bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of genomic sequence inhomogeneity at mid-range scales
Authors: Prakash Ashwin , Shepard Samuel S , He Jie , Hart Benjamin , Chen Miao , Amarachintha Surya P , Mileyeva-Biebesheimer Olga , Bechtel Jason , Fedorov Alexei 
Published: November 2009

Abstract

Background
Mid-range inhomogeneity or MRI is the significant enrichment of particular nucleotides in genomic sequences extending from 30 up to several thousands of nucleotides. The best-known manifestation of MRI is CpG islands representing CG-rich regions. Recently it was demonstrated that MRI could be observed not only for G+C content but also for all other nucleotide pairings (e.g. A+G and G+T) as well as for individual bases. Various types of MRI regions are 4-20 times enriched in mammalian genomes compared to their occurrences in random models.

Results
This paper explores how different types of mutations change MRI regions. Human, chimpanzee and Macaca mulatta genomes were aligned to study the projected effects of substitutions and indels on human sequence evolution within both MRI regions and control regions of average nucleotide composition. Over 18.8 million fixed point substitutions, 3.9 million SNPs, and indels spanning 6.9 Mb were procured and evaluated in human. They include 1.8 Mb substitutions and 1.9 Mb indels within MRI regions. Ancestral and mutant (derived) alleles for substitutions have been determined. Substitutions were grouped according to their fixation within human populations: fixed substitutions (from the human-chimp-macaca alignment), major SNPs (> 80% mutant allele frequency within humans), medium SNPs (20% - 80% mutant allele frequency), minor SNPs (3% - 20%), and rare SNPs (<3%). Data on short (< 3 bp) and medium-length (3 - 50 bp) insertions and deletions within MRI regions and appropriate control regions were analyzed for the effect of indels on the expansion or diminution of such regions as well as on changing nucleotide composition.

Conclusion
MRI regions have comparable levels of de novo mutations to the control genomic sequences with average base composition. De novo substitutions rapidly erode MRI regions, bringing their nucleotide composition toward genome-average levels. However, those substitutions that favor the maintenance of MRI properties have a higher chance to spread through the entire population. Indels have a clear tendency to maintain MRI features yet they have a smaller impact than substitutions. All in all, the observed fixation bias for mutations helps to preserve MRI regions during evolution.
Plasmodium falciparum exposure in utero, maternal age and parity influence the innate activation of foetal antigen presenting cells
Authors: Fievet Nadine , Varani Stefania , Ibitokou Samad , Briand Valérie , Louis Stéphanie , Perrin René Xavier , Massougbogji Achille , Hosmalin Anne , Troye-Blomberg Marita , Deloron Philippe 
Published: November 2009

Abstract

Background
Malaria in pregnancy is associated with immunological abnormalities in the newborns, such as hampered T-helper 1 responses and increased T-regulatory responses, while the effect of maternal Plasmodium falciparum infection on foetal innate immunity is still controversial.

Materials and methods
The immunophenotype and cytokine release by dendritic cells (DC) and monocytes were evaluated in cord blood from 59 Beninese women with or without malaria infection by using flow cytometry.

Results
Accumulation of malaria pigment in placenta was associated with a partial maturation of cord blood myeloid and plasmacytoid DC, as reflected by an up-regulated expression of the major histocompatibility complex class II molecules, but not CD86 molecules. Cells of newborns of mothers with malaria pigment in their placenta also exhibited significantly increased cytokine responses upon TLR9 stimulation. In addition, maternal age and parity influenced the absolute numbers and activation status of cord blood antigen-presenting cells. Lastly, maternal age, but not parity, influenced TLR3, 4 and 9 responses in cord blood cells.

Discussion
Our findings support the view that placental parasitization, as indicated by the presence of malaria pigment in placental leukocytes, is significantly associated with partial maturation of different DC subsets and also to slightly increased responses to TLR9 ligand in cord blood. Additionally, other factors, such as maternal age and parity should be taken into consideration when analysing foetal/neonatal innate immune responses.

Conclusion
These data advocate a possible mechanism by which PAM may modulate foetal/neonatal innate immunity.
Aurora-A down-regulates IkappaBα via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival
Authors: Yao Jin-e , Yan Min , Guan Zhong , Pan Chao-bin , Xia Liang-ping , Li Chuan-xing , Wang Li-hui , Long Zi-jie , Zhao Yan , Li Ming-wei , Zheng Fei-meng , Xu Jie , Lin Dong-jun , Liu Quentin 
Published: November 2009

Abstract

Background
The mitotic Aurora-A kinase exerts crucial functions in maintaining mitotic fidelity. As a bona fide oncoprotein, Aurora-A aberrant overexpression leads to oncogenic transformation. Yet, the mechanisms by which Aurora-A enhances cancer cell survival remain to be elucidated.

Results
Here, we found that Aurora-A overexpression was closely correlated with clinic stage and lymph node metastasis in tongue carcinoma. Aurora-A inhibitory VX-680 suppressed proliferation, induced apoptosis and markedly reduced migration in cancer cells. We further showed that insulin-like growth factor-1, a PI3K physiological activator, reversed VX-680-decreased cell survival and motility. Conversely, wortmannin, a PI3K inhibitor, combined with VX-680 showed a synergistic effect on inducing apoptosis and suppressing migration. In addition, Aurora-A inhibition suppressed Akt activation, and VX-680-induced apoptosis was attenuated by Myr-Akt overexpression, revealing a cross-talk between Aurora-A and PI3K pathway interacting at Akt activation. Significantly, we showed that suppression of Aurora-A decreased phosphorylated Akt and was associated with increased IkappaBα expression. By contrast, Aurora-A overexpression upregulated Akt activity and downregulated IkappaBα, these changes were accompanied by nuclear translocation of nuclear factor-κB and increased expression of its target gene Bcl-xL. Lastly, Aurora-A overexpression induced IkappaBα reduction was abrogated by suppression of Akt either chemically or genetically.

Conclusion
Taken together, our data established that Aurora-A, via activating Akt, stimulated nuclear factor-κB signaling pathway to promote cancer cell survival, and promised a novel combined chemotherapy targeting both Aurora-A and PI3K in cancer treatment.
STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect
Authors: Pitroda Sean P , Wakim Bassam T , Sood Ravi F , Beveridge Mara G , Beckett Michael A , MacDermed Dhara M , Weichselbaum Ralph R , Khodarev Nikolai N 
Published: November 2009

Abstract

Background
The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect.

Methods
We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test.

Results
Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours.

Conclusion
Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.
Phylogenetic analysis of Newcastle disease viruses isolated from waterfowl in the Upper Midwest Region of the United States
Authors: Jindal Naresh , Chander Yogesh , Chockalingam Ashok K , de Abin Martha , Redig Patrick T , Goyal Sagar M 
Published: November 2009

Abstract

Background
This study was conducted to characterize Newcastle disease virus (NDV) isolates obtained from waterfowl from the Upper Midwest region of the United States. A total of 43 NDVs were isolated by inoculation of cloacal samples in embryonated chicken eggs. These isolates were obtained from 24 mallards, seven American green-winged teals, six northern pintails, four blue-winged teals, and two wood ducks. Partial sequences of fusion gene were analyzed to determine the pathotypes and genotypes involved.

Results
Deduced amino acid sequence of the cleavage site of fusion (F) protein revealed that all isolates had avirulent motifs. Of the 43 isolates, 23 exhibited sequence motif of 111GGKQGRL117 at the cleavage site, 19 exhibited 111GEKQGRL117 while one isolate showed 111GERQGRL117. Phylogenetic analysis based on comparison with different classes of NDVs revealed that all 43 isolates clustered with class II NDVs and none with class I NDVs. Within class II, five isolates were phylogenetically close to genotype I NDVs while the remaining 38 were close to genotype II.

Conclusion
We conclude that more than one genotype of NDV circulates in waterfowl in the Upper Midwest region of the US. Continuous surveillance may help better understand the epidemiology of NDVs maintained in wild bird populations and their relationship to NDVs in domestic poultry, if any.
Hes-6, an inhibitor of Hes-1, is regulated by 17β-estradiol and promotes breast cancer cell proliferation
Authors: Hartman Johan , Lam Eric W-F , Gustafsson Jan-Åke , Ström Anders 
Published: November 2009

Abstract
Introduction
Hes-6 is a member of the basic helix-loop-helix (bHLH) family of transcription factors, and its overexpression has been reported in metastatic cancers of different origins. Hes-6 has been described as an inhibitor of Hes-1 during neuronal development, although its function in cancer is not known. In this study, we investigated the function of Hes-6 in breast cancer and tested the hypothesis that Hes-6 enhances breast cancer cell proliferation and is regulated by estrogen.

Methods
To investigate the function of Hes-6, T47D cells stably expressing Hes-6 were generated by lentiviral transduction, and conversely, siRNA also was used to knock down Hes-6 expression in breast cancer cells. The Hes-6-expressing T47D cells were transplanted into immunodeficient mice to study effects on tumor growth.

Results
We found that Hes-6 expression was significantly higher in the high-grade, estrogen receptor (ER)α-negative SKBR3 and MDA-MB-231 cells compared with the ERα-positive, non-metastasizing T47D and MCF-7 breast carcinoma cells. Moreover, the level of Hes-6 mRNA was 28 times higher in breast cancer samples compared with normal breast samples. In Hes-6-expressing T47D cells, Hes-6 ectopic expression was shown to stimulate cell proliferation in vitro as well as breast tumor growth in xenografts. Moreover, expression of Hes-6 resulted in induction of E2F-1, a crucial target gene for the transcriptional repressor Hes-1. Consistently, silencing of Hes-6 by siRNA resulted in downregulation of E2F-1 expression, whereas estrogen treatment caused induction of Hes-6 and downstream targets hASH-1 and E2F-1 in MCF-7 cells.

Conclusions
Together, the data suggest that Hes-6 is a potential oncogene overexpressed in breast cancer, with a tumor-promoting and proliferative function. Furthermore, Hes-6 is a novel estrogen-regulated gene in breast cancer cells. An understanding of the role and regulation of Hes-6 could provide insights into estrogen signaling and endocrine resistance in breast cancer and, hence, could be important for the development of novel anticancer drugs.
Management of severe crush injury in a front-line tent ICU after 2008 Wenchuan earthquake in China: an experience with 32 cases
Authors: Li Wenfang , Qian Jun , Liu Xuefen , Zhang Qiang , Wang Lv , Chen Dechang , Lin Zhaofen 
Published: November 2009

Abstract
Introduction
The experience on management of crush injury after a devastating earthquake is lacking, and there are even less reports on the front-line critical care of these patients. A front-line intensive care unit (ICU) was set up in a tent after the disastrous Wenchuan earthquake (May, 12, 2008, China), where 32 patients suffering from crush injury were treated from May 12 to May 26. This study summarized our experience on management of 32 crush injury patients in a front-line tent ICU.

Methods
We retrospectively analyzed the clinical data of 32 crush injury patients treated in our frontline tent ICU. Using limited equipment, we observed the arterial blood gas parameters, blood routine, alanine aminotransferase, lactate dehydrogenase, creatine kinase, creatinine, blood urea nitrogen, and urine protein of patients. We also closely watched for changes in crush injury symptoms, urine output, and the dangerous complications of crush injury.

Results
Eighteen of the 32 patients developed traumatic shock, 9 had acute renal failure, 6 had acute heart failure, 2 had stress ulcers and 4 had multiple organ dysfunction syndrome (MODS). The symptoms of 17 patients met the criteria of crush syndrome; hemodialysis and prompt surgical intervention were given to them when necessary. Prompt treatment in our tent ICU improved the symptoms of patients to different degrees. The limb distension and sensory dysfunction were improved and the urine output was increased or even restored to the normal level in some patients. Serological parameters were improved in most patients after admission. Five (15.63%) patients underwent amputation due to severe infection in our group. Six (18.75%) patients died, 4 due to MODS and 2 due to acute renal failure.

Conclusions
Severe crushing injuries and life-threatening complications are major causes of death after major disasters like earthquakes. Prompt treatment and close monitoring of the severe complications are of great importance in saving patients' lives. Establishment of a well-equipped front-line ICU close to the epicentre of the earthquake allows for prompt on the spot rescue of critical patients with crush injury, greatly decreasing the mortality rate and complications and avoiding amputation. There should be sufficient equipment to meet the needs of more patients.
Generalized immune activation as a direct result of activated CD4+T cell killing
Authors: Marques Rute , Williams Adam , Eksmond Urszula , Wullaert Andy , Killeen Nigel , Pasparakis Manolis , Kioussis Dimitris , Kassiotis George 
Published: November 2009

Abstract
Background
In addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity.

Results
Here we report that, in a virus-free mouse model, conditional ablation of activated CD4+ T cells, the targets of immunodeficiency viruses, accelerates their turnover and produces CD4+ T cell immune deficiency. More importantly, activated CD4+ T cell killing also results in generalized immune activation, which is attributable to regulatory CD4+ T cell insufficiency and preventable by regulatory CD4+ T cell reconstitution. Immune activation in this model develops independently of microbial exposure. Furthermore, microbial translocation in mice with conditional disruption of intestinal epithelial integrity affects myeloid but not T cell homeostasis.

Conclusions
Although neither ablation of activated CD4+ T cells nor disruption of intestinal epithelial integrity in mice fully reproduces every aspect of HIV-associated immune dysfunction in humans, ablation of activated CD4+ T cells, but not disruption of intestinal epithelial integrity, approximates the two key immune alterations in HIV infection: CD4+ T cell immune deficiency and generalized immune activation. We therefore propose activated CD4+ T cell killing as a common etiology for both immune deficiency and activation in HIV infection.
See minireview http://www.jbiol.com/content/8/10/91
Activation-induced accumulation of B and T lymphocyte attenuator at the immunological synapse in CD4+ T cells
Authors: Owada Takayoshi , Watanabe Norihiko , Oki Mie , Oya Yoshihiro , Saito Yasushi , Saito Takashi , Iwamoto Itsuo , Murphy Theresa L , Murphy Kenneth M , Nakajima Hiroshi 
Published: November 2009

Abstract
The surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation in CD4+ T cells.
BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4+ T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4+ T cell activation.
Induction of HIF-1α and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells
Authors: Larbi Anis , Zelba Henning , Goldeck David , Pawelec Graham 
Published: November 2009

AbstractT cell differentiation and functions are altered at low oxygen, possibly via HIF-1α and glycolysis up-regulation.The majority of in vitro studies involving lymphocytes is performed in AtmO2, and the PhysO2 that T cells encounter are variable but commonly much lower. Previous studies showed changed kinetics and delayed proliferation of human T cells at PhysO2. Here, we show that CD3/CD28-dependent T cell activation induces faster cell cycling at AtmO2 than at PhysO2 (here taken to be 2%). Concomitantly with HIF-1α expression, we observed a switch in the T cell respiratory pathway toward glycolysis at PhysO2. Thus, modulating available glucose levels showed that at PhysO2, T cells rely more on glycolysis, associated with a higher phosphorylation of Aktser473. Although no difference in spontaneous apoptosis of resting cells was detected, it was increased significantly at PhysO2 after T cell activation and was different within the different T cell subsets. This may explain at least partly the differently altered proliferation and subset distribution observed in CD4+ and CD8+ T cells as a result of differences in naïve and memory subset distribution. Together, these findings suggest that T cell activation thresholds, subsequent proliferative capacity, and susceptibility to apoptosis, hitherto studied in air and thought to be crucial for monitoring immune responsiveness, may require re-assessment.
An optimum design for composite helical springs
Authors: Azzam B S 
Published: November 2009

An optimization study on helical compression springs has been performed in this paper. Two objectives are considered: the first objective is to minimize the spring weight, and the second is to maximize the spring stiffness. These two objectives are affected by many engineering design parameters, which can be categorized in three main groups: functional, composite material, and geometrical groups. The objective functions and constraints are mathematically formulated and written in a multi-criteria optimization problem with a non-linear non-equality constraints form. Optimum design parameters, minimum spring weight, and maximum stiffness pertinent to each type of composite material under investigation can then be selected from the results obtained.
Novel materials and modelling for large wind turbine blades
Authors: Dutton A G , Bonnet P A , Hogg P , Lleong Y L 
Published: November 2009

Commercial wind turbines have developed incrementally in size over the last 30 years such that the largest wind turbine up to the end of 2005 had a rated output of 5 MW, a rotor diameter of 124 m, and an individual blade weight of 18 ton. The question therefore arises as to what the ultimate limits on the turbine size might be. Potential design limiting factors in wind turbine design include: static and fatigue strength; overall rotor mass (which has implications for tower head mass, tower structure, and foundations); blade stiffness (required to ensure clearance between the blade tip and the wind turbine tower); blade and tower transportability. The article presents work carried out within the EPSRC SUPERGEN Wind consortium on the potential use of novel materials in wind turbine blades and the resulting consequences on blade strength and integrity. A generalized, parametric finite-element wind turbine blade model has been developed and applied to a ‘baseline’ blade design. Results are presented on static and fatigue strength for new fibre materials and how they can be incorporated into the blade model to demonstrate the likely impact on blade stiffness, strength, and weight. Possible future developments in blade structural design will be discussed in the context of other potential material innovations and ‘smart’ control concepts.