bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linguistics at School: The UK Linguistics Olympiad
Authors: Hudson Richard , Sheldon Neil 
Published: February 2013

AbstractThe UK Linguistics Olympiad, like similar olympiads that have been offered in other countries since they first took place in Moscow in 1965, is an annual competition in which school students test their ability to sort out the underlying patterns and rules in linguistic data. The UK olympiad has only existed since 2010 but by 2012 it already had 2,000 competitors aged between 11 and 18. Its success shows how enthusiastic young people can be about studying language structure. Linguistics olympiads help schools to promote languages and to interest all pupils in language structure; in the UK, this is particularly important in state‐funded schools.
Optimizing Identification of Clinically Relevant Gram-Positive Organisms by Use of the Bruker Biotyper Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry System
Authors: McElvania TeKippe Erin , Shuey Sunni , Winkler David W. , Butler Meghan A. , Burnham Carey-Ann D. 
Published: February 2013

ABSTRACT
Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) can be used as a method for the rapid identification of microorganisms. This study evaluated the Bruker Biotyper (MALDI-TOF MS) system for the identification of clinically relevant Gram-positive organisms. We tested 239 aerobic Gram-positive organisms isolated from clinical specimens. We evaluated 4 direct-smear methods, including “heavy” (H) and “light” (L) smears, with and without a 1-μl direct formic acid (FA) overlay. The quality measure assigned to a MALDI-TOF MS identification is a numerical value or “score.” We found that a heavy smear with a formic acid overlay (H+FA) produced optimal MALDI-TOF MS identification scores and the highest percentage of correctly identified organisms. Using a score of ≥2.0, we identified 183 of the 239 isolates (76.6%) to the genus level, and of the 181 isolates resolved to the species level, 141 isolates (77.9%) were correctly identified. To maximize the number of correct identifications while minimizing misidentifications, the data were analyzed using a score of ≥1.7 for genus- and species-level identification. Using this score, 220 of the 239 isolates (92.1%) were identified to the genus level, and of the 181 isolates resolved to the species level, 167 isolates (92.2%) could be assigned an accurate species identification. We also evaluated a subset of isolates for preanalytic factors that might influence MALDI-TOF MS identification. Frequent subcultures increased the number of unidentified isolates. Incubation temperatures and subcultures of the media did not alter the rate of identification. These data define the ideal bacterial preparation, identification score, and medium conditions for optimal identification of Gram-positive bacteria by use of MALDI-TOF MS.
High Prevalence of Asymptomatic Malaria in a Tribal Population in Eastern India
Authors: Ganguly Swagata , Saha Pabitra , Guha Subhasish K. , Biswas Asit , Das Sonali , Kundu Pratip K. , Maji Ardhendu K. 
Published: February 2013

ABSTRACT

Asymptomatic infection by
Plasmodium falciparum
is an important obstacle to eliminating malaria. Asymptomatic carriers do not seek treatment for infection, and therefore they become a reservoir for the parasite. For this reason, these carriers pose a real public health risk. The systematic identification and treatment of asymptomatic infections should reduce the parasite reservoir. A large reduction in this pool will lower the chance of transmission of the disease. In this study, we screened a tribal population of 1,040 individuals in the Purulia district of West Bengal by using a dual-antigen rapid diagnostic kit (RDK), microscopy, and species-specific PCR. All positive individuals were treated with artemisinin-based combination therapy (ACT) (artesunate plus sulfadoxine-pyrimethamine) and followed for 42 days. Polymorphisms in candidate genes were screened by DNA sequencing. A significant proportion (8.4%) of the study population was infected with
P. falciparum
but showed no clinical manifestations. The PCR method was more sensitive in detecting infection than the RDK or microscopy. The efficacy of the ACT was 97%. In the
pfcrt
gene, the mutation K76T (the mutated amino acid is indicated by bold type) was found in 100% of the cases. In the
pfmdr1
gene, the mutations N86Y and Y184F were noted in 55.5% and 11% of the cases, respectively. Six different haplotypes were identified in the
pfdhfr-pfdhps
genes. Most importantly, the quintuple mutant A
16
I
51
R
59
N
108
I
164
-S
436
G
437
E
540
A
581
A
613
was found in 10% of the isolates, which is potentially important for the development of sulfadoxine-pyrimethamine resistance. A significant proportion of the study population harboring
P. falciparum
does not seek treatment and therefore serves as a reservoir for the parasite, maintaining the natural cycle. If the National Vector Borne Disease Control Programme (NVBDCP) of India is to eliminate malaria, then this hidden parasite burden needs to be addressed properly. Similar study in other parts of the country could help to determine the magnitude of the problem.
Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes
Authors: Johnson Karen E. , Chikoti Leela , Chandran Bala 
Published: February 2013

ABSTRACTInflammasomes are multiprotein complexes that recognize pathogens and pathogen- or danger-associated molecular patterns. They induce the maturation and secretion of powerful proinflammatory interleukin-1B (IL-1β), IL-18, and IL-33 cytokines, which in turn activate expression of other immune genes and lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Inflammasomes are comprised of cytoplasmic sensor molecules, such as NLRP3 and AIM2 or nuclear sensor IFI16, the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD), and the effector protein procaspase-1. Herpes simplex virus 1 (HSV-1), a ubiquitous virus that infects humans and establishes life-long latency, has evolved numerous mechanisms to evade host detection and immune responses. Here, we show that early duringin vitroinfection of human foreskin fibroblasts (2 to 4 h), HSV-1 induced the activation of the IFI16 and NLRP3 inflammasomes and maturation of IL-1β. Independent of viral gene expression, IFI16 recognized the HSV-1 genome in infected cell nuclei, relocalized, and colocalized with ASC in the cytoplasm. However, HSV-1 specifically targeted IFI16 for rapid proteasomic degradation at later times postinfection, which was dependent on the expression of ICP0, an immediate early protein of HSV-1. In contrast, NLRP3, AIM2, and ASC levels were not decreased. Also, caspase-1 was “trapped” in actin clusters at later time points that likely blocked the NLRP3/IFI16 inflammasome activity. In addition, the secretion of mature IL-1β was inhibited. These results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSV-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.
Very-Low-Density Lipoprotein (VLDL)-Producing and Hepatitis C Virus-Replicating HepG2 Cells Secrete No More Lipoviroparticles than VLDL-Deficient Huh7.5 Cells
Authors: Jammart Baptiste , Michelet Maud , Pécheur Eve-Isabelle , Parent Romain , Bartosch Birke , Zoulim Fabien , Durantel David 
Published: February 2013

ABSTRACT
In the plasma samples of hepatitis C virus (HCV)-infected patients, lipoviroparticles (LVPs), defined as (very-) low-density viral particles immunoprecipitated with anti-β-lipoproteins antibodies are observed. This HCV-lipoprotein association has major implications with respect to our understanding of HCV assembly, secretion, and entry. However, cell culture-grown HCV (HCVcc) virions produced in Huh7 cells, which are deficient for very-low-density lipoprotein (VLDL) secretion, are only associated with and dependent on apolipoprotein E (apoE), not apolipoprotein B (apoB), for assembly and infectivity. In contrast to Huh7, HepG2 cells can be stimulated to produce VLDL by both oleic acid treatment and inhibition of the MEK/extracellular signal-regulated kinase (ERK) pathway but are not permissive for persistent HCV replication. Here, we developed a new HCV cell culture model to study the interaction between HCV and lipoproteins, based on engineered HepG2 cells stably replicating a blasticidin-tagged HCV JFH1 strain (JB). Control Huh7.5-JB as well as HepG2-JB cell lines persistently replicated viral RNA and expressed viral proteins with a subcellular colocalization of double-stranded RNA (dsRNA), core, gpE2, and NS5A compatible with virion assembly. The intracellular RNA replication level was increased in HepG2-JB cells upon dimethyl sulfoxide (DMSO) treatment, MEK/ERK inhibition, and NS5A overexpression to a level similar to that observed in Huh7.5-JB cells. Both cell culture systems produced infectious virions, which were surprisingly biophysically and biochemically similar. They floated at similar densities on gradients, contained mainly apoE but not apoB, and were not neutralized by anti-apoB antibodies. This suggests that there is no correlation between the ability of cells to simultaneously replicate HCV as well as secrete VLDL and their capacity to produce LVPs.
Hepatitis C Virus Replication Is Modulated by the Interaction of Nonstructural Protein NS5B and Fatty Acid Synthase
Authors: Huang Jing-Tang , Tseng Ching-Ping , Liao Mei-Huei , Lu Shao-Chun , Yeh Wei-Zhou , Sakamoto Naoya , Chen Chuan-Mu , Cheng Ju-Chien 
Published: February 2013

ABSTRACT

Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) that acts as a key player in the HCV replication complex. Understanding the interplay between the viral and cellular components of the HCV replication complex could provide new insight for prevention of the progression of HCV-associated hepatocellular carcinoma (HCC). In this study, the NS5B protein was used as the bait in a pulldown assay to screen for NS5B-interacting proteins that are present in Huh7 hepatoma cell lysates. After mass spectrophotometric analysis, fatty acid synthase (FASN) was found to interact with NS5B. Coimmunoprecipitation and double staining assays further confirmed the direct binding between NS5B and FASN. The domain of NS5B that interacts with FASN was also determined. Moreover, FASN was associated with detergent-resistant lipid rafts and colocalized with NS5B in active HCV replication complexes. In addition, overexpression of FASN enhanced HCV expression in Huh7/Rep-Feo cells, while transfection of FASN small interfering RNA (siRNA) or treatment with FASN-specific inhibitors decreased HCV replication and viral production. Notably, FASN directly increased HCV NS5B RdRp activity
in vitro
. These results together indicate that FASN interacts with NS5B and modulates HCV replication through a direct increase of NS5B RdRp activity. FASN may thereby serve as a target for the treatment of HCV infection and the prevention of HCV-associated HCC progression.
Isolation and Characterization of Current Human Coronavirus Strains in Primary Human Epithelial Cell Cultures Reveal Differences in Target Cell Tropism
Authors: Dijkman Ronald , Jebbink Maarten F. , Koekkoek Sylvie M. , Deijs Martin , Jónsdóttir Hulda R. , Molenkamp Richard , Ieven Margareta , Goossens Herman , Thiel Volker , van der Hoek Lia 
Published: February 2013

ABSTRACTThe human airway epithelium (HAE) represents the entry port of many human respiratory viruses, including human coronaviruses (HCoVs). Nowadays, four HCoVs, HCoV-229E, HCoV-OC43, HCoV-HKU1, and HCoV-NL63, are known to be circulating worldwide, causing upper and lower respiratory tract infections in nonhospitalized and hospitalized children. Studies of the fundamental aspects of these HCoV infections at the primary entry port, such as cell tropism, are seriously hampered by the lack of a universal culture system or suitable animal models. To expand the knowledge on fundamental virus-host interactions for all four HCoVs at the site of primary infection, we used pseudostratified HAE cell cultures to isolate and characterize representative clinical HCoV strains directly from nasopharyngeal material. Ten contemporary isolates were obtained, representing HCoV-229E (n= 1), HCoV-NL63 (n= 1), HCoV-HKU1 (n= 4), and HCoV-OC43 (n= 4). For each strain, we analyzed the replication kinetics and progeny virus release on HAE cell cultures derived from different donors. Surprisingly, by visualizing HCoV infection by confocal microscopy, we observed that HCoV-229E employs a target cell tropism for nonciliated cells, whereas HCoV-OC43, HCoV-HKU1, and HCoV-NL63 all infect ciliated cells. Collectively, the data demonstrate that HAE cell cultures, which morphologically and functionally resemble human airwaysin vivo, represent a robust universal culture system for isolating and comparing all contemporary HCoV strains.
Adverse drug events in a paediatric intensive care unit: a prospective cohort
Authors: Silva Dafne C B , Araujo Orlei Ribeiro , Arduini Rodrigo G , Alonso Carolina F R , Shibata Audrey R O , Troster Eduardo J 
Published: February 2013

ObjectivesTo describe adverse drug events (ADEs) in children under intensive care, identify risk factors and tools that can detect ADEs early, and the impact on length of stay (LOS).DesignA prospective observational study.SettingPaediatric intensive care unit of a tertiary care teaching hospital.Patients239 patients with a mean age of 67.5 months representing 1818 days of hospitalisation in intensive care unit.InterventionsActive search of charts and electronic patient records using triggers. The statistical analysis involved linear and logistic regression.Measurements and main resultsThe average LOS was 7.6 days. There were 110 proven, probable and possible ADEs in 84 patients (35.1%). We observed 138 instances of triggers. The major classes of drugs associated with events were: antibiotics (n=41), diuretics (n=24), antiseizures (n=23), sedatives and analgesics (n=17) and steroids (n=18). The number of drugs administered was most related to the occurrence of ADEs and also to the LOS (p<0.001). The occurrence of an ADE may result in an increase in the LOS by 1.5 days per event, but this was not statistically significant in this sample. Patients aged less than 48 months also proved to be at a significant risk for ADEs, with an OR of 1.84 (95% CI 1.07 to 3.15, p=0.025). The number of drugs administered also correlated with the number of ADEs (p<0.0001). The chance of having at least one ADE increased linearly as the patient was administered more drugs.ConclusionsThe use of multiple drugs as well as lower patient age favours the occurrence of ADEs. The active search described here provides a systematic approach to this problem.
Quantitative Ultrasound Evaluation of Tumor Cell Death Response in Locally Advanced Breast Cancer Patients Receiving Chemotherapy
Authors: Sadeghi-Naini Ali , Papanicolau Naum , Falou Omar , Zubovits Judit , Dent Rebecca , Verma Sunil , Trudeau Maureen , Boileau Jean Francois , Spayne Jacqueline , Iradji Sara , Sofroni Ervis , Lee Justin , Lemon-Wong Sharon , Yaffe Martin , Kolios Michael C. , Czarnota Gregory J. 
Published: February 2013

Abstract
Purpose: Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivo models. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods.
Experimental Design: Patients (n = 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients.
Results: Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Such differences between clinically and pathologically determined responding and nonresponding patients were statistically significant (P &lt; 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell death with, on average, an increase in mid-band fit and 0-MHz intercept of 9.1 ± 1.2 dBr and 8.9 ± 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months.
Conclusion: This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment. Clin Cancer Res; 19(8); 2163–74. ©2013 AACR.
The Anti-CD19 Antibody–Drug Conjugate SAR3419 Prevents Hematolymphoid Relapse Postinduction Therapy in Preclinical Models of Pediatric Acute Lymphoblastic Leukemia
Authors: Carol Hernan , Szymanska Barbara , Evans Kathryn , Boehm Ingrid , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: February 2013

Abstract
Purpose: Relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) remains a major cause of death from cancer in children. In this study, we evaluated the efficacy of SAR3419, an antibody–drug conjugate of the maytansinoid DM4 and a humanized anti-CD19 antibody, against B-cell precursor (BCP)-ALL and infant mixed lineage leukemia (MLL) xenografts.
Experimental Design: ALL xenografts were established as systemic disease in immunodeficient (NOD/SCID) mice from direct patient explants. SAR3419 was administered as a single agent and in combination with an induction-type regimen of vincristine/dexamethasone/l-asparaginase (VXL). Leukemia progression and response to treatment were assessed in real-time, and responses were evaluated using strict criteria modeled after the clinical setting.
Results: SAR3419 significantly delayed the progression of 4 of 4 CD19+ BCP-ALL and 3 of 3 MLL-ALL xenografts, induced objective responses in all but one xenograft but was ineffective against T-lineage ALL xenografts. Relative surface CD19 expression across the xenograft panel significantly correlated with leukemia progression delay and objective response measure scores. SAR3419 also exerted significant efficacy against chemoresistant BCP-ALL xenografts over a large (10-fold) dose range and significantly enhanced VXL-induced leukemia progression delay in two highly chemoresistant xenografts by up to 82 days. When administered as protracted therapy following remission induction with VXL, SAR3419 prevented disease recurrence into hematolymphoid and other major organs with the notable exception of central nervous system involvement.
Conclusion: These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19+ ALL. Clin Cancer Res; 19(7); 1795–805. ©2013 AACR.
Crizotinib Induces PUMA-Dependent Apoptosis in Colon Cancer Cells
Authors: Zheng Xingnan , He Kan , Zhang Lin , Yu Jian 
Published: February 2013

Abstract
Oncogenic alterations in MET or anaplastic lymphoma kinase (ALK) have been identified in a variety of human cancers. Crizotinib (PF02341066) is a dual MET and ALK inhibitor and approved for the treatment of a subset of non–small cell lung carcinoma and in clinical development for other malignancies. Crizotinib can induce apoptosis in cancer cells, whereas the underlying mechanisms are not well understood. In this study, we found that crizotinib induces apoptosis in colon cancer cells through the BH3-only protein PUMA. In cells with wild-type p53, crizotinib induces rapid induction of PUMA and Bim accompanied by p53 stabilization and DNA damage response. The induction of PUMA and Bim is mediated largely by p53, and deficiency in PUMA or p53, but not Bim, blocks crizotinib-induced apoptosis. Interestingly, MET knockdown led to selective induction of PUMA, but not Bim or p53. Crizotinib also induced PUMA-dependent apoptosis in p53-deficient colon cancer cells and synergized with gefitinib or sorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and therapeutic responses to crizotinib in xenograft models. These results establish a critical role of PUMA in mediating apoptotic responses of colon cancer cells to crizotinib and suggest that mechanisms of oncogenic addiction to MET/ALK-mediated survival may be cell type-specific. These findings have important implications for future clinical development of crizotinib. Mol Cancer Ther; 12(5); 777–86. ©2013 AACR.
Sulforaphane prevents human platelet aggregation through inhibiting the phosphatidylinositol 3-kinase/Akt pathway
Authors: Chuang Wen-Ying , Kung Po-Hsiung , Kuo Chih-Yun , Wu Chin-Chung 
Published: February 2013

SummarySulforaphane, a dietary isothiocyanate found in cruciferous vegetables, has been shown to exert beneficial effects in animal models of cardiovascular diseases. However, its effect on platelet aggregation, which is a critical factor in arterial thrombosis, is still unclear. In the present study, we show that sulforaphane inhibited human platelet aggregation caused by different receptor agonists, including collagen, U46619 (a thromboxane A2 mimic), protease-activated receptor 1 agonist peptide (PAR1-AP), and an ADP P2Y12 receptor agonist. Moreover, sulforaphane significantly reduced thrombus formation on a collagen-coated surface under whole blood flow conditions. In exploring the underlying mechanism, we found that sulforaphane specifically prevented phosphatidylinositol 3-kinase (PI3K)/Akt signalling, without markedly affecting other signlaling pathways involved in platelet aggregation, such as protein kinase C activation, calcium mobilisation, and protein tyrosine phosphorylation. Although sulforaphane did not directly inhibit the catalytic activity of PI3K, it caused ubiquitination of the regulatory p85 subunit of PI3K, and prevented PI3K translocation to membranes. In addition, sulforaphane caused ubiquitination and degradation of phosphoinositide-dependent kinase 1 (PDK1), which is required for Akt activation. Therefore, sulforaphane is able to inhibit the PI3K/Akt pathway at two distinct sites. In conclusion, we have demonstrated that sulforaphane prevented platelet aggregation and reduced thrombus formation in flow conditions; our data also support that the inhibition of the PI3K/Akt pathway by sulforaphane contributes it antiplatelet effects.