bluuebunny/crossref_metadata_2025 huggingface dataset:
Scenes from the Putsch
Authors: Siemens Elena
Published: January 2008

A personal account of a Moscow putsch, this short essay employs Michel De Certeau's distinction between the public and secret space of the city. In extending De Certeau, the article applies his work to the realm of photography and juxtaposes the official and private images of the putsch. “Scenes from the Putsch” is intended as a prologue to this themed issue that gather images and texts from around the world and pays tribute to De Certeau's notion of the “second, poetic geography” understood by the contributors as related to the secondary or unofficial connotations of spaces, as well as more literally to marginal destinations located outside of conventional tourist routes.
Anatomy of the Lisfranc Ligament
Authors: Johnson Anthony , Hill Keith , Ward John , Ficke James
Published: January 2008

Most authors agree that anatomic reduction is the key to optimal results in treatment of injuries of the Lisfranc joint; a few controversies remain. One controversy is the identification of the strongest ligament of the second metatarsal-medial cuneiform articulation—the critical ligament of the Lisfranc joint. The purpose of this study is to objectively quantify the cross-sectional area of each ligament of this crucial joint. Twenty cadaveric feet were dissected to isolate the second metatarsal-medial cuneiform articulation. The point of maximum thickness, height, and width of the dorsal, plantar, and interosseous ligaments were measured using handheld calipers at the second metatarsal attachment. The distribution failed to pass Mauchly's test of sphericity, so the Greenhouse-Geisser method was used to assess differences in the height and width to a P ≤ .05 level of significance. There was a significant difference in the height, width, and area between all ligaments (P < .001). The interosseous ligament was the largest, with the greatest height, width, and cross-sectional area (P < .001). The dorsal ligament was the smallest, with the least height, width, and cross-sectional area (P < .001). Within the Lisfranc complex, the dorsal ligament is the smallest. The plantar ligament is twice as large as the dorsal ligament. The interosseous ligament is the largest. It is, on average, 4.5 times larger than the dorsal ligament and twice as large as the plantar ligament.
The Limits of Presidential Agenda Setting: Predicting Newspaper Coverage of the Weekly Radio Address
Authors: Horvit Beverly , Schiffer Adam J. , Wright Mark
Published: January 2008

Beginning with Ronald Reagan in 1982, U.S. presidents have typically given a radio address every Saturday morning designed primarily to make news in the Sunday newspapers and on the Sunday news programs. A content analysis of the New York Times, the Boston Globe, Houston Chronicle, and Pittsburgh Post-Gazette from 1982 to 2005 shows that coverage of the presidents' addresses has diminished over time both in terms of the percentage of radio addresses covered and the number of paragraphs directly citing the president. Positive predictors of coverage include presidential approval ratings and a foreign-policy topic. Negative influences on coverage include the number of addresses given by all presidents since Reagan, indicating a decreasing lack of novelty, and whether the speech occurred in an election year.
Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules
Authors: Patel-Hett Sunita , Richardson Jennifer L. , Schulze Harald , Drabek Ksenija , Isaac Natasha A. , Hoffmeister Karin , Shivdasani Ramesh A. , Bulinski J. Chloë , Galjart Niels , Hartwig John H. , Italiano Joseph E.
Published: January 2008

The marginal band of microtubules maintains the discoid shape of resting blood platelets. Although studies of platelet microtubule coil structure conclude that it is composed of a single microtubule, no investigations of its dynamics exist. In contrast to previous studies, permeabilized platelets incubated with GTP-rhodamine-tubulin revealed tubulin incorporation at 7.9 (± 1.9) points throughout the coil, and anti-EB1 antibodies stained 8.7 (± 2.0) sites, indicative of multiple free microtubules. To pursue this result, we expressed the microtubule plus-end marker EB3-GFP in megakaryocytes and examined its behavior in living platelets released from these cells. Time-lapse microscopy of EB3-GFP in resting platelets revealed multiple assembly sites within the coil and a bidirectional pattern of assembly. Consistent with these findings, tyrosinated tubulin, a marker of newly assembled microtubules, localized to resting platelet microtubule coils. These results suggest that the resting platelet marginal band contains multiple highly dynamic microtubules of mixed polarity. Analysis of microtubule coil diameters in newly formed resting platelets indicates that microtubule coil shrinkage occurs with aging. In addition, activated EB3-GFP–expressing platelets exhibited a dramatic increase in polymerizing microtubules, which travel outward and into filopodia. Thus, the dynamic microtubules associated with the marginal band likely function during both resting and activated platelet states.
GraphCrunch: A tool for large network analyses
Authors: Milenković Tijana , Lai Jason , Pržulj Nataša
Published: January 2008

Background

The recent explosion in biological and other real-world network data has created the need for improved tools for large network analyses. In addition to well establishedglobalnetwork properties, several new mathematical techniques for analyzinglocalstructural properties of large networks have been developed. Small over-represented subgraphs, called networkmotifs, have been introduced to identify simple building blocks of complex networks. Small induced subgraphs, calledgraphlets, have been used to develop "network signatures" that summarize network topologies. Based on these network signatures, two new highly sensitive measures of network local structural similarities were designed: therelative graphlet frequency distance(RGF-distance) and thegraphlet degree distribution agreement(GDD-agreement).

Finding adequate null-models for biological networks is important in many research domains. Network properties are used to assess the fit of network models to the data. Various network models have been proposed. To date, there does not exist a software tool that measures the above mentioned local network properties. Moreover, none of the existing tools compare real-world networks against a series of network models with respect to these local as well as a multitude of global network properties.

Results

Thus, we introduce GraphCrunch, a software tool that finds well-fitting network models by comparing large real-world networks against random graph models according to various network structural similarity measures. It has unique capabilities of finding computationally expensive RGF-distance and GDD-agreement measures. In addition, it computes several standard global network measures and thus supports the largest variety of network measures thus far. Also, it is the first software tool that compares real-world networks against a series of network models and that has built-in parallel computing capabilities allowing for a user specified list of machines on which to perform compute intensive searches for local network properties. Furthermore, GraphCrunch is easily extendible to include additional network measures and models.

Conclusion

GraphCrunch is a software tool that implements the latest research on biological network models and properties: it compares real-world networks against a series of random graph models with respect to a multitude of local and global network properties. We present GraphCrunch as a comprehensive, parallelizable, and easily extendible software tool for analyzing and modeling large biological networks. The software is open-source and freely available athttp://www.ics.uci.edu/~bio-nets/graphcrunch/. It runs under Linux, MacOS, and Windows Cygwin. In addition, it has an easy to use on-line web user interface that is available from the above web page.
Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma
Authors: Kawasaki Takako , Nosho Katsuhiko , Ohnishi Mutsuko , Suemoto Yuko , Glickman Jonathan N , Chan Andrew T , Kirkner Gregory J , Mino-Kenudson Mari , Fuchs Charles S , Ogino Shuji
Published: January 2008

Background

Cyclooxygenase-2 (COX-2, PTGS2) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway.

Methods

By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration.

Results

Strong (2+) COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515) than in hyperplastic polyps (4.2% = 1/24, p = 0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0% = 0/12, p = 0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515) than in hyperplastic polyps (13% = 3/24, p < 0.0001) and serrated polyps (SSAs and mixed polyps) (25% = 3/12, p = 0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (~85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas.

Conclusion

COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.
Self-excision of the BAC sequences from the recombinant Marek's disease virus genome increases replication and pathogenicity
Authors: Zhao Yuguang , Petherbridge Lawrence , Smith Lorraine P , Baigent Sue , Nair Venugopal
Published: January 2008

Cloning of full length genomes of herpesviruses as bacterial artificial chromosomes (BAC) has greatly facilitated the manipulation of the genomes of several herpesviruses to identify the pathogenic determinants. We have previously reported the construction of the BAC clone (pRB-1B5) of the highly oncogenic Marek's disease virus (MDV) strain RB-1B, which has proven to be a valuable resource for elucidating several oncogenic determinants. Despite the retention of the BAC replicon within the genome, the reconstituted virus was able to induce tumours in susceptible chickens. Nevertheless, it was unclear whether the presence of the BAC influenced the full oncogenic potential of the reconstituted virus. To maximize the closeness of BAC-derived virus to the parental RB-1B strain, we modified the existing pRB-1B5 clone by restoring the Us2 and by introducing SV40-cre cassette within the lox P sites of the mini-F plasmid, to allow self-excision of the plasmid sequences in chicken cells. The reconstituted virus from the modified clone showed significant improvement in replication in vitro and in vivo. Excision of the BAC sequences also enhanced the pathogenicity to levels similar to that of the parental virus, as the cumulative incidence of Marek's disease in groups infected with the recombinant and the parental viruses showed no significant differences. Thus, we have been able to make significant improvements to the existing BAC clone of this highly oncogenic virus which would certainly increase its usefulness as a valuable tool for studies on identifying the oncogenic determinants of this major avian pathogen.
Identification of gene interactions associated with disease from gene expression data using synergy networks
Authors: Watkinson John , Wang Xiaodong , Zheng Tian , Anastassiou Dimitris
Published: January 2008

Background

Analysis of microarray data has been used for the inference of gene-gene interactions. If, however, the aim is the discovery of disease-related biological mechanisms, then the criterion for defining such interactions must be specifically linked to disease.

Results

Here we present a computational methodology that jointly analyzes two sets of microarray data, one in the presence and one in the absence of a disease, identifying gene pairs whose correlation with disease is due to cooperative, rather than independent, contributions of genes, using the recently developed information theoretic measure of synergy. High levels of synergy in gene pairs indicates possible membership of the two genes in a shared pathway and leads to a graphical representation of inferred gene-gene interactions associated with disease, in the form of a "synergy network." We apply this technique on a set of publicly available prostate cancer expression data and successfully validate our results, confirming that they cannot be due to pure chance and providing a biological explanation for gene pairs with exceptionally high synergy.

Conclusion

Thus, synergy networks provide a computational methodology helpful for deriving "disease interactomes" from biological data. When coupled with additional biological knowledge, they can also be helpful for deciphering biological mechanisms responsible for disease.
Serum keratan sulfate transiently increases in the early stage of osteoarthritis during strenuous running of rats: protective effect of intraarticular hyaluronan injection
Authors: Tang Tao , Muneta Takeshi , Ju Young-Jin , Nimura Akimoto , Miyazaki Kyosuke , Masuda Hiroyuki , Mochizuki Tomoyuki , Sekiya Ichiro
Published: January 2008

Introduction

Osteoarthritis is influenced by genetic and environment factors, including mechanical stress; however, the relationship between running and the development of osteoarthritis remains a matter of controversy. We investigated whether osteoarthritic change could be obtained in a rat strenuous running model, whether serum keratan sulfate in rats could be detected by HPLC and was associated with onset or progression of osteoarthritis, and whether hyaluronan injection suppressed development of osteoarthritis and elevation of serum keratan sulfate.

Methods

Wistar rats were forced to run 30 km in 6 weeks on a treadmill machine. Articular cartilage of the knees was evaluated macroscopically and immunohistologically. Serum keratan sulfate was examined every week by HPLC. The effect of weekly knee injection of hyaluronan was also investigated.

Results

Cartilage surfaces stained with India ink became irregular, metachromasia by safranin-O staining appeared to be almost lost, and Mankin's score significantly worsened after 30 km of running. Serum keratan sulfate in rats was detected by HPLC and transiently increased (peaked at 3 to 4 weeks) along with depletion of keratan sulfate in cartilage tissue. Hyaluronan treatment suppressed morphological progression of osteoarthritis and elevation of serum keratan sulfate.

Conclusion

Rat strenuous running induced osteoarthritis. Serum keratan sulfate was associated with progression of osteoarthritis. Weekly intraarticular injection of hyaluronan controlled the development of osteoarthritis, and the effect was reflected by serum keratan sulfate.
Electrical protein detection in cell lysates using high-density peptide-aptamer microarrays
Authors: Evans David , Johnson Steven , Laurenson Sophie , Davies A Giles , Ko Ferrigno Paul , Wälti Christoph
Published: January 2008

Background

The dissection of biological pathways and of the molecular basis of disease requires devices to analyze simultaneously a staggering number of protein isoforms in a given cell under given conditions. Such devices face significant challenges, including the identification of probe molecules specific for each protein isoform, protein immobilization techniques with micrometer or submicrometer resolution, and the development of a sensing mechanism capable of very high-density, highly multiplexed detection.

Results

We present a novel strategy that offers practical solutions to these challenges, featuring peptide aptamers as artificial protein detectors arrayed on gold electrodes with feature sizes one order of magnitude smaller than existing formats. We describe a method to immobilize specific peptide aptamers on individual electrodes at the micrometer scale, together with a robust and label-free electronic sensing system. As a proving proof of principle experiment, we demonstrate the specific recognition of cyclin-dependent protein kinases in whole-cell lysates using arrays of ten electrodes functionalized with individual peptide aptamers, with no measurable cross-talk between electrodes. The sensitivity is within the clinically relevant range and can detect proteins against the high, whole-cell lysate background.

Conclusion

The use of peptide aptamers selected in vivo to recognize specific protein isoforms, the ability to functionalize each microelectrode individually, the electronic nature and scalability of the label-free detection and the scalability of the array fabrication combine to yield the potential for highly multiplexed devices with increasingly small detection areas and higher sensitivities that may ultimately allow the simultaneous monitoring of tens or hundreds of thousands of protein isoforms.
Phase I/II Trial of Weekly Intravenous 130-nm Albumin-Bound Paclitaxel As Initial Chemotherapy in Patients With Stage IV Non–Small-Cell Lung Cancer
Authors: Rizvi Naiyer A. , Riely Gregory J. , Azzoli Christopher G. , Miller Vincent A. , Ng Kenneth K. , Fiore John , Chia Gloria , Brower Martin , Heelan Robert , Hawkins Michael J. , Kris Mark G.
Published: January 2008

Purpose

Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) is an albumin-bound formulation of paclitaxel that has demonstrated improved efficacy compared with paclitaxel in the treatment of metastatic breast cancer. We undertook this trial to determine the maximum-tolerated dose (MTD) and single-agent activity of NAB-paclitaxel administered on a weekly basis to patients with stage IV non–small-cell lung cancer (NSCLC).

Patients and Methods

This was an open-label, single-arm, phase I/II study. Patients were treated with NAB-paclitaxel intravenously during 30 minutes without corticosteroid or antihistamine premedications on days 1, 8, and 15 of a 28-day cycle. Radiologic tumor assessment was performed every 8 weeks.

Results

Dose levels of 100 and 125 mg/m2 were tolerated without dose-limiting toxicities (DLTs). At 150 mg/m2 the MTD was exceeded; two of three patients experienced a DLT (grade 3 sensory neuropathy and febrile neutropenia). The 125 mg/m2 dose level was expanded and determined to be the MTD. A total of 40 patients were treated at 125 mg/m2. The objective response rate was 30% (12 of 40 patients; 95% CI, 16% to 44%), median time to progression was 5 months (95% CI, 3 to 8 months), and median overall survival was 11 months (95% CI, 7 months to not reached). The 1-year survival was 41%.

Conclusion

NAB-paclitaxel 125 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle was well tolerated and demonstrated encouraging single-agent activity. No corticosteroid premedication was administered and no hypersensitivity reactions were seen. Additional studies of single-agent NAB-paclitaxel as well as platinum-based combinations are warranted.
Effect of Once-Weekly Epoetin Beta on Survival in Patients With Metastatic Breast Cancer Receiving Anthracycline- and/or Taxane-Based Chemotherapy: Results of the Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) Study
Authors: Aapro Matti , Leonard Robert C. , Barnadas Agustí , Marangolo Maurizio , Untch Michael , Malamos Nikolaos , Mayordomo José , Reichert Dietmar , Pedrini José Luiz , Ukarma Lidia , Scherhag Armin , Burger Hans-Ulrich
Published: January 2008

Purpose

The Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC).

Patients and Methods

BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia–free survival, Hb response, safety, and quality of life (QoL).

Results

After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia–free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value.

Conclusion

In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.
Prevalence, Severity, and Impact of Symptoms on Female Family Caregivers of Patients at the Initiation of Radiation Therapy for Prostate Cancer
Authors: Fletcher Barbara Swore , Paul Steven M. , Dodd Marylin J. , Schumacher Karen , West Claudia , Cooper Bruce , Lee Kathryn , Aouizerat Bradley , Swift Patrick , Wara William , Miaskowski Christine A.
Published: January 2008

Purpose

In a sample of family caregivers (FCs) of patients with prostate cancer who were to begin radiation therapy (RT), the purposes were to determine the prevalence and severity of depression, anxiety, pain, sleep disturbance, and fatigue; determine the relationships among these symptoms and between these symptoms and functional status and quality of life (QOL); evaluate for differences in functional status and QOL between FCs with low and high levels of these symptoms; and determine which factors predicted FCs’ functional status and QOL.

Patients and Methods

FCs were recruited before patients initiated RT and completed self-report questionnaires that evaluated demographic characteristics, symptoms, functional status, and QOL.

Results

Sixty female FCs participated in the study. On the basis of established cut point scores for each symptom questionnaire, 12.2% of the FCs had clinically meaningful levels of depression, 40.7% anxiety, 15.0% pain, 36.7% sleep disturbance, 33.3% morning fatigue, and 30.0% evening fatigue. FCs who were older and who had lower levels of state anxiety and higher levels of depression, morning fatigue, and pain reported significantly poorer functional status (R2 = 38.7%). FCs who were younger, had more years of education, were working, and who had higher levels of depression, morning fatigue, sleep disturbance, and lower levels of evening fatigue reported significantly lower QOL scores (R2 = 70.1%).

Conclusion

A high percentage of FCs experienced clinically meaningful levels of a variety of symptoms. These symptoms have a negative impact on the FCs’ functional status and QOL.
Phase II Trial of Preoperative Chemoradiotherapy Followed by Surgical Resection in Patients With Superior Sulcus Non–Small-Cell Lung Cancers: Report of Japan Clinical Oncology Group Trial 9806
Authors: Kunitoh Hideo , Kato Harubumi , Tsuboi Masahiro , Shibata Taro , Asamura Hisao , Ichonose Yukito , Katakami Nobuyuki , Nagai Kanji , Mitsudomi Tetsuya , Matsumura Akihide , Nakagawa Ken , Tada Hirohito , Saijo Nagahiro
Published: January 2008

Purpose

To evaluate the safety and efficacy of preoperative chemoradiotherapy followed by surgical resection for superior sulcus tumors (SSTs).

Patients and Methods

Patients with pathologically documented non–small-cell lung cancer with invasion of the first rib or more superior chest wall were enrolled as eligible; those with distant metastasis, pleural dissemination, and/or mediastinal node involvement were excluded. Patients received two cycles of chemotherapy every 4 weeks as follows; mitomycin 8 mg/m2 on day 1, vindesine 3 mg/m2 on days 1 and 8, and cisplatin 80 mg/m2 on day 1. Radiotherapy directed at the tumor and the ipsilateral supraclavicular nodes was started on day 2 of each course, at the total dose of 45 Gy in 25 fractions, with a 1-week split. Thoracotomy was undertaken 2 to 4 weeks after completion of the chemoradiotherapy. Those with unresectable disease received boost radiotherapy.

Results

From May 1999 to November 2002, 76 patients were enrolled, of whom 20 had T4 disease; 75 patients were fully assessable. Chemoradiotherapy was generally well tolerated. Fifty-seven patients (76%) underwent surgical resection, and pathologic complete resection was achieved in 51 patients (68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths, including two deaths owing to postsurgical complications and one death owing to sepsis during chemoradiotherapy. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively.

Conclusion

This trimodality approach is safe and effective for the treatment of patients with SSTs.
The Endocrine Phenotype in Silver-Russell Syndrome Is Defined by the Underlying Epigenetic Alteration
Authors: Binder Gerhard , Seidel Ann-Kathrin , Martin David D. , Schweizer Roland , Schwarze C. Philipp , Wollmann Hartmut A. , Eggermann Thomas , Ranke Michael B.
Published: January 2008

Context: Around 50% of children with Silver-Russell syndrome (SRS) carry a hypomethylation of the imprinting control region 1 at the IGF2/H19 locus on 11p15, the functional significance of which is unknown.

Objective: We aimed to compare the genotype in SRS with the endocrine phenotype.

Design: The retrospective study included all SRS children who were treated during the last 18 yr at our hospital and for comparison a cohort of GH treated nonsyndromic short children born small for gestational age (SGA).

Patients: The 61 patients with SRS included were defined by the presence of intrauterine growth retardation, lack of catch-up growth, and at least two of the criteria: typical face, relative macrocephaly, and skeletal asymmetry. Routine karyotype and GH secretion was normal in all children studied. A subgroup of 53 patients was treated with GH.

Materials and Methods: Genomic DNA was available from 44 children. Multiplex ligation probe-dependent amplification analysis was performed to detect hypomethylation at the imprinting control region 1 on 11p15. Uniparental disomy of chromosome 7 (UPD7) was analyzed by short tandem repeats typing. Serum levels of GH, IGF-I, and IGF-binding protein (IGFBP)-3 were measured by RIA.

Results: Epimutations at 11p15 were found in 19 of 44, UPD7 in five of 44, and small structural aberrations of the short arm of chromosome 11 in two of 44 children. Of 44 cases, 18 were negative for any genetic defect known (41%). The most severe phenotype was found in children with 11p15-SRS. Children with UPD7-SRS had a significantly higher birth length (P < 0.004) but lost height sd score (SDS) postpartum, whereas children with 11p15-SRS showed no change in height SDS. IGF-I and IGFBP-3 serum levels were inadequately high in 11p15-SRS at −0.02 SDS (1.07, sd) and +1.38 SDS (1.01), compared with the low levels in UPD7-SRS and in the cohort of 58 nonsyndromic SGA children (P < 0.0009). During GH therapy, IGFBP-3 serum levels increased above normal values in 11p15-SRS (P < 10−4), whereas IGF-I increase was moderate. There was a trend toward more height gain in children with UPD7 than in those with 11p15 epimutation under GH therapy (+2.5 vs. +1.9 height SDS after 3 yr) (P = 0.08).

Conclusions: Children with SRS and an 11p15 epimutation have IGFBP-3 excess and show endocrine characteristics suggesting IGF-I insensitivity, whereas children with SRS and UPD7 were not different from nonsyndromic short children born SGA. This phenotype-genotype correlation implicates divergent endocrine mechanisms of growth failure in SRS.
Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei
Authors: Fridberg Alina , Olson Cheryl L. , Nakayasu Ernesto S. , Tyler Kevin M. , Almeida Igor C. , Engman David M.
Published: January 2008

Sphingolipids and their metabolites have been thought crucial for cell growth and cell cycle progression, membrane and protein trafficking, signal transduction, and formation of lipid rafts; however, recent studies in trypanosomes point to the dispensability of sphingolipids in some of these processes. In this study, we explore the requirements for de novo sphingolipid biosynthesis in the insect life cycle stage of the African trypanosome Trypanosoma brucei by inhibiting the enzyme serine palmitoyltransferase (SPT2) by using RNA interference or treatment with a potent SPT2 inhibitor myriocin. Mass spectrometry revealed that upon SPT2 inhibition, the parasites contained substantially reduced levels of inositolphosphorylceramide. Although phosphatidylcholine and cholesterol levels were increased to compensate for this loss, the cells were ultimately not viable. The most striking result of sphingolipid reduction in procyclic T. brucei was aberrant cytokinesis, characterized by incomplete cleavage-furrow formation, delayed kinetoplast segregation and emergence of cells with abnormal DNA content. Organelle replication continued despite sphingolipid depletion, indicating that sphingolipids act as second messengers regulating cellular proliferation and completion of cytokinesis. Distention of the mitochondrial membrane, formation of multilamellar structures within the mitochondrion and near the nucleus, accumulation of lipid bodies and, less commonly, disruption of the Golgi complex were observed after prolonged sphingolipid depletion. These findings suggest that some aspects of vesicular trafficking may be compromised. However, flagellar membrane targeting and the association of the flagellar membrane protein calflagin with detergent-resistant membranes were not affected, indicating that the vesicular trafficking defects were mild. Our studies indicate that sphingolipid biosynthesis is vital for cell cycle progression and cell survival, but not essential for the normal trafficking of flagellar membrane-associated proteins or lipid raft formation in procyclic T. brucei.
LUMA interacts with emerin and influences its distribution at the inner nuclear membrane
Authors: Bengtsson Luiza , Otto Henning
Published: January 2008

We present here a first characterization of LUMA, an unique integral inner nuclear membrane (INM) protein. LUMA is a highly conserved protein even in some bacteria and shares a PFAM domain of unknown function with orthologs from many species. Assessing LUMA topology by using protease protection of membrane-inserted LUMA and antibody epitope accessibility assays reveals that LUMA contains four transmembrane domains and a large hydrophilic domain located between membrane spans 1 and 2. The large hydrophilic domain is exposed to the perinuclear space whereas both LUMA termini reside cyto- or nucleoplasmically. Nuclear envelope targeting of LUMA mainly depends on the membrane spans. LUMA's transmembrane domains also promote homooligomerization. LUMA binds A- and B-type lamins and depends on A-type lamins for its INM localization. Furthermore, it interacts with emerin. Both downregulation of LUMA and overexpression of dominant-negative acting LUMA fragments causes redistribution of emerin. We propose that LUMA functions as a tetraspanin-like membrane organizer and has the potential to contribute to the pathomechanism of dystrophic diseases, such as Emery-Dreifuss muscular dystrophy.
Actin stress fibers transmit and focus force to activate mechanosensitive channels
Authors: Hayakawa Kimihide , Tatsumi Hitoshi , Sokabe Masahiro
Published: January 2008

Mechanosensitive (MS) channels are expressed in various cells in a wide range of phylogenetic lineages from bacteria to humans. Understanding the molecular and biophysical mechanisms of their activation is an important research pursuit. It is controversial whether eukaryotic MS channels need accessory proteins – typically cytoskeletal structures – for activation, because MS channel activities are modulated by pharmacological treatments that affect the cytoskeleton. Here we demonstrate that direct mechanical stimulation (stretching) of an actin stress fiber using optical tweezers can activate MS channels in cultured human umbilical vein endothelial cells (HUVECs). Furthermore, by using high-speed total internal reflection microscopy, we visualized spots of Ca2+ influx across individual MS channels distributed near focal adhesions in the basal surface of HUVECs. This study provides the first direct evidence that the cytoskeleton works as a force-transmitting and force-focusing molecular device to activate MS channels in eukaryotic cells.
Facile Single-step Technique for Simultaneous In Situ Fabrication of Ag/Ag2S–Polymer Nanocomposites via PPS Cyclization Route
Authors: Waghmare Sujata , Shinde Manish , Gholap Ramkrishna , Rao N Koteswara , Seth Tanay , Amalnerkar Dinesh
Published: January 2008

We herein propose a facile single-step approach involving solid-state reaction between silver salt and engineering thermoplastic polyphenylene sulfide for simultaneous in situ generation of nanoscale metallic silver as well as semiconducting silver sulfide.
Total Syntheses of Doubly Locked Biliverdin Derivatives toward Elucidation of the Stereochemistry of Phytochrome Chromophore
Authors: Khawn Htoi , Chen Li-Yi , Kinoshita Hideki , Inomata Katsuhiko
Published: January 2008

To elucidate the stereochemistry of phytochrome chromophore in far-red light absorbing form (Pfr), four different types of doubly locked biliverdin (BV) derivatives, 5Zs15Ea-BV, 5Za15Ea-BV, 5Es15Ea-BV, and 5Ea15Ea-BV, were synthesized for the first time in free acid forms.
Microwave-assisted Aromatic C–O Bond Formation: A Rapid and Efficient Method for the Synthesis of Aryl Ethers
Authors: Xu Boyan , Xue Jijun , Zhu Jianrong , Li Ying
Published: January 2008

A rapid and efficient aromatic C–O bond formation has been developed based on microwave-assistant, which is particularly useful for the intramolecular coupling of halides with alcohols. This method needs not the use of transition-metal catalyst. It was also demonstrated that the method can be used in the synthesis of bioactive natural flavans.
Durinskiol B: A New Durinskiol Congener from the Symbiotic Marine Dinoflagellate Durinskia sp.
Authors: Siwu Eric Richard Oktavianus , Ohno Osamu , Kita Masaki , Uemura Daisuke
Published: January 2008

Durinskiol B (1) was isolated from the symbiotic marine dinoflagellate Durinskia sp., along with durinskiol A (2). The planar structure of 1 was determined by detailed NMR analysis. Durinskiol B (1) has structure similarity with durinskiol A (2) except for the existence of one methyl excess in the side chain of durinskiol B.
The RNA binding protein Hfq interacts specifically with tRNAs
Authors: Lee Taewoo , Feig Andrew L.
Published: January 2008

Hfq is an RNA binding protein that has been studied extensively for its role in the biology of small noncoding RNAs (ncRNAs) in bacteria, where it facilitates post-transcriptional gene regulation during stress responses. We show that Hfq also binds with high specificity and nanomolar affinity to tRNAs despite their lack of a canonical A/U rich single-stranded sequence. This affinity is comparable to that of Hfq for its validated ncRNA targets. Two sites on tRNAs are protected by Hfq binding, one on the D-stem and the other on the T-stem. Mutational analysis and competitive binding experiments indicate that Hfq uses its proximal surface (also called the L4 face) to bind tRNAs, the same surface that interacts with ncRNAs but a site distinct from where poly(A) oligonucleotides bind. hfq knockout strains are known to have broad pleiotropic phenotypes, but none of them are easily explained by or imply a role for tRNA binding. We show that hfq deletion strains have a previously unrecognized phenotype associated with mistranslation and significantly reduced translational fidelity. We infer that tRNA binding and reduced fidelity are linked by a role for Hfq in tRNA modification.
Sequence-specific activation of TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells
Authors: Kodym Reinhard , Kodym Elisabeth , Story Micheal D.
Published: January 2008

Short double-stranded RNAs (dsRNA) are potent biological entities triggering a number of cellular effects. Most prominent among these is the post-transcriptional gene silencing of target genes by small interfering RNAs (siRNAs). In addition dsRNAs activate signal transduction processes through molecules like PKR or the Toll-like receptor important in viral defense and in explaining off target effects of siRNAs. Only a few of these dsRNA triggered pathways have been characterized yet. Here we show that the splicing variant D of the TAK1 gene is activated by short double-stranded RNAs in a sequence-specific manner. Activation of TAK1-D leads to the downstream activation of the p38 MAPK and of SAPK/JNK but not the NFκB pathway. In the human lung cancer cell line NCI-H460 the activation of these pathways leads to cell cycle arrest and apoptosis. Our results demonstrate that TAK1-D is activated by siRNAs of specific sequences, offering a new explanation for off target effects triggered by these molecules. In addition the dsRNA triggered activation of a cell death pathway in the human lung cancer cell line studied suggests that TAK1-D might be a new and promising therapeutic target for the treatment of nonsmall cell lung cancer.
A novel sequence-specific RNA quantification method using nicking endonuclease, dual-labeled fluorescent DNA probe, and conformation-interchangeable oligo-DNA
Authors: Hosoda Kazufumi , Matsuura Tomoaki , Kita Hiroshi , Ichihashi Norikazu , Tsukada Koji , Urabe Itaru , Yomo Tetsuya
Published: January 2008

We have developed a novel, single-step, isothermal, signal-amplified, and sequence-specific RNA quantification method (L-assay). The L-assay consists of nicking endonuclease, a dual-labeled fluorescent DNA probe (DL-probe), and conformation-interchangeable oligo-DNA (L-DNA). This signal-amplified assay can quantify target RNA concentration in a sequence-specific manner with a coefficient of variation (Cv) of 5% and a lower limit of detection of 0.1 nM. Moreover, this assay allows quantification of target RNA even in the presence of a several thousandfold excess by weight of cellular RNA. In addition, this assay can be used to measure the changes in RNA concentration in real-time and to quantify short RNAs (<30 nucleotides). The L-assay requires only incubation under isothermal conditions, is inexpensive, and is expected to be useful for basic research requiring high-accuracy, easy-to-use RNA quantification, and real-time quantification.
An efficient in vitro translation system from mammalian cells lacking the translational inhibition caused by eIF2 phosphorylation
Authors: Zeenko Vladimir V. , Wang Chuanping , Majumder Mithu , Komar Anton A. , Snider Martin D. , Merrick William C. , Kaufman Randal J. , Hatzoglou Maria
Published: January 2008

In vitro translation systems are used to investigate translational mechanisms and to synthesize proteins for characterization. Most available mammalian cell-free systems have reduced efficiency due to decreased translation initiation caused by phosphorylation of the initiation factor eIF2α on Ser51. We describe here a novel cell-free protein synthesis system using extracts from cultured mouse embryonic fibroblasts that are homozygous for the Ser51 to- Ala mutation in eIF2α (A/A cells). The translation efficiency of a capped and polyadenylated firefly luciferase mRNA in A/A cell extracts was 30-fold higher than in wild-type extracts. Protein synthesis in extracts from A/A cells was active for at least 2 h and generated up to 20 μg/mL of luciferase protein. Additionally, the A/A cell-free system faithfully recapitulated the selectivity of in vivo translation for mRNA features; translation was stimulated by a 5′-end cap (m7GpppN) and a 3′-end poly(A) tail in a synergistic manner. The system also showed similar efficiencies of cap-dependent and IRES-mediated translation (EMCV IRES). Significantly, the A/A cell-free system supported the post-translational modification of proteins, as shown by glycosylation of the HIV type-1 gp120 and cleavage of the signal peptide from β-lactamase. We propose that cell-free systems from A/A cells can be a useful tool for investigating mechanisms of mammalian mRNA translation and for the production of recombinant proteins for molecular studies. In addition, cell-free systems from differentiated cells with the Ser51Ala mutation should provide a means for investigating cell type-specific features of protein synthesis.
Clinical Risk Factors for Fracture in Postmenopausal Osteoporotic Women: A Review of the Recent Literature
Authors: LaFleur Joanne , McAdam-Marx Carrie , Kirkness Carmen , Brixner Diana I
Published: January 2008

Objective:

To review recent literature regarding relationships among age, weight or body mass index (BMI), bone mineral density (BMD), maternal history of fracture, or personal prior history of fracture and fragility fractures in women with postmenopausal osteoporosis (PMO).

Data Sources:

A MEDLINE database search (1995–June 30, 2007) was conducted to identify literature related to risk factors of interest for PMO-related fractures.

Study Selection and Data Extraction:

Cohort studies, case—control studies, and meta-analyses that reported fracture outcomes were included if they provided an estimate of relative risk for at least 1 of the 5 selected clinical risk factors (CRFs) and studied women with PMO or stratified risk estimates by age and sex. Of 313 identified studies that evaluated fractures as an endpoint, 245 did not report risk estimates for a CRF of interest and/or did not report data for a PMO population.

Data Synthesis:

In the 68 included articles, the risks associated with the evaluated CRFs were high and significant. Prior fracture was a strong predictor of fracture and increased risk up to 18 times. Each standard deviation below the referent mean for BMD was associated with an increased fracture risk of up to 4.0 times; maternal fracture history increased risk 1.3–2.9 times. Age (per 5 year increment) increased risk by 1.2–5.0 times; low weight or BMI inconsistently showed a 0.5–3.0 times greater risk.

Conclusions:

Low BMD is widely used as a diagnostic indicator for osteoporosis; however, other CRFs play an important role in determining fracture risk among women with PMO.
Trk: A Neuromodulator of Age-Specific Behavioral and Neurochemical Responses to Cocaine in Mice
Authors: Niculescu Michelle , Perrine Shane A. , Miller Jonathan S. , Ehrlich Michelle E. , Unterwald Ellen M.
Published: January 2008

Responses to psychostimulants vary with age, but the molecular etiologies of these differences are largely unknown. The goal of the present research was to identify age-specific behavioral and molecular adaptations to cocaine and to elucidate the mechanisms involved therein. Postweanling, periadolescent, and adult male CD-1 mice were exposed to cocaine (20 mg/kg) for 7 d. The rewarding effects of cocaine were assessed, as were the response to a Trk antagonist and the regulation of dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32). Cocaine was rewarding in both periadolescent and adult mice using a conditioned place preference procedure. In contrast, postweanling mice failed to demonstrate significant cocaine-induced place preference. Because components of the neurotrophin system including brain-derived neurotrophic factor and TrkB are developmentally regulated, their role in the age-specific effects of cocaine was determined using the Trk receptor antagonist K252a. Postweanling mice that received K252a before daily cocaine showed a significant place preference to the cocaine-paired environment that was not seen in the absence of K252a. DARPP-32 protein levels were significantly upregulated in the lateral region of the caudate–putamen exclusively in postweanling mice after chronic cocaine. Daily pretreatment with K252a attenuated the induction of DARPP-32 in the postweanling striatum. These data indicate that Trk neurotransmission plays a role in age-specific behavioral and molecular responses to cocaine and concurrently modulates DARPP-32 levels.
The N-Terminal Domain of Nogo-A Inhibits Cell Adhesion and Axonal Outgrowth by an Integrin-Specific Mechanism
Authors: Hu Fenghua , Strittmatter Stephen M.
Published: January 2008

Myelin-derived Nogo-A protein limits axonal growth after CNS injury. One domain binds to the Nogo-66 receptor to inhibit axonal outgrowth, whereas a second domain, Amino-Nogo, inhibits axonal outgrowth and cell adhesion through unknown mechanisms. Here, we show that Amino-Nogo inhibition depends strictly on the composition of the extracellular matrix, suggesting that Amino-Nogo inhibits the function of certain integrins. Amino-Nogo inhibition can be partially overcome by antibodies that activate integrin β1 or by the addition of Mn2+, an integrin activator. Furthermore, Amino-Nogo reduces focal adhesion kinase activation by fibronectin. Analysis of various cell lines reveals that αvβ3, α5, and α4 integrins are sensitive to Amino-Nogo, but α6 integrin is not. Both αv and α5 integrins have widespread expression in adult brain and are found in axonal growth cones. Thus, inhibition of integrin signaling by Amino-Nogo contributes to the failure of CNS axon regeneration.