent pathways. Resveratrol is a widely recognized activator of Sirt; however, the biologically-effective high concentrations used in cell and animal studies are generally impractical or difficult to achieve in humans. Accordingly, we sought to determine whether leucine would exhibit synergy with low levels of resveratrol on sirtuin-dependent outcomes in adipocytes and in diet-induced obese (DIO) mice.

Methods

3T3-L1 mouse adipocytes were treated with Leucine (0.5 mM), β-hydroxy-β-methyl butyrate (HMB) (5 μM) or Resveratrol (200 nM) alone or in combination. In addition, diet-induced obese mice were treated for 6-weeks with low (2 g/kg diet) or high (10 g/kg diet) dose HMB, Leucine (24 g/kg diet; 200% of normal level) or low (12.5 mg/kg diet) or high (225 mg/kg diet) dose resveratrol, alone or as combination with leucine-resveratrol or HMB-resveratrol.

Results

Fatty acid oxidation, AMPK, Sirt1 and Sirt3 activity in 3T3-L1 adipocytes and in muscle cells, were significantly increased by the combinations compared to the individual treatments. Similarly, 6-week feeding of low-dose resveratrol combined with either leucine or its metabolite HMB to DIO mice increased adipose Sirt1 activity, muscle glucose and palmitate uptake (measured via PET/CT), insulin sensitivity (HOMAIR), improved inflammatory stress biomarkers (CRP, IL-6, MCP-1, adiponectin) and reduced adiposity comparable to the effects of high dose resveratrol, while low-dose resveratrol exerted no independent effect.

Conclusion

These data demonstrate that either leucine or its metabolite HMB may be combined with a low concentration of resveratrol to exert synergistic effects on Sirt1-dependent outcomes; this may result in more practical dosing of resveratrol in the management of obesity, insulin-resistance and diabetes.
An analysis of two indigenous reproductive health illnesses in a Nahua community in Veracruz, Mexico
Authors: Smith-Oka Vania
Published: August 2012

Background

This article describes the local concepts indigenous Nahua women hold regarding their reproduction. Specifically it provides a description of two indigenous illnesses—isihuayo and necaxantle, it discusses their etiology, symptoms, and treatments, and it analyzes them within the local ethnomedical framework and sociopolitical context. A perception of female vulnerability is shown to be an underlying shaper of women’s experiences of these illnesses.

Methods

This research took place in a small Nahua village in Mexico. Qualitative data on local perceptions of these illnesses were collected by a combination of participant observation and interviews. Ethnobotanical data was obtained through interviews, and medicinal plants were collected in home gardens, fields, stream banks, and forested areas. The total study population consisted of traditional birth attendants (N = 5), clinicians (N = 8), and laywomen (N = 48).

Results

Results showed that 20% of the village women had suffered from one or both of these illnesses. The article includes a detailed description of the etiology, symptoms, and treatments of these illnesses. Data shows that they were caused by mechanical, physical, and social factors related to a woman’s weakness and/or lack of support. Traditional birth attendants often treated women’s illnesses. Five medicinal plants were salient in the treatment of these illnesses: Ocimum basilicum L., Mentzelia aspera L., Pedilanthus tithymaloides (L.) Poit., and Piper umbellatum L. were used for isihuayo, while Solanum wendlandii Hook f. was used for necaxantle.

Conclusions

The research on these two ethnomedical conditions is a useful case study to understanding how indigenous women experience reproductive health. Reproductive health is not simply about clinically-based medicine but is also about how biomedicine intersects with the local bodily concepts. By describing and analyzing indigenous women’s ill health, one can focus upon the combination of causes—which extend beyond the physical body and into the larger structure that the women exist in.
Pharmacokinetic analysis of topical tobramycin in equine tears by automated immunoassay
Authors: Czerwinski Sarah L , Lyon Andrew W , Skorobohach Brian , Léguillette Renaud
Published: August 2012

Background

Ophthalmic antibiotic therapy in large animals is often used empirically because of the lack of pharmacokinetics studies. The purpose of the study was to determine the pharmacokinetics of topical tobramycin 0.3% ophthalmic solution in the tears of normal horses using an automated immunoassay analysis.

Results

The mean tobramycin concentrations in the tears at 5, 10, 15, 30 minutes and 1, 2, 4, 6 hours after administration were 759 (±414), 489 (±237), 346 (±227), 147 (±264), 27.6 (±28.4), 14.8 (±66.6), 6.7 (±18.6), and 23.4 (±73.4) mg/L. Mean tobramycin concentration was maintained above the MIC90for commonly isolated bacteria for 68.5 min.

Conclusion

A single dose of topical tobramycin resulted in therapeutic concentrations of tobramycin in the tears for 1 h after administration. Therapeutic levels of tobramycin remained in equine tears 6 times longer than was reported in rabbit tears.
Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling
Authors: Creamer Matthew S , Stites Edward C , Aziz Meraj , Cahill James A , Tan Chin Wee , Berens Michael E , Han Haiyong , Bussey Kimberley J , Von Hoff Daniel D , Hlavacek William S , Posner Richard G
Published: August 2012

Background

Mathematical/computational models are needed to understand cell signaling networks, which are complex. Signaling proteins contain multiple functional components and multiple sites of post-translational modification. The multiplicity of components and sites of modification ensures that interactions among signaling proteins have the potential to generate myriad protein complexes and post-translational modification states. As a result, the number of chemical species that can be populated in a cell signaling network, and hence the number of equations in an ordinary differential equation model required to capture the dynamics of these species, is prohibitively large. To overcome this problem, the rule-based modeling approach has been developed for representing interactions within signaling networks efficiently and compactly through coarse-graining of the chemical kinetics of molecular interactions.

Results

Here, we provide a demonstration that the rule-based modeling approach can be used to specify and simulate a large model for ERBB receptor signaling that accounts for site-specific details of protein-protein interactions. The model is considered large because it corresponds to a reaction network containing more reactions than can be practically enumerated. The model encompasses activation of ERK and Akt, and it can be simulated using a network-free simulator, such as NFsim, to generate time courses of phosphorylation for 55 individual serine, threonine, and tyrosine residues. The model is annotated and visualized in the form of an extended contact map.

Conclusions

With the development of software that implements novel computational methods for calculating the dynamics of large-scale rule-based representations of cellular signaling networks, it is now possible to build and analyze models that include a significant fraction of the protein interactions that comprise a signaling network, with incorporation of the site-specific details of the interactions. Modeling at this level of detail is important for understanding cellular signaling.
Processing of DNA double strand breaks by alternative non-homologous end-joining in hyperacetylated chromatin
Authors: Manova Vasilissa , Singh Satyendra K , Iliakis George
Published: August 2012

Background

Mammalian cells employ at least two subpathways of non-homologous end-joining for the repair of ionizing radiation induced DNA double strand breaks: The canonical DNA-PK-dependent form of non-homologous end-joining (D-NHEJ) and an alternative, slowly operating, error-prone backup pathway (B-NHEJ). In contrast to D-NHEJ, which operates with similar efficiency throughout the cell cycle, B-NHEJ operates more efficiently in G2-phase. Notably, B-NHEJ also shows strong and as of yet unexplained dependency on growth activity and is markedly compromised in serum-deprived cells, or in cells that enter the plateau-phase of growth. The molecular mechanisms underpinning this response remain unknown. Since chromatin structure or changes in chromatin structure are prime candidate-B-NHEJ-modulators, we study here the role of chromatin hyperacetylation, either by HDAC2 knockdown or treatment with the HDAC inhibitor TSA, on the repair by B-NHEJ of IR-induced DSBs.

Results

siRNA-mediated knockdown of HDAC2 fails to provoke histone hyperacetylation in Lig4

-/-
MEFs and has no detectable effect on B-NHEJ function. Treatment with TSA that inhibits multiple HDACs causes efficient, reversible chromatin hyperacetylation in Lig4
-/- MEFs, as well as in human HCT116 Lig4
-/- cells and the human glioma cell line M059K. The IR yield of DSBs in TSA-treated cells remains similar to that of untreated cells despite the expected chromatin relaxation. In addition, chromatin hyperacetylation leaves unchanged repair of DSBs by B-NHEJ in irradiated exponentially growing, or plateau-phase cells. Notably, under the experimental conditions employed here, chromatin hyperacetylation fails to detectably modulate B-NHEJ in M059K cells as well.

Conclusions

In summary, the results show that chromatin acetylation or deacetylation does not affect the kinetics of alternative NHEJ in all types of cells examined both in exponentially growing and serum deprived cultures. We conclude that parameters beyond chromatin acetylation determine B-NHEJ efficiency in the plateau-phase of growth.
Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis
Authors: Stawski Lukasz , Han Rong , Bujor Andreea M , Trojanowska Maria
Published: August 2012

Introduction

Systemic sclerosis (SSc) is an autoimmune inflammatory disorder of unknown etiology characterized by fibrosis of the skin and internal organs. Ang II (angiotensin II), a vasoconstrictive peptide, is a well-known inducer of kidney, heart, and liver fibrosis. The goal of this study was to investigate the profibrotic potential of Ang II in the mouse skin.

Methods

Ang II was administered by subcutaneous osmotic mini pumps to C57BL/6 male mice. Collagen-content measurements were performed with Gomori Trichrome staining and hydroxyproline assay. The mRNA expression level of collagens, TGF-β1, TGF-β2, TGF-β3, CTGF, αSMA, CD3, Emr1, CD45/B220, MCP1, and FSP1 were quantified with real-time polymerase chain reaction (PCR). Immunostaining was performed for markers of inflammation and fibrosis, including, phospho-Smad2, αSMA, CD3, Mac3, CD45/B220, and CD163B. Fibrocytes were identified by double staining with CD45/FSP1 and CD45/PH4. Endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT) were identified by double staining with VE-cadherin/FSP1.

Results

Ang II-infused mice develop prominent dermal fibrosis in the area proximal to the pump, as shown by increased collagen and CTGF mRNA levels, increased hydroxyproline content, and more tightly packed collagen fibers. In addition, elevated mRNA levels of TGF-β2 and TGF-β3 along with increased expression of pSmad2 were observed in the skin of Ang II-treated mice. Dermal fibrosis was accompanied by an increased number of infiltrating fibrocytes, and an increased number of αSMA-positive cells, as well as CD163B+ macrophages in the upper dermis. This correlated with significantly increased mRNA levels of αSMA, Emr1, and MCP1. Infiltration of CD3-, CD45/B220-, and Mac3-positive cells was observed mainly in the hypodermis. Furthermore, an increased number of double-positive VE-cadherin/FSP1 cells were detected in the hypodermis only.

Conclusions

This work demonstrates that Ang II induces both inflammation and fibrosis in the skin via MCP1 upregulation and accumulation of activated fibroblasts. Additionally, our data suggest that populations of these fibroblasts originate from circulating blood cells. Ang II infusion via osmotic minipumps could serve as a useful mouse model of skin fibrosis to gain new insights into pathogenic mechanisms and to test new antifibrotic therapies.
Continuous venovenous hemodialysis with regional citrate anticoagulation in patients with liver failure: a prospective observational study
Authors: Schultheiß Caroline , Saugel Bernd , Phillip Veit , Thies Philipp , Noe Sebastian , Mayr Ulrich , Haller Bernhard , Einwächter Henrik , Schmid Roland M , Huber Wolfgang
Published: August 2012

Introduction

Liver failure patients might be at risk for citrate accumulation during continuous venovenous hemodialysis (CVVHD) with regional citrate anticoagulation. The aim of this study was to investigate the predictive capability of baseline liver function parameters regarding citrate accumulation, expressed as an increase in the calcium total/calcium ionized (Catot/Caion) ratio ≥2.5, and to describe the feasibility of citrate CVVHD in liver failure patients.

Methods

We conducted a prospective observational study in medical ICU patients treated in a German university hospital. We performed 43 CVVHD runs using citrate for regional anticoagulation in 28 critically ill patients with decompensated liver cirrhosis or acute liver failure (maximum of two CVVHD runs per patient). Liver function was characterized before CVVHD using laboratory parameters, calculation of Child-Pugh and Model of End-stage Liver Disease scores, and determination of the plasma disappearance rate of indocyanine green. In addition to blood gas analysis, we measured total calcium and citrate in serum at baseline and after definitive time points for each CVVHD run.

Results

Accumulation of citrate in serum correlated with an increase in the Catot/Caion ratio. Although the critical upper threshold of Catot/Caion ratio ≥2.5 was exceeded 10 times in seven different CVVHD runs, equalization of initial metabolic acidosis was possible without major disturbances of acid-base and electrolyte status. Standard laboratory liver function parameters showed poor predictive capabilities regarding citrate accumulation in terms of an elevated Catot/Caion ratio ≥2.5. In contrast, serum lactate ≥3.4 mmol/l and prothrombin time ≤26% predicted an increase in the Catot/Caion ratio ≥2.5 with high sensitivity (86% for both lactate and prothrombin time) and specificity (86% for lactate, 92% for prothrombin time).

Conclusions

Despite substantial accumulation of citrate in serum, CVVHD with regional citrate anticoagulation seems feasible in patients with severely impaired liver function. Citrate accumulation in serum is reflected by an increase in the Catot/Caion ratio. To identify patients at risk for citrate accumulation in terms of a Catot/Caion ratio ≥2.5, baseline serum lactate (threshold ≥3.4 mmol/l) and prothrombin time (threshold ≤26%) may be useful for risk prediction in daily clinical practice. Careful monitoring of electrolytes and acid-base status is mandatory to ensure patient safety.