bluuebunny/crossref_metadata_2025_split huggingface dataset:
Localization and Importance of the Adenovirus E4orf4 Protein during Lytic Infection
Authors: Miron Marie-Joëlle , Blanchette Paola , Groitl Peter , Dallaire Frederic , Teodoro Jose G. , Li Suiyang , Dobner Thomas , Branton Philip E. 
Published: December 2008

ABSTRACT

The human adenovirus type 5 (Ad5) E4orf4 product has been studied extensively although in most cases as expressed from vectors in the absence of other viral products. Thus, relatively little is known about its role in the context of an adenovirus infection. Although considerable earlier work had indicated that the E4orf4 protein is not essential for replication, a recent study using
dl
359, an Ad5 mutant believed to produce a nonfunctional E4orf4 protein, suggested that E4orf4 is essential for virus growth in primary small-airway epithelial cells (C. O'Shea, et al., EMBO J. 24:1211-1221, 2005). Hence, to examine further the role of E4orf4 during virus infection, we generated for the first time a set of E4orf4 virus mutants in a common Ad5 genetic background. Such mutant viruses included those that express E4orf4 proteins containing various individual point mutations, those defective entirely in E4orf4 expression, and a mutant expressing wild-type E4orf4 fused to the green fluorescent protein. E4orf4 protein was found to localize primarily in nuclear structures shown to be viral replication centers, in nucleoli, and in perinuclear bodies. Importantly, E4orf4 was shown not to be essential for virus growth in either human tumor or primary cells, at least in tissue culture. Unlike E4orf4-null virus, mutant
dl
359 appeared to exhibit a gain-of-function phenotype that impairs virus growth. The
dl
359 E4orf4 protein, which contains a large in-frame internal deletion, clustered in aggregates enriched in Hsp70 and proteasome components. In addition, the late viral mRNAs produced by
dl
359 accumulated abnormally in a nuclear punctate pattern. Altogether, our results indicate that E4orf4 protein is not essential for virus growth in culture and that expression of the
dl
359 E4orf4 product interferes with viral replication, presumably through interactions with structures in the nucleus.
Epstein-Barr Virus Episome Stability Is Coupled to a Delay in Replication Timing
Authors: Zhou Jing , Snyder Andrew R. , Lieberman Paul M. 
Published: December 2008

ABSTRACT

The temporal regulation of DNA replication is thought to be important for chromosome organization and genome stability. We show here that Epstein-Barr virus (EBV) genomes replicate in mid- to late S phase and that agents that accelerate replication timing of EBV reduce viral genome stability. Hydroxyurea (HU) treatment, which is known to eliminate EBV episomes, shifted EBV replication to earlier times in the cell cycle. HU treatment correlated with hyperacetylation of histone H3 and loss of telomere repeat factor 2 (TRF2) binding at the EBV origin of plasmid replication (
OriP
). Deletion of TRF2 binding sites within
OriP
or short hairpin RNA depletion of TRF2 advanced the replication timing of
OriP-
containing plasmids. Inhibitors of class I histone deacetylases (HDACs) increased histone acetylation at
OriP
, advanced the replication timing of EBV, and reduced EBV genome copy number. We also show that HDAC1 and -2 form a stable complex with TRF2 at OriP and that HU treatment inhibits HDAC activity. We propose that the TRF2-HDAC complex enhances EBV episome stability by providing a checkpoint that delays replication initiation at OriP.
Opposing Effects of Inhibiting Cap Addition and Cap Methylation on Polyadenylation during Vesicular Stomatitis Virus mRNA Synthesis
Authors: Li Jianrong , Rahmeh Amal , Brusic Vesna , Whelan Sean P. J. 
Published: December 2008

ABSTRACT

The multifunctional large (L) polymerase protein of vesicular stomatitis virus (VSV) contains enzymatic activities essential for RNA synthesis, including mRNA cap addition and polyadenylation. We previously mapped amino acid residues G1154, T1157, H1227, and R1228, present within conserved region V (CRV) of L, as essential for mRNA cap addition. Here we show that alanine substitutions to these residues also affect 3′-end formation. Specifically, the cap-defective polymerases produced truncated transcripts that contained A-rich sequences at their 3′ termini and predominantly terminated within the first 500 nucleotides (nt) of the
N
gene. To examine how the cap-defective polymerases respond to an authentic VSV termination and reinitiation signal present at each gene junction, we reconstituted RNA synthesis using templates that contained genes inserted (
I
) at the leader-
N
gene junction. The
I
genes ranged in size from 382 to 1,098 nt and were typically transcribed into full-length uncapped transcripts. In addition to lacking a cap structure, the full-length I transcripts synthesized by the cap-defective polymerases lacked an authentic polyadenylate tail and instead contained 0 to 24 A residues. Moreover, the cap-defective polymerases were also unable to copy efficiently the downstream gene. Thus, single amino acid substitutions in CRV of L protein that inhibit cap addition also inhibit polyadenylation and sequential transcription of the genome. In contrast, an amino acid substitution, K1651A, in CRVI of L protein that completely inhibits cap methylation results in the hyperpolyadenylation of mRNA. This work reveals that inhibiting cap addition and cap methylation have opposing effects on polyadenylation during VSV mRNA synthesis and provides evidence in support of a link between correct 5′ cap formation and 3′ polyadenylation.
Parental poison prevention practices and their relationship with perceived toxicity: cross-sectional study
Authors: Patel B , Groom L , Prasad V , Kendrick D 
Published: December 2008

Objective:To describe poison prevention practices for a range of substances and explore the relationship between prevention practices and perceptions of toxicity.Design:Cross-sectional study using a validated postal questionnaire.Participants:Parents with children aged 12–35 months on 23 health visitors’ caseloads.Setting:Areas of various levels of deprivation in Nottingham, UK.Main outcome measures:Possession and storage of substances, putting substances away immediately after use, and perceptions of toxicity.Results:Dishwasher tablets (68%), toilet cleaner (71%), bleach (74%), oven cleaner (78%), oral contraceptives (80%), and essential oils (81%) were least likely to be stored safely. Children’s painkillers (69%), cough medicine (72%), and essential oils (77%) were least likely to be put away immediately after use. More than 50% of parents perceived antibiotics and oral contraceptives as harmful in small quantities and cough medicines as harmful only in large quantities. Six substances perceived by parents to be more harmful were more likely to be put away immediately after use. Parents perceiving dishwasher tablets (OR 1.96, 95% CI 1.05 to 3.66), essential oils (OR 2.80, 95% CI 1.35 to 5.81), turpentine (OR 14.54, 95% CI 2.75 to 76.95), and rat/ant killer (OR 15.33, 95% CI 2.01 to 116.82) as more harmful were more likely to store these substances safely.Conclusions:Parents’ perceptions of toxicity of substances were sometimes inaccurate. Perceived toxicity was associated with putting substances away immediately after use for six substances and with safe storage for four substances. The effect of addressing perceptions of toxicity on poison prevention practices requires evaluation.
Incidence and burden of road traffic injuries in urban India
Authors: Dandona R , Kumar G A , Ameer M A , Ahmed G M , Dandona L 
Published: December 2008

Background:The scale of road traffic injuries (RTIs) in India is uncertain because of limitations in the availability and reliability of incidence data.Objective:To report these data for Hyderabad city in southern India.Methods:In a cross-sectional population-based survey, 10 459 participants aged 5–49 years (94.3% participation), selected using three-stage systematic cluster sampling, were interviewed. Participants recalled RTIs in the preceding 3 months and RTI-related death and disability in the household in the preceding 3 years. RTI was defined as an injury resulting from a road traffic crash irrespective of the severity.Results:The age/sex-adjusted annual incidence of non-fatal RTI requiring a recovery period of ⩽7, 8–29, and ⩾30 days was 13% (95% CI 12.6% to 13.4%), 5.8% (95% CI 5.5% to 6.0%), and 1.2% (95% CI 1.1% to 1.4%), respectively. The overall adjusted rate for non-fatal RTI was 20.7% (95% CI 20.0% to 21.3%). The relative risk of RTI requiring a recovery period of >7 days was significantly higher in the third per capita monthly income quartile (1.24 (95% CI 1.12 to 1.37); p<0.05). The incidence of non-fatal RTI was highest in pedestrians, motorized two-wheeled vehicle users, and cyclists: 6.4, 6.3, and 5.1/100 persons/year, respectively. Annual RTI mortality and disability rates were 38.2 (95% CI 17.5 to 58.8) and 35.1 (95% CI 12.4 to 57.7) per 100 000 population, respectively.Conclusions:There is a high burden of RTI in this urban population. With the recent attention focused on RTI by the Government of India, these findings may assist in planning appropriate initiatives to reduce the RTI burden.
Regulation of CD151 by Hypoxia Controls Cell Adhesion and Metastasis in Colorectal Cancer
Authors: Chien Chun-Wei , Lin Shih-Chieh , Lai Yen-Yu , Lin Bo-Wen , Lin Shao-Chieh , Lee Jenq-Chang , Tsai Shaw-Jenq 
Published: December 2008

AbstractPurpose: The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells; however, how cancer cells accomplish this process remains unclear. Thus, we aimed to investigate the underlying mechanism that controls the early event of metastasis.Experimental Design: One hundred and thirty-seven paired colorectal carcinoma and normal colon tissues were examined by immunohistochemical staining and Western blot for the expression of CD151, a member of the tetraspanin family that plays important roles in cell adhesion and motility. The effect of CD151 on cancer cell adhesion was investigated under normoxia and hypoxia conditions.Results: The level of CD151 was down-regulated in colon cancer compared with the paired normal counterparts. Expression of CD151 was negatively regulated by hypoxia inducible factor-1–dependent hypoxic stress. Suppression of CD151 by hypoxia caused the detachment of cancer cells from the surrounding matrix and neighboring cells whereas restoration of CD151 expression during reoxygenation facilitated the adhesion capacity. Clinical examination further showed that metastasized cancer cells expressed a greater level of CD151 compared with that of primary tumor.Conclusion: Regulation of CD151 by oxygen tension may play an important role in cancer metastasis by regulating the detachment from the primary site and homing in the secondary site.
Self-, peer-, and teacher-assessments in Japanese university EFL writing classrooms
Authors: Matsuno Sumie 
Published: December 2008

Multifaceted Rasch measurement was used in the present study with 91 student and 4 teacher raters to investigate how self- and peer-assessments work in comparison with teacher assessments in actual university writing classes. The results indicated that many self-raters assessed their own writing lower than predicted. This was particularly true for high-achieving students. Peer-raters were the most lenient raters; however, they rated high-achieving writers lower and low-achieving writers higher. This tendency was independent of their own writing abilities and therefore offered no support for the hypothesis that high-achieving writers rated severely and low-achieving writers rated leniently. On the other hand, most peer-raters were internally consistent and produced fewer bias interactions than self- and teacher-raters. Each of the four teachers was internally consistent; however, each displayed a unique bias pattern. Self-, peer-, and teacher-raters assessed Grammar severely and Spelling leniently. The analysis also revealed that teacher-raters assessed Spelling, Format, and Punctuation differently from the other criteria. It was concluded that self-assessment was somewhat idiosyncratic and therefore of limited utility as a part of formal assessment. Peer-assessors on the other hand were shown to be internally consistent and their rating patterns were not dependent on their own writing performance. They also produced relatively few bias interactions. These results suggest that in at least some contexts, peer-assessments can play a useful role in writing classes. By using multifaceted Rasch measurement, teachers can inform peer-raters of their bias patterns and help them develop better quality assessment criteria, two steps that might lead to better quality peer-assessment.
Lack of Association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian, African American, and Asian children and adults
Authors: Onel KB , Huo D , Hastings D , Fryer-Biggs J , Crow MK , Onel K 
Published: December 2008

The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE ( n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE.
Menstrual and hormonal alterations in juvenile systemic lupus erythematosus
Authors: Medeiros PB , Febrônio MV , Bonfá E , Borba EF , Takiuti AD , Silva CAA 
Published: December 2008

Menstrual cycles of 30 patients with juvenile systemic lupus erythematosus (JSLE) were compared with 30 age-matched controls. The mean age of patients with JSLE and controls was similar (17.4 ± 3.2 vs 17.06 ± 2.08 years, P = 0.66). The mean menarche age was higher in JSLE than controls (13.13 ± 1.4 vs 11.56 ± 1.5 years, P = 0.0008). On the contrary, the mean maternal menarche age was similar in both groups ( P = 0.62). Menstrual abnormalities and longer length cycles were more frequently observed in JSLE than controls (63% vs 10%, P = 0.0001; 23% vs 0%, P = 0.0105, respectively). The median of follicle stimulating hormone was significantly higher in patients with JSLE compared with controls (4.6 vs 3.4 IU/L, P = 0.0207), and the median of progesterone was lower (32.5 vs 70 ng/mL, P = 0.0033). The median of luteinizing hormone was lower in patients with JSLE with menstrual abnormalities versus normal cycles (2.9 vs 5.5 IU/L, P = 0.019) and both had a high percentage of decreased progesterone levels (63% vs 73%, P = 0.70). Our findings support the notion that menstrual disturbances are frequent and may be associated with pituitary dysfunction leading to a decreased progesterone production. We also reported that in spite of premature ovarian failure being a rare event in JSLE the follicular reserve seems to be low regardless of intravenous cyclophosphamide treatment.
Identifying Grant Funding: Mentored Career Development and Transition Awards
Authors: McDonagh Kevin T. 
Published: December 2008

Abstract
NIH Career Development Awards are designed to provide outstanding, clinically trained professionals with salary support and protected time to pursue a course of intensive, mentored research experience necessary to achieve full scientific independence. The ideal candidate for a career development award is a health scientist nearing the completion of postdoctoral training or in the early years of a faculty position. The K series of NIH awards provide several options for mentored training that are appropriate for investigators interested in laboratory or clinical investigation in the biologic and medical sciences.
Transitioning from Fellowship to a Physician-Scientist Career Track
Authors: Melnick Ari 
Published: December 2008

Abstract
Given the remarkable advances in bio-medicine in recent years, there has never been a better time to devote one’s efforts towards bench to beside medicine. Accordingly, well-trained physician-scientists are in high demand in the private and academic sectors, and there is increasing awareness of the need to support and nurture such individuals. Clinical fellows in hematology, oncology and hematopathology with an interest in the physician-scientist career path must be well prepared to succeed in transitioning from fellowship to their first academic position. This article will discuss some of the key elements that prospective clinical scientists need to assemble in order to survive this critical period.
Clinical Relevance of Anemia and Transfusion Iron Overload in Myelodysplastic Syndromes
Authors: Cazzola Mario , Della Porta Matteo G. , Malcovati Luca 
Published: December 2008

AbstractMost patients with myelodysplastic syndrome eventually become dependent on regular red cell transfusions. This dependency has a negative impact on clinical outcome, primarily because it may be associated with more severe marrow failure. In addition, however, transfusion dependency may involve clinical consequences of chronic anemia and iron overload. Although transfusion iron is primarily taken up by the reticuloendothelial cells, the metal is later redistributed to parenchymal cells. This redistribution is modulated by several factors, including the degree of ineffective erythropoiesis through its suppressive effect on hepcidin production. Body iron status is routinely assessed by serum ferritin and transferrin saturation, but there is a need of reliable tools for locating iron accumulation in patients. Magnetic resonance imaging T2* provides a non-invasive method for detecting and quantifying both liver and myocardial iron overload. Clinical consequences of parenchymal iron overload have been reported not only in thalassemia major, but also in patients with myelodysplastic syndrome. Transfusion-dependent patients with isolated erythroid dysplasia and low risk of leukemic evolution are more likely to develop parenchymal iron overload and its toxicity, and therefore may benefit from chelation therapy. There may also be a benefit of chelation therapy in patients with transfusion iron overload undergoing allogeneic stem cell transplantation. Deferoxamine and deferasirox are currently available for treatment of transfusion iron overload in patients with myelodysplastic syndrome.
What Do You Do with the “Pink Sheets?”
Authors: Chao Nelson 
Published: December 2008

Abstract
Applying for a grant seems like an enormous challenge, sometimes akin to Sisyphus’ task of rolling the boulder up the hill. In many ways, obtaining funding can be challenging, yet year after year, new investigators do obtain funding, even though there are times when the funding percentage can be low. This review offers some suggestions of what to do after the first or second round of critiques are back. There are some relatively straightforward steps one can take to improve one’s chances of success. The joy of funding is worth it!
Duration of Anticoagulation Therapy for Venous Thromboembolism
Authors: Bounameaux Henri , Perrier Arnaud 
Published: December 2008

AbstractTreatment of acute deep vein thrombosis and pulmonary embolism-often denominated together as venous thromboembolism (VTE)- consists of parenteral administration of heparin (usually low-molecular-weight heparin or alternatively unfractionated heparin or fondaparinux) overlapped and followed by oral vitamin K antagonists that are administered for a certain period (usually 3 to 12 months). Recommended or suggested durations differ according to guidelines. Practically, the clinical decision in an individual patient depends upon the estimated risks of VTE recurrence and treatment-induced bleeding. The risk of VTE recurrence is higher in idiopathic events (about 10% per year during the first two years and 3% per year thereafter) (odds ratio of 2.4, compared to secondary events); in male subjects (at least before the age of 60, with an odds ratio of 2–4); in patients with persistently elevated D-dimer level (odds ratio of 2.3, compared with normal level); and during the first two years after discontinuation of treatment. The annual risk of major bleeding on anticoagulant treatment vary largely in observational studies with figures of 2% to 29%, depending on the patient characteristics. The case-fatality rate is 8% (DVT), 12% (PE) for recurrent VTE, and about 10% for major bleed. These figures do not support long-term anticoagulant therapy, except in those patients exhibiting a very high risk of recurrence and/or a very low risk of bleeding.New therapeutic aspects might impact on the duration of anticoagulant therapy after a venous thromboembolic event. They include the possibility of pursuing anticoagulant treatment at a reduced INR after an initial period with an INR 2-3, and the advent of new, more specific and orally active anticoagulants. These features might modify the risk-benefit balance of extending anticoagulant therapy beyond the usual, limited duration.
Skeletal Imaging and Management of Bone Disease
Authors: Roodman G. David 
Published: December 2008

AbstractUp to 90% of patients with multiple myeloma develop bone lesions. The lesions are purely osteolytic because of increased osteoclast activity and markedly suppressed or absent osteoblast activity. The “gold standard” for imaging myeloma bone lesions is the metastatic bone survey. However, plain radiographs are relatively insensitive and can only demonstrate lytic disease when 30% of trabecular bone loss has occurred. Technicium-99m bone scanning is not appropriate for evaluating myeloma patients since bone scans underestimate the extent of bone involvement in patients with myeloma. The limited reproducibility of bone surveys have led to the use of computerized tomography (CT) scanning, magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to evaluate the extent of bone disease. CT scans are more sensitive than plain radiographs for detecting small lytic lesions, and MRI scans detect marrow involvement by the tumor. PET scans have been used to detect bone lesions in patients with myeloma, are more sensitive than plain radiographs, and have the same sensitivity as MRIs for detecting bone disease in the spine and pelvis. Treatment of myeloma bone disease involves treatment of the underlying malignancy and its manifestations. Current treatments that will be discussed include bisphosphonate therapy, kyphoplasty, vertebroplasty, radiation therapy, and novel agents to suppress osteoclastic bone resorption. In addition, complications with bisphosphonate therapy will be reviewed, in particular, osteonecrosis of the jaw associated with bisphosphonate therapy. As survival of myeloma patients increases, therapies to prevent the complications of aggressive myeloma bone disease become more important.