julilili42/papers huggingface dataset:
A transducer-independent optical sensor system for the detection of biochemical binding reactions
2005-11-09

In this article we present a very simple, transducer-independent label-free optical detection method based on reflectometry for bioanalytical applications. A laboratory setup of this 1λ-reflectometry delivers results that are comparable with established detection principles like Surface Plasmon Resonance or Reflectometric Interference Spectroscopy. Additionally we present a first version of a miniaturized setup of this method to show its potential due to its simplicity.
Breakdown of abdominal patterning in the Tribolium Kruppel mutant jaws
2005-11-10

During Drosophila segmentation, gap genes function as short-range gradients that determine the boundaries of pair-rule stripes. A classical example is Drosophila Krüppel (Dm'Kr) which is expressed in the middle of the syncytial blastoderm embryo. Patterning defects in Dm'Kr mutants are centred symmetrically around its bell-shaped expression profile. We have analysed the role of Krüppel in the short-germ beetle Tribolium castaneum where the pair-rule stripes corresponding to the 10 abdominal segments arise during growth stages subsequent to the blastoderm. We show that the previously described mutation jaws is an amorphic Tc'Kr allele. Pair-rule gene expression in the blastoderm is affected neither in the amorphic mutant nor in Tc'Kr RNAi embryos. Only during subsequent growth of the germ band does pair-rule patterning become disrupted. However, only segments arising posterior to the Tc'Kr expression domain are affected, i.e. the deletion profile is asymmetric relative to the expression domain. Moreover,stripe formation does not recover in posterior abdominal segments, i.e. the Tc'Krjaws phenotype does not constitute a gap in segment formation but results from a breakdown of segmentation past the 5th eve stripe. Alteration of pair-rule gene expression in Tc'Krjaws mutants does not suggest a direct role of Tc'Kr in defining specific stripe boundaries as in Drosophila. Together, these findings show that the segmentation function of Krüppel in this short-germ insect is fundamentally different from its role in the long-germ embryo of Drosophila. The role of Tc'Kr in Hox gene regulation, however, is in better accordance to the Drosophila paradigm.
Clinical aspects of Mayer–Rokitansky–Kuester–Hauser syndrome: recommendations for clinical diagnosis and staging
2005-11-11

In accordance with the literature, this study shows that associated malformations are present in more than a third of cases. Therefore, new basic guidelines for standard diagnostic classification involving patients with suspected MRKH are presented.
Blunted hypertensive effect of combined fructose and high-salt diet in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1
2005-11-11

Serum- and glucocorticoid-inducible kinase (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase stimulates the renal epithelial Na + channel and may thus participate in blood pressure regulation. Hyperinsulinemia is triggered by dietary fructose, which sensitizes blood pressure for salt intake. The role of SGK1 in hypertensive effects of combined fructose and high-salt intake was thus explored in SGK1 knockout mice ( sgk1 −/− ) and their wild-type littermates ( sgk1 +/+ ). Renal SGK1 transcript levels of sgk1 +/+ mice were significantly elevated after fructose diet. Under control diet, fluid intake, urinary flow rate, urinary Na + , K + , and Cl − excretion, and blood pressure were similar in sgk1 −/− and sgk1 +/+ mice. Addition of 10% fructose to drinking water increased fluid intake and urinary flow rate in both genotypes, and did not significantly alter urinary Na + , K + , and Cl − output in either genotype. Additional high NaCl diet (4% NaCl) did not significantly alter fluid intake and urine volume but markedly increased urinary output of Na + and Cl − , approaching values significantly ( P &lt; 0.05) larger in sgk1 −/− than in sgk1 +/+ mice (Na + : 2,572 ± 462 vs. 1,428 ± 236; Cl − : 2,364 ± 388 vs. 1,379 ± 225 μmol/24 h). Blood pressure was similar in sgk1 +/+ and sgk1 −/− mice at control diet or fructose alone but increased only in sgk1 +/+ mice (115 ± 1 vs. 103 ± 0.7 mmHg, P &lt; 0.05) after combined fructose and high-salt intake. Acute intravenous insulin infusion (during glucose clamp) caused antinatriuresis in sgk1 +/+ mice, an effect significantly blunted in sgk1 −/− mice. The observations reveal a pivotal role of SGK1 in insulin-mediated sodium retention and the salt-sensitizing hypertensive effect of high fructose intake.
PVC-plasticizer DEHP in medical products: do thin coatings really reduce DEHP leaching into blood?
2005-11-11

The hemocompatibility of artificial surfaces in extracorporeal blood circulation systems can be improved by coatings. According to the literature, heparin coatings should avoid the leaching of the plasticizer di(2-ethylhexyl) phthalate (DEHP) into the blood from components made from plasticized polyvinyl chloride (PVC). DEHP and its metabolites are known to impair the fertility of male rodents; effects on human fertility are assumed. Three different surface coatings with and without heparin were examined in a Chandler Loop model at 37°C using fresh human blood to evaluate their hemocompatibility and barrier property to plasticizer. The levels of toxic oxidation products of DEHP generated in the blood, particularly, were found as high as in the uncoated tubing. The coatings improved the hemocompatibility, but are not safe protection against the hazardous metabolites of DEHP. For pregnant women, neonates and children, we would recommend using the available surface-coated plasticized PVC tubing sets, but free of DEHP.
Cor triventriculare with pericardial aplasia and mitral valve prolapse: a novel congenital dysplastic syndrome?
2005-11-11

A 37-year-old man was admitted to our hospital because of an apical abnormality, which was incidentally detected for the first time 10 years ago by echocardiography. The patient reported on normal physical activity and denied clinical signs of heart failure. His ECG showed antero-septal ST-segment alterations. For further assessment, magnetic resonance imaging was performed on a 1.5 T whole body scanner (Intera CV, Philips Medical Systems, Best, The Netherlands). The four-chamber view displays an ...
Transparent end-host-based service composition through network virtualization
2005-11-11

Mobile devices have become a popular medium for delivering multimedia services to end users. A large variety of solutions have been proposed to flexibly compose such services and to provide quality-of-service guarantees for the resulting contents. However, low-level mobility artifacts resulting from network transitions (disconnected operation, reconfiguration, etc.) still prevent a seamless user experience of these technologies. This paper presents an architecture for supporting legacy applications with such solutions in mobile scenarios. Through network virtualization, it hides mobility artifacts and ensures connectivity at the network and transport level. Its adoption for multimedia applications poses unique challenges and advantages, which are discussed herein.
Combining the enantioselectivity of a cyclodextrin and a diamide selector in a mixed binary gas‐chromatographic chiral stationary phase
2005-11-14

Abstract The present work reports on the investigation of a mixed binary chiral stationary phase (CSP) prepared by simultaneous attachment of permethylated‐β‐cyclodextrin ( D selector) and resorcinarene with pendant l ‐ or d ‐valine diamide groups ( L′ and D′ selectors, respectively) to a polysiloxane matrix via platinum‐catalyzed hydrosilylation. The gas‐chromatographic investigation of a number of racemates on the four different CSPs ( D, D′, DD′, and DL′ ) showed that the enantioselectivity of the individual chiral selectors was retained in the mixed binary CSPs. As a consequence, hydrocarbons, underivatized alcohols, ketones, and almost all proteinogenic amino acid derivatives could be separated simultaneously on each of the mixed CSPs. Matched and mismatched cases of enantioseparation on the mixed binary CSPs were observed but turned out to be of minor importance for enantiomeric separation. In general, more racemates were separated with α ≥ 1.02 on the mixed phases as compared to the single phases. In order to analyze the influence of the presence of the diamide selector on the enantioselectivity of the cyclodextrin selector, a mixed ternary CSP containing the selector D and a racemic mixture of the selectors D′ and L′ [ D ( D′L′ )] was prepared and investigated. Merits and limitations of the approach of mixed binary CSPs are discussed. © 2005 Wiley‐Liss, Inc. Chirality
Multiple synergizing factors contribute to the strength of the CD8+ T cell response against listeriolysin O
2005-11-15

Immunodominance in CD8+ T cell responses against Listeria monocytogenes is a well-recognized but still not fully understood phenomenon. From listeriolysin, the major virulence factor of L. monocytogenes, only a single epitope, pLLO91-99, is presented by MHC class I molecules in BALB/c mice which dominates the cytotoxic T cell response against this bacterial pathogen. To obtain more insights into the molecular and cellular mechanisms underlying immunodominance of this particular epitope, we compared the various steps involved in the presentation and recognition of pLLO91-99 derived from a wild-type toxin with an equivalent epitope from a mutated toxin. This fully functional variant contains within the pLLO91-99 epitope a conservative isoleucine to alanine replacement at the C-terminal anchor residue which results in loss of antigenicity. The binding properties of the variant peptide to soluble Kd remained unaffected and cytotoxic T cells capable of recognizing the pLLO99A/Kd complex were detectable in BALB/c mice. However, such T cells required higher concentrations of antigen in order to be optimally activated in vitro. A comparison between the TAP translocation efficiency of wild-type and mutant peptide demonstrated that the mutation at the C-terminus leads to a reduced transportation rate. Furthermore, the amino acid substitution changes the in vitro proteasomal cleavage pattern, resulting in a reduced liberation of the correct peptide from a polypeptide precursor. Thus, in all assays employed the immunodominant epitope performs optimally while the variant was found to be inferior. The synergy of all these steps most likely is the decisive factor in the immunodominance of pLLO91-99.
A Fully Computational Model for Predicting Percutaneous Drug Absorption
2005-11-16

The prediction of transdermal absorption for arbitrary penetrant structures has several important applications in the pharmaceutical industry. We propose a new data-driven, predictive model for skin permeability coefficients k(p) based on an ensemble model using k-nearest-neighbor models and ridge regression. The model was trained and validated with a newly assembled data set containing experimental data and structures for 110 compounds. On the basis of three purely computational descriptors (molecular weight, calculated octanol/water partition coefficient, and solvation free energy), we have developed a model allowing for the reliable, purely computational prediction of skin permeability coefficients. The model is both accurate and robust, as we showed in an extensive validation (correlation coefficient for leave-one-out cross validation: Q = 0.948, mean standard error: 0.2 for log k(p)).
Acyl Transfer in Clorobiocin Biosynthesis: Involvement of Several Proteins in the Transfer of the Pyrrole‐2‐carboxyl Moiety to the Deoxysugar
2005-11-16

Abstract Clorobiocin is an aminocoumarin antibiotic containing a pyrrole‐2‐carboxyl moiety, attached through an ester bond to a deoxysugar. The pyrrole moiety is important for the binding of the antibiotic to its biological target, gyrase. The complete biosynthetic gene cluster for clorobiocin has been cloned and sequenced from the natural producer, Streptomyces roseochromogenes DS 12.976. In this study, the genes cloN1 and cloN7 were deleted separately from a cosmid containing the complete clorobiocin cluster. The modified cosmids were introduced into the genome of the heterologous host Streptomyces coelicolor M512 by using the integration functions of the ΦC31 phage. While a heterologous producer strain harbouring the intact clorobiocin biosynthetic gene cluster accumulated clorobiocin, the cloN1 ‐ and cloN7 ‐defective integration mutants accumulated a clorobiocin derivative that lacked the pyrrole‐2‐carboxyl moiety, while also producing free pyrrole‐2‐carboxylic acid. The structures of these metabolites were confirmed by NMR and MS analysis. These results showed that CloN1 and CloN7, together with the previously investigated CloN2, are involved in the transfer of the pyrrole‐2‐carboxyl moiety to the deoxysugar of clorobiocin. A possible mechanism for the role of these three proteins in the acyl‐transfer process is suggested.
Combined Modality Treatment of Two or Four Cycles of ABVD Followed by Involved Field Radiotherapy in the Treatment of Patients with Early Stage Hodgkin’s Lymphoma: Update Interim Analysis of the Randomised HD10 Study of the German Hodgkin Study Group (GHSG).
2005-11-16

Abstract Combined modality treatment is regarded as standard by most study groups for patients with early-stage Hodgkin’s lymphoma (HL). However, the optimal chemotherapy, the number of cycles needed and the optimal radiotherapy dose is still unclear. The GHSG thus conducted a randomised study for patients with early stage favourable Hodgkin’s lymphoma (HD10) in which these questions were addressed. A total of 1370 patients were randomised from 5/1998 to 1/2003 between two or four cycles of ABVD and independently to 20Gy or 30Gy involved field (IF) radiotherapy. For the second interim analysis at a median follow up of 28 months, 847 patients were available. Patients were equally balanced for age, gender, stage, histology, performance status and risk factors. Compared with two cycles, there was more toxicity in patients receiving four cycles of ABVD for leucopenia, hair loss and infection. Concerning radiotherapy dose, there was more toxicity associated with 30Gy for dysphagia, mucositis and leucopenia. The rate of complete remissions ranged between 98% and 99% with no significant differences among treatment arms. Freedom from treatment failure (FFTF) and overall survival showed no differences between the four treatment arms. The curves for overall survival and FFTF were nearly superimposable for all four arms. This analysis suggests that 2 chemotherapy cycles with involved field radiotherapy may be sufficient for patients with early favourable HL, but a reliable assessment must await the final analysis including all randomised patients and with adequate follow-up. The results of the third interim analysis (10/2005) including 1110 patients with a median follow up of more than 3 years will be presented.
Regulation of CXCR1, CXCR2 and CXCR4 in Human Neutrophils: Potential Role in the Release from the Bone Marrow, Clearance of Senescent Cells, and Cell Function at Sites of Inflammation.
2005-11-16

Abstract In the mouse model, it has been shown that the interleukin-8 (IL-8) receptor CXCR2 is involved in the release of mature neutrophils from the bone marrow into the circulation. When neutrophils age, upregulation of CXCR4 and downmodulation of CXCR2 result in homing and subsequent sequestration of senescent cells in the bone marrow. In our study, we observed a similar time-dependent (starting at 3 hrs., maximum at 12–18 hrs.) downregulation of CXCR2 in human neutrophils during aging in ex vivo culture, while expression of the second IL-8 receptor CXCR1, which is mainly responsible for the IL-8-induced chemotaxis, was unchanged. Furthermore, strong upregulation of CXCR4 was noted on the cell surface which could not solely be attributed to re-expression of internalized, intracellular receptors, as an increased amount of CXCR4 mRNA was detected by Northern blot analysis in these cells. The increase in CXCR4 expression was not influenced by inflammatory cytokines such as TNF and IL-1, as well as by IL-8 or G-CSF. Accordingly, SDF-1-induced transendothelial migration of aged neutrophils was 6-fold increased and even exceeded migration in response to IL-8. We conclude that also in human neutrophils, loss of CXCR2 and gain of CXCR4 expression on the cell surface may favor homing and sequestration of senescent cells in the bone marrow. At sites of inflammation however, retained expression of CXCR1 and increased expression of CXCR4 still allow a response of aged, pre-apoptotic neutrophils to the chemotactic mediators IL-8 and SDF-1, as the latter is not only released in the bone marrow, but also at sites of tissue damage and necrosis.
Human GITR Ligand Is Expressed on Tumor Cells and Reduces Cytokine Production and Cellular Cytotoxicity of NK Cells Identified to Express GITR.
2005-11-16

Abstract Members of the tumor necrosis factor (TNF) superfamily mediate multiple cellular functions including cellular proliferation, differentiation, and cell death. Human Glucocorticoid-induced TNF Receptor (GITR) has been shown to be expressed on T cells, is upregulated following activation and mediates costimulatory signals. The human GITR ligand (GITRL) has been reported to be expressed on antigen presenting cells and various healthy nonlymphoid tissues including small intestine, ovary, testis, kidney and endothelial cells. We analyzed multiple tumor cell lines of hematopoietic and epithelial origin as well as of germ cell lineage and various gliomas by RT-PCR and FACS analysis. Both GITRL m-RNA and protein are expressed in various carcinomas, gliomas and tumor cells of germ cell lineage, but not in hematopoietic tumor cells. Furthermore, we demonstrate that human NK cells constitutively express low levels of GITR, and this expression is upregulated following activation by, e.g., IL-2 or IL-15 as detected by quantitative PCR and FACS analysis. To address the functional interaction of GITRL with its receptor on NK cells, we generated a GITRL-IgG fusion protein (GITRL-Ig). Stimulation of activated NK cells with GITRL-Ig lead to significantly reduced IFN-g production of NK cells as measured by ELISA. Similarly, a significant reduction of IFN-g release was observed following coculture of GITR expressing NK cells with C1R cells transfected with GITRL but not with the respective mock transfectants. Furthermore, ligation of GITR on NK cells lead to significantly decreased killing of target cells as demonstrated by cellular cytotoxicity assays. Taken together, our data demonstrate that GITR not only plays an important role in adaptive immunity but is also involved in the regulation of NK cell effector functions. Since tumor cells express significant levels of GITRL, and ligation of GITR on NK cells markedly reduces cytokine production and cellular cytotoxicity, our data indicate that GITR-GITRL interactions play an important role in the escape of tumor cells from innate immune surveillance.
Sphingosine 1-Phosphate (S1P) Induces Migration and ERK/MAP-Kinase-Dependent Proliferation in Chronic Lymphocytic Leukemia (B-CLL) Due to Expression of the G Protein-Coupled Receptors S1P1/4.
2005-11-16

Abstract Egress of lymphocytes from lymphoid organs into the circulation has been shown to depend on the presence of the lipid mediator sphingosine 1-phosphate (S1P) in the peripheral blood, and expression of corresponding S1P receptors (i.e., S1P1), that belong to the family of 7-transmembrane G protein-coupled receptors (GPCR). As circulating lymphocytic lymphoma cells are a hallmark of chronic lymphocytic leukemia, we analyzed expression of different S1P receptors and the effects of S1P on B-CLL cells. By qualitative and quantitative (TaqMan) RT-PCR, significant mRNA expression of S1P1 and S1P4 was found in CLL cell lines (EHEB, MEC-1) and in most samples (S1P1 in 88%, S1P4 in 100%) of primary CD19+ cells isolated from the peripheral blood of untreated B-CLL patients. mRNA of other S1P receptors (S1P2, S1P3, S1P5) was less consistently detected. Normal, nonmalignant B cells were strongly positive for S1P1, while other S1P receptors were weakly expressed or negative. S1P induced typical effects of chemotactic GPCR, such as actin polymerization (analyzed by flow cytometry) and chemotaxis (measured in a modified Boyden chamber assay) in CLL cell lines and primary B-CLL cells. After serum deprivation in vitro, S1P induced phosphorylation of ERK/MAP-kinase as analyzed by Western blot, demonstrating that S1P receptors expressed in CLL were able to activate signaling pathways of GPCR not only related to cell migration and chemotaxis, but also to cell proliferation. Of note, the S1P1 ligand FTY720, which induces receptor internalization after prolonged exposure and acts as an antagonist, resulted in apoptosis in CLL cell lines and primary CLL cells in vitro, as measured by MTT-test and staining with Annexin-FITC, respectively. We conclude that sphingosine 1-phosphate, which is present in the peripheral blood in considerable amounts, contributes to the trafficking of B-CLL cells expressing the GPCRs S1P1/4, and to their prolonged survival.
Dose Reduced Conditioning and CD3/CD19 Depletion for Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults: Fast Engraftment and Low Toxicity.
2005-11-16

Abstract Haploidentical hematopoietic cell transplantation (HHCT) has been made feasible with the use of megadoses of CD34+ peripheral blood stem cells. Despite this progress, HHCT is still complicated by high treatment related toxicity, slow engraftment and immune reconstitution. A new regimen using graft CD3/CD19 depletion with anti-CD3- and anti-CD19-coated microbeads on a CliniMACS device and dose reduced conditioning may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer-, dendritic- and graft-facilitating-cells. As dose reduced conditioning fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2) and OKT-3 (5 mg/day, day -5 to +14) without posttransplant immunosuppression was used. So far 9 consecutive adult patients have been transplanted with this regimen. Median age of the patients was 37 (range, 27–58) years and the diagnoses were AML (n=3), ALL (n=3), NHL (n=2) and multiple myeloma (n=1). All patients were high risk with relapse after preceding hematopoietic cell transplantation. The CD3/CD19 depleted haploidentical grafts contained a median of 8 x 10E6 (range, 5.2–17x10E6) CD34+ cells/kg, 6x10E7 (range, 0.02–8.6 x10E7) CD56+ cells/kg and 2x10E4 (range, 0.006–8.2x10E4) CD3+ T-cells/kg. 8 of 9 patients had a donor-recipient KIR-mismatch. The conditioning regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis and nausea. In 4/9 patients reversible peripheral neuropathy grade 2–3 occurred, combined with multifocal leucencephalopathy in one patient. Subsequently the dose of fludarabine was reduced to 150 mg/m2. Engraftment was rapid with median time to neutrophils &amp;gt;500/μL of 13 (range, 10–17) days, platelets &amp;gt;20000/μL of 11 (range, 8–14) days and full donor chimerism after two weeks in all patients. All evaluable patients had fast immune reconstitution with T-cells &amp;gt;100/μL by day +100. Five cases of grade 2 skin GVHD rapidly responded to steroids. Three patients with controlled fungal pneumonia at time of transplant had resolution of infiltrates with neutrophil reconstitution and antifungal therapy. Treatment related mortality in the first 100 days was low with one death due to idiopathic pneumonia syndrome. Three patients died after day 100, one each due to relapse, systemic adenoviral infection and CMV infection. Overall survival is 5/9 patients with a median follow-up of 406 days (range, 44–661). In conclusion, this regimen seems to be promising in adult high risk patients lacking a suitable donor and a prospective phase I/II study is ongoing.