bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a comprehensive structural variation map of an individual human genome
Authors: Pang Andy W , MacDonald Jeffrey R , Pinto Dalila , Wei John , Rafiq Muhammad A , Conrad Donald F , Park Hansoo , Hurles Matthew E , Lee Charles , Venter J Craig , Kirkness Ewen F , Levy Samuel , Feuk Lars , Scherer Stephen W 
Published: May 2010

Abstract
Background
Several genomes have now been sequenced, with millions of genetic variants annotated. While significant progress has been made in mapping single nucleotide polymorphisms (SNPs) and small (<10 bp) insertion/deletions (indels), the annotation of larger structural variants has been less comprehensive. It is still unclear to what extent a typical genome differs from the reference assembly, and the analysis of the genomes sequenced to date have shown varying results for copy number variation (CNV) and inversions.

Results
We have combined computational re-analysis of existing whole genome sequence data with novel microarray-based analysis, and detect 12,178 structural variants covering 40.6 Mb that were not reported in the initial sequencing of the first published personal genome. We estimate a total non-SNP variation content of 48.8 Mb in a single genome. Our results indicate that this genome differs from the consensus reference sequence by approximately 1.2% when considering indels/CNVs, 0.1% by SNPs and approximately 0.3% by inversions. The structural variants impact 4,867 genes, and >24% of structural variants would not be imputed by SNP-association.

Conclusions
Our results indicate that a large number of structural variants have been unreported in the individual genomes published to date. This significant extent and complexity of structural variants, as well as the growing recognition of their medical relevance, necessitate they be actively studied in health-related analyses of personal genomes. The new catalogue of structural variants generated for this genome provides a crucial resource for future comparison studies.
A human functional protein interaction network and its application to cancer data analysis
Authors: Wu Guanming , Feng Xin , Stein Lincoln 
Published: May 2010

Abstract
Background
One challenge facing biologists is to tease out useful information from massive data sets for further analysis. A pathway-based analysis may shed light by projecting candidate genes onto protein functional relationship networks. We are building such a pathway-based analysis system.

Results
We have constructed a protein functional interaction network by extending curated pathways with non-curated sources of information, including protein-protein interactions, gene coexpression, protein domain interaction, Gene Ontology (GO) annotations and text-mined protein interactions, which cover close to 50% of the human proteome. By applying this network to two glioblastoma multiforme (GBM) data sets and projecting cancer candidate genes onto the network, we found that the majority of GBM candidate genes form a cluster and are closer than expected by chance, and the majority of GBM samples have sequence-altered genes in two network modules, one mainly comprising genes whose products are localized in the cytoplasm and plasma membrane, and another comprising gene products in the nucleus. Both modules are highly enriched in known oncogenes, tumor suppressors and genes involved in signal transduction. Similar network patterns were also found in breast, colorectal and pancreatic cancers.

Conclusions
We have built a highly reliable functional interaction network upon expert-curated pathways and applied this network to the analysis of two genome-wide GBM and several other cancer data sets. The network patterns revealed from our results suggest common mechanisms in the cancer biology. Our system should provide a foundation for a network or pathway-based analysis platform for cancer and other diseases.
Short RNA half-lives in the slow-growing marine cyanobacterium Prochlorococcus
Authors: Steglich Claudia , Lindell Debbie , Futschik Matthias , Rector Trent , Steen Robert , Chisholm Sallie W 
Published: May 2010

Abstract
Background
RNA turnover plays an important role in the gene regulation of microorganisms and influences their speed of acclimation to environmental changes. We investigated whole-genome RNA stability of Prochlorococcus, a relatively slow-growing marine cyanobacterium doubling approximately once a day, which is extremely abundant in the oceans.

Results
Using a combination of microarrays, quantitative RT-PCR and a new fitting method for determining RNA decay rates, we found a median half-life of 2.4 minutes and a median decay rate of 2.6 minutes for expressed genes - twofold faster than that reported for any organism. The shortest transcript half-life (33 seconds) was for a gene of unknown function, while some of the longest (approximately 18 minutes) were for genes with high transcript levels. Genes organized in operons displayed intriguing mRNA decay patterns, such as increased stability, and delayed onset of decay with greater distance from the transcriptional start site. The same phenomenon was observed on a single probe resolution for genes greater than 2 kb.

Conclusions
We hypothesize that the fast turnover relative to the slow generation time in Prochlorococcus may enable a swift response to environmental changes through rapid recycling of nucleotides, which could be advantageous in nutrient poor oceans. Our growing understanding of RNA half-lives will help us interpret the growing bank of metatranscriptomic studies of wild populations of Prochlorococcus. The surprisingly complex decay patterns of large transcripts reported here, and the method developed to describe them, will open new avenues for the investigation and understanding of RNA decay for all organisms.
Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis
Authors: Brahmamdam Pavan , Inoue Shigeaki , Unsinger Jacqueline , Chang Katherine C , McDunn Jonathan E , Hotchkiss Richard S 
Published: May 2010

Abstract
Blocking the negative co-stimulatory molecule PD-1 prevents immune suppression, blocks apoptosis, and improves survival in sepsis.
There is increasing recognition that a major pathophysiologic event in sepsis is the progression to an immunosuppressive state in which the host is unable to eradicate invading pathogens. Although there are likely numerous causes for the immunosuppression, expression of negative costimulatory molecules on immune effector cells is a likely contributing factor. PD-1 is a recently described, negative costimulatory molecule that has potent effects to inhibit T cell activation, cytokine production, and cytotoxic functions. PD-1 plays a critical role in the host response to specific pathogens, but relatively little work has been done on the possible effects of PD-1 in sepsis. We hypothesized that the anti-PD-1 antibody would improve survival in sepsis. Mice underwent CLP, and PD-1 expression was quantitated. Additionally, the effects of anti-PD-1 antibody on lymphocyte apoptosis, cytokine production, host immunity, and survival were determined. PD-1 expression increased beginning 48 h after sepsis, and &gt;20% of CD4 and CD8 T cells were positive by 7 days. Anti-PD-1 antibody administered 24 h after sepsis prevented sepsis-induced depletion of lymphocytes and DCs, increased Bcl-xL, blocked apoptosis, and improved survival. Anti-PD-1 also prevented the loss in DTH, a key indicator of immunocompetence in sepsis. Thus, delayed administration of anti-PD-1 antibody, an important therapeutic advantage, was effective in sepsis. Furthermore, these results add to the growing body of evidence that modulation of the positive and negative costimulatory pathways on immune cells represents a viable therapeutic approach in reversing immunosuppression and improving sepsis survival.
Immune cell recruitment to inflammatory loci is impaired in mice deficient in basement membrane protein laminin α4
Authors: Kenne Ellinor , Soehnlein Oliver , Genové Guillem , Rotzius Pierre , Eriksson Einar E , Lindbom Lennart 
Published: May 2010

Abstract
Mice lacking basement membrane laminin-411 show im-paired leukocyte recruitment to extravascular tissue due to defective migration through the vessel wall.
For leukocytes to penetrate the vessel wall, they need to interact sequentially with the endothelial lining and the perivascular BM. The matrix protein laminin-411 is a major constituent of the vascular BM. The laminin α4 chain is a component of laminin-411 and has structural and signaling functions. Here, we addressed the role of BM laminin α4 in leukocyte recruitment to inflammatory loci. We used several recruitment models in Lam4−/− and WT mice to determine whether lack of laminin-411 in the perivascular BM influences extravasation of inflammatory cells. Recruitment of all major leukocyte subsets (neutrophils, monocytes, and lymphocytes) was reduced in Lam4−/− mice compared with WT. With the use of intravital microscopy, we concluded that this decrease was a result of impaired diapedesis through the vessel wall, as neither leukocyte adhesion to the endothelial lining nor migration in extravascular tissue was hampered in Lam4−/− mice. Collectively, our data suggest a reduced ability of immune cells to penetrate the vessel wall in mice deficient in laminin α4.
Technical Advance: Generation of human pDC equivalents from primary monocytes using Flt3-L and their functional validation under hypoxia
Authors: Sekar Divya , Brüne Bernhard , Weigert Andreas 
Published: May 2010

Abstract
Method for the generation of human pDC equivalents ex vivo from primary monocytes, whose differentiation can be manipulated by environmental stimuli such as hypoxia.
The division of labor between DC subsets is evolutionarily well-defined. mDC are efficient in antigen presentation, whereas pDC act as rheostats of the immune system. They activate NK cells, cause bystander activation of mDC, and interact with T cells to induce tolerance. This ambiguity positions pDC at the center of inflammatory diseases, such as cancer, arthritis, and autoimmune diseases. The ability to generate human mDC ex vivo made it possible to engineer them to suit therapy needs. Unfortunately, a similar, easily accessible system to generate human pDC is not available. We describe a method to generate human pDC equivalents ex vivo, termed mo-pDC from peripheral blood monocytes using Flt3-L. mo-pDC showed a characteristic pDC profile, such as high CD123 and BDCA4, but low CD86 and TLR4 surface expression and a low capacity to induce autologous lymphocyte proliferation and to phagocytose apoptotic debris in comparison with mDC. Interestingly, mo-pDC up-regulated the pDC lineage-determining transcription factor E2-2 as well as expression of BDCA2, which is under the transcriptional control of E2-2 but not its inhibitor ID2, during differentiation. mo-pDC produced high levels of IFN-α when pretreated overnight with TNF-α. Under hypoxia, E2-2 was down-regulated, and ID2 was induced in mo-pDC, whereas surface expression of MHCI, CD86, and BDCA2 was decreased. Furthermore, mo-pDC produced high levels of inflammatory cytokines when differentiated under hypoxia compared with normoxia. Hence, mo-pDC can be used to study differentiation and functions of human pDC under microenvironmental stimuli.
Experimental analysis of friction-induced vibrations at the finger contact surface
Authors: Fagiani R , Massi F , Chatelet E , Berthier Y , Sestieri A 
Published: May 2010

When a finger moves to scan the surface of an object, the sliding contact generates vibrations that propagate in the finger skin and transmit the information about the object characteristics to mechanoreceptors. Mechanoreceptors convert vibrations into electric impulses sent to the brain. In this context, by appropriate experiments, a frequency analysis of the signal characterizing the surface scanning can be carried out to investigate the vibration spectrum measured on the finger and to highlight how the tactile sense is connected to the measured frequency spectra. Although the correlation between the surface roughness with respect to the tactile sensation is deeply analysed in the literature, the vibration spectra induced by the finger—surface scanning and the consequent activation of mechanoreceptors on the skin were rarely investigated. In particular, in this paper, interests will be focused on the changes shown in the vibration spectra, caused by variations in the characteristic contact parameters such as scanning velocity and roughness.
Axially Chiral Anilido–Aldimine Aluminum Complexes with a Pseudobinaphthyl Skeleton
Authors: Hayashi Kazuhiro , Nakajima Yumiko , Ozawa Fumiyuki , Kawabata Takeo 
Published: May 2010

Abstract
Axially chiral anilido–aldimine aluminum complexes with a pseudobinaphthyl skeleton 3a and 3b have been prepared. X-ray analysis indicates that complex 3b adopts a conformation similar to that of 1,1′-binaphthyls. The racemization barrier of 3a was determined to be 23.0 kcal mol−1, which was higher by ca. 4 kcal mol−1 than the corresponding diarylamine precursor with an N–H–N hydrogen bond.
Photostability of Water-dispersible CdTe Quantum Dots: Capping Ligands and Oxygen
Authors: Emin Saim , Loukanov Alexandre , Wakasa Masanobu , Nakabayashi Seiichiro , Kaneko Yasuko 
Published: May 2010

Abstract
Here we report the effect of various capping ligands on the optical properties and photostability of CdTe quantum dots in aqueous solutions. Ligand exchange procedure is used to prepare water dispersive CdTe nanocrystals capped with aminoethanethiol, 3-mercaptopropionic and dihydrolipoic acids. The dynamics of photoexcited states is examined by transient photoluminescent spectroscopy. Our results demonstrate that the luminescence intensity of water-dispersible CdTe quantum dots is strongly influenced by molecular oxygen under light irradiation.
Significant Sirolimus and Dronedarone Interaction in a Kidney Transplant Recipient
Authors: Tichy Eric M , Medwid Andrew J , Mills Elizabeth A , Formica Richard N , Kulkarni Sanjay 
Published: May 2010

Objective: To report the potential clinically significant pharmacokinetic interaction between sirolimus and dronedarone. Case Summary: A 67-year-old man status post-kidney transplant in 2004 was maintained on an immunosuppressive regimen consisting of sirolimus, mycophenolate mofetil, and prednisone. He had been maintained for more than 1 year on a stable dose of sirolimus (5 mg/day), with concentrations ranging between 5 and 13.5 ng/mL. The patient was admitted to the hospital with a complaint of bloody diarrhea; shortly after admission, he developed atrial fibrillation for which dronedarone 400 mg twice daily was initiated. Sirolimus concentrations obtained 3 days after initiation of dronedarone revealed a trough concentration that was increased by more than 3-fold (38.6 ng/mL) from his baseline trough concentration. After sirolimus was held for 6 days, the trough concentration was 7.8 ng/mL. The dosage was reduced to 1 mg/day; there was no need for further adjustment. Discussion: While the potential for an interaction between sirolimus and dronedarone is listed in the package insert of dronedarone, there are no documented reports of this interaction in the peer-reviewed literature. Since sirolimus is a narrow therapeutic index medication, information about the severity and magnitude of the interaction with dronedarone may help clinicians avoid therapeutic misadventures when this combination is employed. Our case clearly demonstrates a significant pharmacokinetic interaction between sirolimus and dronedarone. The Horn Drug Interaction Probability Scale indicates that the occurrence of an interaction between sirolimus and dronedarone in our case is probable. Conclusions: Due to the potential for sirolimus toxicity and excessive immunosuppression, the concurrent use of dronedarone and sirolimus should be avoided when possible. If concurrent administration cannot be avoided, we suggest close monitoring and a 50–75% dose reduction of sirolimus prior to dronedarone initiation.
miR-221/222 suppression protects against endoplasmic reticulum stress-induced apoptosis via p27Kip1- and MEK/ERK-mediated cell cycle regulation
Authors: Dai Rongyang , Li Juan , Liu Youping , Yan Dongmei , Chen Shaokun , Duan Chunyan , Liu Xiaoyan , He Tao , Li Hong 
Published: May 2010

Abstract
Cancer cells are relatively resistant to endoplasmic reticulum (ER) stress-induced apoptosis. However, the underlying mechanisms remain largely unclear. We observed that the microRNAs miR-221/222 are associated with apoptosis regulation under ER stress in human hepatocellular carcinoma (HCC) cells. Induction of ER stress does not trigger significant apoptosis but obviously causes downregulation of miR-221/222 in HCC cells. In these cells, ER stress-induced apoptosis is enhanced by miR-221/222 mimics and attenuated by miR-221/222 inhibitors. miR-221/222 promoted-apoptosis under ER stress is associated with p27Kip1- and MEK/ERK-mediated cell cycle regulation. Our results suggest that suppression of miR-221/222 plays a crucial role in the protection against apoptosis induced by ER stress in HCC cells.
Human SepSecS or SLA/LP: selenocysteine formation and autoimmune hepatitis
Authors: Palioura Sotiria , Herkel Johannes , Simonović Miljan , Lohse Ansgar W. , Söll Dieter 
Published: May 2010

AbstractSelenocysteine, the 21st genetically encoded amino acid, is the major form of the antioxidant trace element selenium in the human body. In eukaryotes and archaea its synthesis proceeds through a phosphorylated intermediate in a tRNA-dependent fashion. The final step of selenocysteine formation is catalyzed byO-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) that converts phosphoseryl-tRNASecto selenocysteinyl-tRNASec. The human SepSecS protein is also known as soluble liver antigen/liver pancreas (SLA/LP), which represents one of the antigens of autoimmune hepatitis. Here we review the discovery of human SepSecS and the current understanding of the immunogenicity of SLA/LP in autoimmune hepatitis.
The type III secretion injectisome, a complex nanomachine for intracellular ‘toxin’ delivery
Authors: Cornelis Guy R. 
Published: May 2010

Abstract
The type III secretion injectisome is a nanomachine that delivers bacterial proteins into the cytosol of eukaryotic target cells. It consists of a cylindrical basal structure spanning the two bacterial membranes and the peptidoglycan, connected to a hollow needle, eventually followed by a filament (animal pathogens) or to a long pilus (plant pathogens). Export employs a type III pathway. During assembly, all the protein subunits of external elements are sequentially exported by the basal structure itself, implying that the export apparatus can switch its substrate specificity over time. The length of the needle is controlled by a protein that it also secreted during assembly and presumably acts as a molecular ruler.
Tissue kallikrein promotes prostate cancer cell migration and invasion via a protease-activated receptor-1-dependent signaling pathway
Authors: Gao Lin , Smith Robert S. , Chen Li-Mei , Chai Karl X. , Chao Lee , Chao Julie 
Published: May 2010

AbstractWe recently demonstrated that tissue kallikrein (TK) promotes keratinocyte migration through activation of protease-activated receptor-1 (PAR1) and transactivation of the epi-dermal growth factor receptor (EGFR). In this study, we investigated the potential role of PAR1in mediating the effect of TK on cancer cell migration, invasion and proliferation. Our results show that TK promotes DU145 prostate cancer cell migration in a concentration-dependent manner, but has no effect on A549 lung cancer cells. Active TK markedly increases DU145 cell migration and invasion, which are blocked by aprotinin but minimally affected by icatibant; kinin treatment has little effect. TK-induced cell migration and invasion are abolished by inhibition of PAR1using a pharmacological inhibitor or RNA interference. The effect of TK on cell migration and invasion are also blocked by inhibitors of protein kinase C, c-Src, matrix metalloproteinase, EGFR and extracellular signal-regulated kinase (ERK). Moreover, TK stimulates ERK phosphorylation, which is inhibited by an EGFR antagonist. Additionally, TK but not kinin stimulates DU145 cell proliferation through activation of the kinin B2 receptor, but not PAR1and EGFR. These results indicate differential signaling pathways mediated by TK in promoting prostate cancer cell migration and invasion via PAR1activation, and proliferation via kinin B2 receptor stimulation.
Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
Authors: Yasukochi Atsushi , Kawakubo Tomoyo , Nakamura Seiji , Yamamoto Kenji 
Published: May 2010

AbstractWe previously described that cathepsin E specifically induces growth arrest and apoptosis in several human prostate cancer cell linesin vitroby catalyzing the proteolytic release of soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from the tumor cell surface. It also prevents tumor growth and metastasisin vivothrough multiple mechanisms, including induction of apoptosis, angiogenesis inhibition and enhanced immune responses. Using the prostate cancer cell line PPC-1, which is relatively resistant to cell death by doxorubicin (40–50% cytotoxicity), we first report that a combination treatment with cathepsin E can overcome resistance of the cells to this agent.In vitrostudies showed that combined treatment of PPC-1 cells with the two agents synergistically induces viability loss, mainly owing to down-regulation of a short form of the FLICE inhibitory protein FLIP. The enhanced antitumor activity was corroborated byin vivostudies with athymic mice bearing PPC-1 xenografts. Intratumoral application of cathepsin E in doxorubicin-treated mice results in tumor cell apoptosis and tumor regression in xenografts by enhanced TRAIL-induced apoptosis through doxorubicin-induced c-FLIP down-regulation and by a decrease in tumor cell proliferation. These results indicate that combination of cathepsin E and doxorubicin is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant prostate cancer PPC-1 cells, thus indicating therapeutic potential for clinical use.
Decoding transcription and microRNA-mediated translation control in Drosophila development
Authors: Gaul Ulrike 
Published: May 2010

Abstract
The spatio-temporal regulation of gene expression lies at the heart of animal development. In this article we present an overview of our recent work to apply systems biological approaches to the study of transcription and microRNA-mediated translation control in Drosophila development. We have identified many new cis-regulatory elements within the segmentation gene network, a transcriptional hierarchy governing pattern formation along the antero-posterior axis of the embryo, and developed a novel thermodynamic model to predict their expression. A similar thermodynamic approach that takes into account the secondary structure of the target mRNA significantly improves the prediction of microRNA binding sites.