bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consolidating the set of known human protein-protein interactions in preparation for large-scale mapping of the human interactome
Authors: Ramani Arun K , Bunescu Razvan C , Mooney Raymond J , Marcotte Edward M 
Published: April 2005

Abstract
Background
Extensive protein interaction maps are being constructed for yeast, worm, and fly to ask how the proteins organize into pathways and systems, but no such genome-wide interaction map yet exists for the set of human proteins. To prepare for studies in humans, we wished to establish tests for the accuracy of future interaction assays and to consolidate the known interactions among human proteins.

Results
We established two tests of the accuracy of human protein interaction datasets and measured the relative accuracy of the available data. We then developed and applied natural language processing and literature-mining algorithms to recover from Medline abstracts 6,580 interactions among 3,737 human proteins. A three-part algorithm was used: first, human protein names were identified in Medline abstracts using a discriminator based on conditional random fields, then interactions were identified by the co-occurrence of protein names across the set of Medline abstracts, filtering the interactions with a Bayesian classifier to enrich for legitimate physical interactions. These mined interactions were combined with existing interaction data to obtain a network of 31,609 interactions among 7,748 human proteins, accurate to the same degree as the existing datasets.

Conclusion
These interactions and the accuracy benchmarks will aid interpretation of current functional genomics data and provide a basis for determining the quality of future large-scale human protein interaction assays. Projecting from the approximately 15 interactions per protein in the best-sampled interaction set to the estimated 25,000 human genes implies more than 375,000 interactions in the complete human protein interaction network. This set therefore represents no more than 10% of the complete network.
Nanoarchaea: representatives of a novel archaeal phylum or a fast-evolving euryarchaeal lineage related to Thermococcales?
Authors: Brochier Celine , Gribaldo Simonetta , Zivanovic Yvan , Confalonieri Fabrice , Forterre Patrick 
Published: April 2005

Abstract
Background
Cultivable archaeal species are assigned to two phyla - the Crenarchaeota and the Euryarchaeota - by a number of important genetic differences, and this ancient split is strongly supported by phylogenetic analysis. The recently described hyperthermophile Nanoarchaeum equitans, harboring the smallest cellular genome ever sequenced (480 kb), has been suggested as the representative of a new phylum - the Nanoarchaeota - that would have diverged before the Crenarchaeota/Euryarchaeota split. Confirming the phylogenetic position of N. equitans is thus crucial for deciphering the history of the archaeal domain.

Results
We tested the placement of N. equitans in the archaeal phylogeny using a large dataset of concatenated ribosomal proteins from 25 archaeal genomes. We indicate that the placement of N. equitans in archaeal phylogenies on the basis of ribosomal protein concatenation may be strongly biased by the coupled effect of its above-average evolutionary rate and lateral gene transfers. Indeed, we show that different subsets of ribosomal proteins harbor a conflicting phylogenetic signal for the placement of N. equitans. A BLASTP-based survey of the phylogenetic pattern of all open reading frames (ORFs) in the genome of N. equitans revealed a surprisingly high fraction of close hits with Euryarchaeota, notably Thermococcales. Strikingly, a specific affinity of N. equitans and Thermococcales was strongly supported by phylogenies based on a subset of ribosomal proteins, and on a number of unrelated molecular markers.

Conclusion
We suggest that N. equitans may more probably be the representative of a fast-evolving euryarchaeal lineage (possibly related to Thermococcales) than the representative of a novel and early diverging archaeal phylum.
MIP-1α[CCL3] acting on the CCR1 receptor mediates neutrophil migration in immune inflammation via sequential release of TNF-α and LTB4
Authors: Ramos Cleber D L , Canetti Claudio , Souto Janeusa T , Silva João S , Hogaboam Cory M , Ferreira Sergio H , Cunha Fernando Q 
Published: April 2005

AbstractIn the present study, we investigated the involvement of macrophage-inflammatory protein-1α (MIP-1α)[CC chemokine ligand 3 (CCL3)], MIP-1β[CCL4], regulated on activation, normal T expressed and secreted (RANTES)[CCL5], and CC chemokine receptors (CCRs) on neutrophil migration in murine immune inflammation. Previously, we showed that ovalbumin (OVA)-triggered neutrophil migration in immunized mice depends on the sequential release of tumor necrosis factor α (TNF-α) and leukotriene B4(LTB4). Herein, we show increased mRNA expression for MIP-1α[CCL3], MIP-1β[CCL4], RANTES[CCL5], and CCR1 in peritoneal cells harvested from OVA-challenged, immunized mice, as well as MIP-1α[CCL3] and RANTES[CCL5] but not MIP-1β[CCL4] proteins in the peritoneal exudates. OVA-induced neutrophil migration response was muted in immunized MIP-1α[CCL3]−/− mice, but it was not inhibited by treatment with antibodies against RANTES[CCL5] or MIP-1β[CCL4]. MIP-1α[CCL3] mediated neutrophil migration in immunized mice through induction of TNF-α and LTB4 synthesis, as these mediators were detected in the exudates harvested from OVA-challenged immunized wild-type but not MIP-1α[CCL3]−/− mice; administration of MIP-1α[CCL3] induced a dose-dependent neutrophil migration, which was inhibited by treatment with an anti-TNF-α antibody in TNF receptor 1 (p55−/−)-deficient mice or by MK 886 (a 5-lipoxygenase inhibitor); and MIP-1α[CCL3] failed to induce LTB4 production in p55−/− mice. MIP-1α[CCL3] used CCR1 to promote neutrophil recruitment, as OVA or MIP-1α[CCL3] failed to induce neutrophil migration in CCR1−/− mice, in contrast to CCR5−/− mice. In summary, we have demonstrated that neutrophil migration observed in this model of immune inflammation is mediated by MIP-1α[CCL3], which via CCR1, induces the sequential release of TNF-α and LTB4. Therefore, whether a similar pathway mediates neutrophil migration in human immune-inflammatory diseases, the development of specific CCR1 antagonists might have a therapeutic potential.
Regulation of matrix metalloproteinase-9 release from IL-8-stimulated human neutrophils
Authors: Chakrabarti Subhadeep , Patel Kamala D 
Published: April 2005

AbstractMatrix metalloproteinase-9 (MMP-9) is present in the tertiary granules of neutrophils and can be released following stimulation. We examined the signaling mechanisms that regulate interleukin-8 (IL-8)-mediated MMP-9 release from neutrophils. IL-8 activates neutrophils by interacting with two receptors: CXC chemokine receptor 1 (CXCR1) and CXCR2. Blocking CXCR1 had no effect on IL-8-mediated MMP-9 release, whereas blocking CXCR2 significantly reduced MMP-9 release. We also found that stimulating CXCR2 alone was sufficient to induce MMP-9 release. This process was independent of changes in the intracellular calcium concentration. Src-family kinases and protein kinase C (PKC) were involved in two mutually exclusive pathways regulating IL-8-mediated MMP-9 release. Inhibition of extracellular signal-regulated kinase (ERK)1/2 blocked IL-8-mediated MMP-9 release; however, inhibition of p38 mitogen-activated protein kinase had no effect on MMP-9 release. We found ERK1/2 was activated downstream of PKC, but not Src-family kinases, in this system. These data suggest that IL-8-induced MMP-9 release from neutrophils is mediated through CXCR2 and involves two distinct pathways, one involving PKC and ERK1/2 and the other involving Src-family kinases. Furthermore, our data show that the mechanisms that regulate MMP-9 release from tertiary granules are different from those that regulate primary granule release.
Measurements of plasma oxycodone, noroxycodone and oxymorphone levels in a patient with bilateral nephrectomy who is undergoing haemodialysis
Authors: Lee M A , Leng M E F , Cooper R M 
Published: April 2005

The use of opioid analgesics in renal dysfunction is potentially problematic and many patients with end stage renal disease are unable to tolerate these medications. A greater understanding of the pharmacokinetics of opioid analgesics is vital in informing safe and effective practice. Using pharmacokinetic analysis, this case study demonstrates for the first time that oxycodone and its metabolites are removed by haemodialysis. As such, care should be taken when using oxycodone in patients undergoing haemodialysis.
Vascular viewpoint
Authors: Mohammed Naufal , Anand Sonia S 
Published: April 2005

Question: Is carotid endarterectomy (CEA) an effective and safe treatment for the prevention of stroke among patients with >60% internal carotid artery stenosis who had no neurologic symptoms in the previous 6 months. Population: Men and women with severe (>60%) unilateral or bilateral carotid artery stenosis not associated with neurologic symptoms in the past 6 months, where both doctor and patient were uncertain whether to choose or to defer immediate CEA. Design and methods: During 1993-2003, 3120 asymptomatic patients with >60% carotid stenosis were randomized equally to immediate CEAversus indefinite deferral of CEA, and were followed for up to 5 years. The primary end point was risk of stroke or death at 5 years. Analysis was by intention to treat. The treatment of patients with antiplatelet agents, antihypertensive and lipid-lowering therapies was left to the discretion of the clinician. Results: Among patients randomized to immediate CEA (50% had CEA by 1 month, 88% by 1 year) versus deferred, the incidence of stroke or death at 5 years was 6.4% versus 11.8% (95% CI: 3.0-7.7, p < 0.0001); 3.5% versus 6.1% for fatal or disabling strokes (95% CI: 0.8-4.3, p = 0.004), and 2.1% versus 4.2% for fatal strokes (95% CI: 0.6-3.6, p = 0.006). The perioperative stroke incidence was marginally higher in the delayed group versus the immediate group (4.5% versus 2.8%) and overall the risk per CEA of perioperative stroke or death was 3.1%. After excluding the perioperative events from the analysis, the 5-year stroke risks were 3.8% versus 11% (95% CI: 5.0-9.4], p < 0.0001). Surgery primarily prevented carotid territory ischemic strokes (2.7% vs 9.5%; gain 6.8% [4.8-8.8], p < 0.0001). The impact of immediate surgery was consistent in all age groups, among men and women, and across the spectrum of carotid stenosis (i.e. 70%, 80% and 90% carotid stenosis). Conclusion: In asymptomatic patients younger than 75 years of age with carotid stenosis of 70% or more on ultrasound, immediate CEA reduces the 5-year incidence of stroke and death.
Stability of Neuroendocrine and Behavioral Responsiveness in Aging Fischer 344/Brown-Norway Hybrid Rats
Authors: Kasckow John W. , Segar Tracy M. , Xiao Chun , Furay Amy R. , Evanson Nathan K. , Ostrander Michelle M. , Herman James P. 
Published: April 2005

AbstractAging in rodents and primates is accompanied by changes in hypothalamic-pituitary-adrenal (HPA) activity. We examined behavioral and neuroendocrine responses in 3, 15-, and 30-month-old F344/Brown-Norway rats. Basal corticosterone and ACTH levels did not differ with age, although ACTH responses, but not corticosterone responses to restraint stress, were significantly lower in the 30-month-old group relative to 3- and 15-month-old rats. Induction of c-fos mRNA in the paraventricular nucleus from restraint was not affected by age. Furthermore, there was an enhanced sensitivity to dexamethasone suppression in aged animals as evidenced by lesser ACTH and corticosterone release after dexamethasone administration. Evaluation of emotional behaviors in the forced swim test revealed no differences between the age groups. With fear conditioning, aged rats had decreased freeze times relative to middle-aged or young rats. Regression analysis revealed no significant correlations between the behavioral and HPA axis data in any group. Overall, the data suggest that an apparent decrease in pituitary drive is compensated for at the level of the adrenal, resulting in stable patterns of glucocorticoid secretion. The lack of a correlation between HPA axis measures and emotional as well as fear conditioning-related behaviors indicates that corticosteroid dysfunction may not predict age-related behavioral deficits in this aging model.
Calcium Has a Permissive Role in Interleukin-1β-Induced c-Jun N-Terminal Kinase Activation in Insulin-Secreting Cells
Authors: Størling Joachim , Zaitsev Sergei V. , Kapelioukh Iouri L. , Karlsen Allan E. , Billestrup Nils , Berggren Per-Olof , Mandrup-Poulsen Thomas 
Published: April 2005

AbstractThe c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1β-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic β-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1β activation of JNK in β-cells are largely unknown. In this study, we investigated whether Ca2+ plays a role for IL-1β-induced JNK activation. In insulin-secreting rat INS-1 cells cultured in the presence of 11 mm glucose, combined pharmacological blockade of L- and T-type Ca2+ channels suppressed IL-1β-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1β-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1β-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca2+ channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse βTC3 cells. Ca2+ influx, specifically via L-type but not T-type channels, contributed to IL-1β activation of JNK. Activation of p38 and ERK in response to IL-1β was also dependent on L-type Ca2+ influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca2+ ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca2+ ATPase, all caused an amplification of IL-1β-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca2+ [bis-(o-aminophenoxy)-N,N,N′,N′-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca2+/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1β-stimulated c-jun phosphorylation in INS-1 or βTC3 cells. Our data suggest that Ca2+ plays a permissive role in IL-1β activation of the JNK signaling pathway in insulin-secreting cells.
Regulation of Parathyroid Hormone-Related Peptide by Estradiol: Effect on Tumor Growth and Metastasis in Vitro and in Vivo
Authors: Rabbani S. A. , Khalili P. , Arakelian A. , Pizzi H. , Chen G. , Goltzman D. 
Published: April 2005

AbstractWe evaluated the capacity of estradiol (E2) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E2 caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E2 tamoxifen. E2 also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E2 production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.
Distinctive Actions of Membrane-Targeted Versus Nuclear Localized Estrogen Receptors in Breast Cancer Cells
Authors: Rai Deshanie , Frolova Antonina , Frasor Jonna , Carpenter Anne E. , Katzenellenbogen Benita S. 
Published: April 2005

AbstractEstrogens regulate multiple activities in breast cancer cells, including proliferation. Whereas these hormones are most commonly known to regulate gene transcription through direct interaction with estrogen receptors (ERs) and with specific DNA sequences of target genes, recent studies show that ER also activates a number of rapid signaling events that are initiated at the cell membrane. To study the membrane-initiated effects of estrogen and separate them from the activities initiated by the nuclear localized ER in human breast cancer cells, we generated MDA-MB-231 breast cancer cell lines that have stably integrated either the wild-type nuclear form of ER (WT-ER) or a modified, membrane-targeted ER (MT-ER) that lacks a nuclear localization sequence and is dually acylated with a myristoylation sequence at the N terminus and a palmitoylation sequence at the C terminus. We demonstrate that MT-ER is membrane localized in the absence of estradiol (E2), showing punctate membrane and cytoplasmic speckles after E2 exposure. In contrast to WT-ER, MT-ER was not down-regulated by E2 or by antiestrogen ICI 182,780 exposure, and MT-ER failed to regulate endogenous E2-responsive genes highly up-regulated by WT-ER. Cells expressing MT-ER showed a greater serum response element-mediated transcriptional response that was partially inhibited by antiestrogen ICI 182,780. The MT-ER and WT-ER differentially altered ERK1/2 and Akt activities and the proliferation of breast cancer cells in response to E2. Hence, this study reveals distinct actions of the MT-ER vs. the WT-ER in effecting estrogen actions in breast cancer cells.
Role of the Basic Helix-Loop-Helix Transcription Factor, Scleraxis, in the Regulation of Sertoli Cell Function and Differentiation
Authors: Muir Tera , Sadler-Riggleman Ingrid , Skinner Michael K. 
Published: April 2005

AbstractSertoli cells are a postmitotic terminally differentiated cell population in the adult testis that form the seminiferous tubules and provide the microenvironment and structural support for developing germ cells. The transcription factors that regulate Sertoli cell differentiation remain to be elucidated. The basic helix-loop-helix transcription factors are involved in the differentiation of a variety of cell lineages during development and are expressed in pubertal Sertoli cells. A yeast-two-hybrid procedure was used to screen a Sertoli cell library from 20-d-old pubertal rats to identify dimerization partners with the ubiquitous E47 basic helix-loop-helix transcription factor. Scleraxis was identified as one of the interacting partners. Among the cell types of the testis, scleraxis expression was found to be specific to Sertoli cells. Analysis of the expression pattern of scleraxis mRNA in developing Sertoli cells revealed an increase in scleraxis message at the onset of puberty. Sertoli cells respond to FSH to promote expression of differentiated gene products such as transferrin that aid in proper development of the germ cells. Analysis of the hormonal regulation of scleraxis expression revealed a 4-fold increase in scleraxis mRNA in response to the presence of FSH or dibutryl cAMP in cultured Sertoli cells. An antisense oligonucleotide procedure and overexpression analysis were used to determine whether scleraxis regulates the expression of Sertoli cell differentiated gene products. An antisense oligonucleotide to scleraxis down-regulated transferrin promoter activity in Sertoli cells. A transient overexpression of scleraxis in Sertoli cells stimulated transferrin and androgen binding protein promoter activities and the expression of a number of differentiated genes. Observations suggest scleraxis functions in a number of adult tissues and is involved in the regulation and maintenance of Sertoli cell function and differentiation. This is one of the first adult and nontendon/chondrocyte-associated functions described for scleraxis.
Physiological Role for the Cochaperone FKBP52 in Androgen Receptor Signaling
Authors: Cheung-Flynn Joyce , Prapapanich Viravan , Cox Marc B. , Riggs Daniel L. , Suarez-Quian Carlos , Smith David F. 
Published: April 2005

AbstractMolecular chaperones mediate multiple aspects of steroid receptor function, but the physiological importance of most receptor-associated cochaperones has not been determined. To help fill this gap, we targeted for disruption the mouse gene for the 52-kDa FK506 binding protein, FKBP52, a 90-kDa heat shock protein (Hsp90)-binding immunophilin found in steroid receptor complexes. A mouse line lacking FKBP52 (52KO) was generated and characterized. Male 52KO mice have several defects in reproductive tissues consistent with androgen insensitivity; among these defects are ambiguous external genitalia and dysgenic prostate. FKBP52 and androgen receptor (AR) are coexpressed in prostate epithelial cells of wild-type mice. However, FKBP52 and AR are similarly coexpressed in testis even though testis morphology and spermatogenesis in 52KO males are usually normal. Molecular studies confirm that FKBP52 is a component of AR complexes, and cellular studies in yeast and human cell models demonstrate that FKBP52 can enhance AR-meditated transactivation. AR enhancement requires FKBP52 peptidylprolyl isomerase activity as well as Hsp90-binding ability, and enhancement probably relates to an affect of FKBP52 on AR-folding pathways. In the presence of FKBP52, but not other cochaperones, the function of a minimally active AR point mutant can be dramatically restored. We conclude that FKBP52 is an AR folding factor that has critically important physiological roles in some male reproductive tissues.
Fast and Slow Skeletal Troponin I in Serum from Patients with Various Skeletal Muscle Disorders: A Pilot Study
Authors: Simpson Jeremy A , Labugger Ralf , Collier Christine , Brison Robert J , Iscoe Steve , Van Eyk Jennifer E 
Published: April 2005

Abstract
Background: Detection of skeletal muscle injury is hampered by a lack of commercially available assays for serum markers specific for skeletal muscle; serum concentrations of skeletal troponin I (sTnI) could meet this need. Moreover, because sTnI exists in 2 isoforms, slow (ssTnI) and fast (fsTnI), corresponding to slow- and fast-twitch muscles, respectively, it could provide insight into differential injury/recovery of specific fiber types. The purpose of this study was to investigate whether the 2 isoforms of sTnI and their modified forms are present in the blood of patients with various skeletal muscle disorders.
Methods: Serial serum samples were obtained from 25 patients with various skeletal muscle injuries. Serum proteins were separated by a modified sodium dodecyl sulfate–polyacrylamide gel electrophoresis protocol followed by Western blotting for sTnI with monoclonal antibodies specific to ssTnI and fsTnI.
Results: We observed (a) intact and, in some cases, degraded sTnI products; (b) evidence of posttranslational modifications in addition to proteolysis; and (c) differential detectability of both skeletal isoforms in the same patient.
Conclusions: It is possible to monitor both sTnI isoforms; this could lead to the development of new diagnostic assays for skeletal muscle damage.