bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ror1 Is a Pseudokinase That Is Crucial for Met-Driven Tumorigenesis
Authors: Gentile Alessandra , Lazzari Luca , Benvenuti Silvia , Trusolino Livio , Comoglio Paolo M. 
Published: April 2011

Abstract
The human kinome includes Ror1, a poorly characterized orphan receptor. Here we report the findings of an investigation of Ror1 contributions to cancer, undertaken through an integrated screening of 43 cancer cell lines where we measured protein expression, tyrosine phosphorylation, and growth response following RNAi-mediated Ror1 suppression. Ror1 was expressed in approximately 75% of the cancer cell lines without apparent histotype distribution. Gastric carcinoma cells (HS746T) and non–small cell lung carcinoma cells (NCI-H1993) exhibited high levels of Ror1 tyrosine phosphorylation, and Ror1 suppression caused growth inhibition. Biochemical assays revealed unexpectedly that Ror1 is a pseudokinase that is devoid of catalytic activity. Intriguingly, the two cell lines featuring tyrosine-phosphorylated Ror1 both exhibited amplification and activation of the Met oncogene. Ror1 phosphorylation was abrogated by Met inhibition, indicating Met-dependent transphosphorylation of Ror1. Conversely, Ror1 was not transphosphorylated by other constitutively active tyrosine kinases, including EGFR and ErbB2. Constitutive silencing of Ror1 in HS746T and NCI-H1993 carcinoma cells impaired proliferation in vitro and induced a dramatic inhibition of tumorigenesis in vivo. Together, our findings suggest a critical role for Ror1 in malignant phenotypes sustained by the Met oncogene. Cancer Res; 71(8); 3132–41. ©2011 AACR.
Cancer-Associated Loss-of-Function Mutations Implicate DAPK3 as a Tumor-Suppressing Kinase
Authors: Brognard John , Zhang You-Wei , Puto Lorena A. , Hunter Tony 
Published: April 2011

Abstract
Cancer kinome sequencing studies have identified several protein kinases predicted to possess driver (i.e., causal) mutations. Using bioinformatic applications, we have pinpointed DAPK3 (ZIPK) as a novel cancer-associated kinase with functional mutations. Evaluation of nonsynonymous point mutations, discovered in DAPK3 in various tumors (T112M, D161N, and P216S), reveals that all three mutations decrease or abolish kinase activity. Furthermore, phenotypic assays indicate that the three mutations observed in cancer abrogate the function of the kinase to regulate both the cell cycle and cell survival. Coexpression of wild-type (WT) and cancer mutant kinases shows that the cancer mutants dominantly inhibit the function of the WT kinase. Reconstitution of a non–small cell lung cancer cell line that harbors an endogenous mutation in DAPK3 (P216S) with WT DAPK3 resulted in decreased cellular aggregation and increased sensitivity to chemotherapy. Our results suggest that DAPK3 is a tumor suppressor in which loss-of-function mutations promote increased cell survival, proliferation, cellular aggregation, and increased resistance to chemotherapy. Cancer Res; 71(8); 3152–61. ©2011 AACR.
Acidic buffer or plus cyclosporine A post-conditioning protects isolated rat hearts against ischemia-reperfusion injury
Authors: Xin Duan  , Bingyang Ji  , Kun Yu  , Feilong Hei  , Jinping Liu  , Cun Long  
Published: April 2011

Background: It is well documented that transient acidosis during reperfusion is protective. The aim of this study was to evaluate the cardioprotection of acidic buffer or plus cyclosporine A in isolated rat hearts after cardioplegic arrest. Methods: Langendorff-perfused Sprague—Dawley rat hearts were perfused for 20 min with Krebs—Henseleit (K-H) buffer followed by 30 min of crystalloid cardioplegia and 60 min of reperfusion. Control hearts were perfused with Krebs—Henseleit buffer. Acidic buffer post-conditioning hearts were perfused with acidic K-H buffer (pH 6.8) for the first 3 min of reperfusion. Acidic buffer plus cyclosporine A hearts were perfused with K-H acidic buffer (pH 6.8) containing cyclosporine A (0.2 μmol/L) for the first 3 min of reperfusion. Results: Compared with the control group, acidic buffer or plus cyclosporine A post-conditioning significantly improved myocardial performance, decreased cytochrome C release into the cytosol, increased Bcl-2 expression and decreased Bax expression, decreased sensitivity of mPTP-opening to [Ca2+] and the rate of apoptosis after reperfusion. Conclusion: These findings suggested that acidic buffer or plus cyclosporine A post-conditioning prevented apoptosis-related mitochondrial permeabilization and provided the myocardial protection after cardioplegic arrest.
Preoperative Measurement of Cartilage Defects by MRI Underestimates Lesion Size
Authors: Gomoll Andreas H. , Yoshioka Hiroshi , Watanabe Atsuya , Dunn John C. , Minas Tom 
Published: April 2011

Objective: Anecdotal evidence suggests that MRI frequently underestimates the size of cartilage defects when compared with final lesion size after debridement of all degenerated tissue. This has potential implications for the choice of cartilage repair technique since most treatment algorithms are primarily driven by defect size. We conducted an investigation comparing size estimates based on preoperative MRI with final defect size after debridement. Our aim was to provide surgeons with more objective data to assist in predicting true defect size based on MRI scanning. Design: Patients were included in this retrospective study if they had undergone preoperative MRI and open cartilage repair within 12 months to minimize potential confounding by defect progression on MRI. Defect sizes measured after debridement were obtained from surgical notes and compared with MRI size estimates by 2 musculoskeletal radiologists. Results: Thirty-eight patients were enrolled with a median age of 37 years, median number of 1.7 defects, and a total median defect area of 6 cm2 per knee. Preoperative MRI scanning had predicted a median defect area of 3.6 cm2. This reflected a difference of 65% ( P < 0.001) between MRI and final defect area after debridement when 85% of all individual defects were larger than predicted by preoperative MRI. Conclusions: Our study compared the size of cartilage defects measured by preoperative MRI with surgical measurements after debridement. On average, the final total defect area per knee was 65% larger than estimated preoperatively by MRI. Individual defects were larger than predicted by 47% to 377%, depending on defect location.
Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro
Authors: Perdomo José , Yan Feng , Ahmadi Zohra , Jiang Xing-Mai , Stocker Roland , Chong Beng H. 
Published: April 2011

Abstract
The development of immune cytopenias is a well-recognized side effect of many drugs. Quinine- and quinidine-dependent antibodies are classic examples of drug-induced effects that cause severe, life-threatening thrombocytopenia. Whereas the effects of drug-dependent antibodies on platelets have been well documented, their effects on megakaryocyte (Mk) biology are still unclear. We analyzed sera from several quinine-induced thrombocytopenia (QITP) patients on highly pure Mks (98% glycoprotein IIb-positive [GPIIb+]; 92% GPIX+) derived from human CD34+ cells cultured with human thrombopoietin. We demonstrate by flow cytometry and confocal microscopy that QITP IgGs bind Mks efficiently in the presence of quinine. Incubation of day-4 Mks with QITP sera or purified IgG resulted in induction of apoptosis, a significant decrease in cell viability, and an increase in cell death. Furthermore, QITP sera preferentially reduced the number of late GPIX+/GPIbα+ Mks and the number of receptors per cell in the surviving population. Ploidy distribution, lobularity, and average cell size of Mks remained unchanged after treatment. In addition, treated Mks showed a marked decrease in their proplatelet production capacity, suggesting that drug-dependent antibodies hinder platelet production. Therefore, QITP antibodies considerably reduce the proplatelet production capabilities of Mks despite undetectable effects on DNA content, morphology, and cell size.
New markers for minimal residual disease detection in acute lymphoblastic leukemia
Authors: Coustan-Smith Elaine , Song Guangchun , Clark Christopher , Key Laura , Liu Peixin , Mehrpooya Mohammad , Stow Patricia , Su Xiaoping , Shurtleff Sheila , Pui Ching-Hon , Downing James R. , Campana Dario 
Published: April 2011

Abstract
To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19+CD10+ B-cell progenitors (n = 4). Expression of 30 genes differentially expressed by ≥ 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 105 BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity.
Clostridium botulinum group III: a group with dual identity shaped by plasmids, phages and mobile elements
Authors: Skarin Hanna , Håfström Therese , Westerberg Josefina , Segerman Bo 
Published: April 2011

Abstract

Background

Clostridium botulinum strains can be divided into four physiological groups that are sufficiently diverged to be considered as separate species. Here we present the first complete genome of a C. botulinum strain from physiological group III, causing animal botulism. We also compare the sequence to three new draft genomes from the same physiological group.

Results
The 2.77 Mb chromosome was highly conserved between the isolates and also closely related to that of C. novyi. However, the sequence was very different from the human C. botulinum group genomes. Replication-directed translocations were rare and conservation of synteny was high. The largest difference between C. botulinum group III isolates occurred within their surprisingly large plasmidomes and in the pattern of mobile elements insertions. Five plasmids, constituting 13.5% of the total genetic material, were present in the completed genome. Interestingly, the set of plasmids differed compared to other isolates. The largest plasmid, the botulinum-neurotoxin carrying prophage, was conserved at a level similar to that of the chromosome while the medium-sized plasmids seemed to be undergoing faster genetic drift. These plasmids also contained more mobile elements than other replicons. Several toxins and resistance genes were identified, many of which were located on the plasmids.

Conclusions
The completion of the genome of C. botulinum group III has revealed it to be a genome with dual identity. It belongs to the pathogenic species C. botulinum, but as a genotypic species it should also include C. novyi and C. haemolyticum. The genotypic species share a conserved chromosomal core that can be transformed into various pathogenic variants by modulation of the highly plastic plasmidome.
An Outbreak of Varicella among Schoolchildren in Taipei
Authors: Lai Chao-Chih , Chen Szu-Ching , Jiang Donald Dah-Shyong 
Published: April 2011

Abstract

Background
The reported cases with varicella have not decreased and outbreaks of varicella among vaccinated children continue to be reported 9 years after the public vaccination program in Taipei. We investigated an outbreak to determine varicella vaccine coverage and effectiveness.

Methods
An outbreak occurred in an elementary school which located in southern Taipei from April 2007 through May 2007. A retrospect cohort study was performed by using a self-administered questionnaire for parents.

Results
Ten out of sixteen varicella cases were vaccinated. Overall vaccine coverage was 71.2%. The common reasons for not receiving varicella vaccine were that varicella vaccine was unavailable because the student didn't live in Taipei (29.4%) or the children could not be vaccinated due to certain illnesses (23.5%). The sensitivity and specificity of self-reported vaccination status was 0.900 (95% CI: 0.864, 0.935) and 0.611 (95% CI: 0.514, 0.701).
The vaccine effectiveness was 69.3%-100.0% against any disease severity of varicella. Overall vaccine effectiveness against moderate or severe varicella was 85.5%. Attending cram school was associated with the risk of developing the varicella illness (RR: 13.39; 95% CI: 5.38, 33.31). Unvaccinated students tended to show moderate to severe (>50 lesions) afflictions of the disease (RR: 4.17; 95% CI: 1.15, 15.14).

Conclusions
Because of the low vaccination coverage, varicella outbreaks continue to be reported in Taipei. Increasing vaccine coverage and second dose vaccination for increasing vaccine effectiveness may be considered.
Distribution of hepatitis c virus (hcv) genotypes in patients with chronic infection from Rondônia, Brazil
Authors: Vieira Deusilene S , Alvarado-Mora Mónica V , Botelho Lívia , Carrilho Flair J , Pinho João RR , Salcedo Juan M 
Published: April 2011

Abstract

Background
Hepatitis C virus (HCV) is an important human pathogen affecting around 3% of the human population. In Brazil, it is estimated that there are approximately 2 to 3 million HCV chronic carriers. There are few reports of HCV prevalence in Rondônia State (RO), but it was estimated in 9.7% from 1999 to 2005. The aim of this study was to characterize HCV genotypes in 58 chronic HCV infected patients from Porto Velho, Rondônia (RO), Brazil.

Methods
A fragment of 380 bp of NS5B region was amplified by nested PCR for genotyping analysis. Viral sequences were characterized by phylogenetic analysis using reference sequences obtained from the GenBank (n = 173). Sequences were aligned using Muscle software and edited in the SE-AL software. Phylogenetic analyses were conducted using Bayesian Markov chain Monte Carlo simulation (MCMC) to obtain the MCC tree using BEAST v.1.5.3.

Results
From 58 anti-HCV positive samples, 22 were positive to the NS5B fragment and successfully sequenced. Genotype 1b was the most prevalent in this population (50%), followed by 1a (27.2%), 2b (13.6%) and 3a (9.0%).

Conclusions
This study is the first report of HCV genotypes from Rondônia State and subtype 1b was found to be the most prevalent. This subtype is mostly found among people who have a previous history of blood transfusion but more detailed studies with a larger number of patients are necessary to understand the HCV dynamics in the population of Rondônia State, Brazil.
Peripheral Effects of Morphine and Expression of μ-Opioid Receptors in the Dorsal Root Ganglia during Neuropathic Pain: Nitric Oxide Signaling
Authors: Hervera Arnau , Negrete Roger , Leánez Sergi , Martín-Campos Jesús M , Pol Olga 
Published: April 2011

Background: The local administration of μ-opioid receptor (MOR) agonists attenuates neuropathic pain but the precise mechanism implicated in this effect is not completely elucidated. We investigated if nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric oxide synthases could modulate the local antiallodynic effects of morphine through the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway activation and affect the dorsal root ganglia MOR expression during neuropathic pain. Results: In wild type (WT) mice, the subplantar administration of morphine dose-dependently decreased the mechanical and thermal allodynia induced by the chronic constriction of the sciatic nerve (CCI), which effects were significantly diminished after their co-administration with different subanalgesic doses of a selective NOS1 (N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N′-nitroguanidine tris(trifluoroacetate) salt; NANT), NOS2 (L-N(6)-(1-iminoethyl)-lysine; L-NIL), L-guanylate cyclase (1H-[ 1 , 2 , 4 ]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ), PKG ((Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs) inhibitor or a KATP channel blocker (glibenclamide). The evaluation of the expression of MOR in the dorsal root ganglia from sham-operated and sciatic nerve-injured WT, NOS1 knockout (KO) and NOS2-KO mice at 21 days after surgery demonstrated that, although the basal mRNA and protein levels of MOR were similar between WT and both NOS-KO animals, nerve injury only decreased their expression in WT mice. Conclusions: These results suggest that the peripheral nitric oxide-cGMP-PKG-KATP signaling pathway activation participates in the local antiallodynic effects of morphine after sciatic nerve injury and that nitric oxide, synthesized by NOS1 and NOS2, is implicated in the dorsal root ganglia down-regulation of MOR during neuropathic pain.
Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice
Authors: Ganay Thibault , Boizot Alexia , Burrer Renaud , Chauvin Jean Paul , Bomont Pascale 
Published: April 2011

AbstractBackgroundGiant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and the sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting.ResultsWe investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology.ConclusionsTogether, our results show that gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.
Langerhans cells are not required for epidermal Vγ3 T cell homeostasis and function
Authors: Taveirne Sylvie , De Colvenaer Veerle , Van Den Broeck Tina , Van Ammel Els , Bennett Clare L , Taghon Tom , Vandekerckhove Bart , Plum Jean , Clausen Björn E , Kaplan Daniel H , Leclercq Georges 
Published: April 2011

ABSTRACTThis study tested the hypothesis that Vγ3 TCR-bearing T cells are influenced by LCs. Vγ3 T cells and LCs are located in the epidermis of mice. Vγ3 T cells represent the main T cell population in the skin epithelium and play a crucial role in maintaining the skin integrity, whereas LCs are professional APCs. Although Vγ3 T cells and LCs form an interdigitating network in the epidermis, not much is known about their reciprocal influence and/or interdependence. We used two different LC-deficient mouse models, in which LCs are constitutively or inducibly depleted, to investigate the role of LCs in maturation, homeostasis, and function of Vγ3 T cells. We show that Vγ3 T cell numbers are unaltered by LC deficiency, and Vγ3 T cells isolated from LC-deficient mice are phenotypically and upon in vitro stimulation, functionally indistinguishable from Vγ3 T cells isolated from WT mice based on their cytotoxic potential and cytokine production. Additionally, in vivo skin-wounding experiments show no major difference in response of Vγ3 T cells to wounding in the absence or presence of LCs. These observations indicate that Vγ3 T cells develop and function independently of LCs.
Singing the blues: from experimental biology to conservation application
Authors: Settele Josef , Barbero Francesca , Musche Martin , Thomas Jeremy A. , Schönrogge Karsten 
Published: April 2011

Summary
Chemical communication plays a major role in the organisation of ant societies, and is mimicked to near perfection by certain large blue (Maculinea) butterflies that parasitise Myrmica ant colonies. The recent discovery of differentiated acoustical communication between different castes of ants, and the fact that this too is mimicked by the butterflies, adds a new component of coevolutionary complexity to a fascinating multitrophic system of endangered species, and it could inspire new ways to engage the public in their conservation.
Whole-body kinematics of a fruit bat reveal the influence of wing inertia on body accelerations
Authors: Iriarte-Díaz José , Riskin Daniel K. , Willis David J. , Breuer Kenneth S. , Swartz Sharon M. 
Published: April 2011

SUMMARYThe center of mass (COM) of a flying animal accelerates through space because of aerodynamic and gravitational forces. For vertebrates, changes in the position of a landmark on the body have been widely used to estimate net aerodynamic forces. The flapping of relatively massive wings, however, might induce inertial forces that cause markers on the body to move independently of the COM, thus making them unreliable indicators of aerodynamic force. We used high-speed three-dimensional kinematics from wind tunnel flights of four lesser dog-faced fruit bats, Cynopterus brachyotis, at speeds ranging from 2.4 to 7.8 m s–1 to construct a time-varying model of the mass distribution of the bats and to estimate changes in the position of their COM through time. We compared accelerations calculated by markers on the trunk with accelerations calculated from the estimated COM and we found significant inertial effects on both horizontal and vertical accelerations. We discuss the effect of these inertial accelerations on the long-held idea that, during slow flights, bats accelerate their COM forward during ‘tip-reversal upstrokes’, whereby the distal portion of the wing moves upward and backward with respect to still air. This idea has been supported by the observation that markers placed on the body accelerate forward during tip-reversal upstrokes. As in previously published studies, we observed that markers on the trunk accelerated forward during the tip-reversal upstrokes. When removing inertial effects, however, we found that the COM accelerated forward primarily during the downstroke. These results highlight the crucial importance of the incorporation of inertial effects of wing motion in the analysis of flapping flight.