gebhart/patrepeval huggingface dataset:
μ-Amyloid Peptide-induced Apoptosis Regulated by a Novel Protein Containing a G Protein Activation Module (2001)

Degeneration of neurons in Alzheimer's disease is mediated by beta-amyloid peptide by diverse mechanisms, which include a putative apoptotic component stimulated by unidentified signaling events. This report describes a novel beta-amyloid peptide-binding protein (denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved structure. The BBP subtype bound human beta-amyloid peptide in vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to beta-amyloid peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to beta-amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic beta-amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease.
Pharmacology of the Cardiac Sarcoplasmic Reticulum Calcium ATPase‐Phospholamban Interaction (1998)

Accumulating evidence points to the critical role of phospholamban (PLB) regulation of the cardiac sarcoplasmic reticulum (SR) calcium ATPase in influencing the kinetics of calcium handling within the cardiac myocyte under normal and pathological conditions. Based on the data, it has been hypothesized that PLB inhibitors (e.g., calcium ATPase stimulators) would be of potential importance as positive lusitropes and inotropes in the treatment of heart failure. Experiments measuring tension transients in saponin-permeabilized cardiac muscles from genetically engineered mice under a variety of SR calcium loading conditions provide evidence of the functional alterations that can be achieved by manipulation of the degree of PLB inhibition of the calcium pump. Testing of the above hypothesis will ultimately require a selective, high-affinity, membrane-permeable small molecule stimulator of the cardiac calcium pump. Screening for cardiac calcium pump activators has produced a series of agents exerting apparently different mechanisms of action; some may be tools to help to elucidate the nature of the PLB-calcium ATPase interaction(s). The rationale for PLB as a drug target, the optimal profile of a PLB inhibitor, and the properties of several low-molecular-weight compounds will be explored.
Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions. (1992)

Accumulating evidence indicates that lung cancer arises due to multiple genetic changes in both dominant oncogenes, such as ras, and tumor suppressor genes, such as p53. In this report we examined whether the wild-type p53 gene is able to suppress in vitro and/or in vivo cellular growth of lung cancer cell lines which carry multiple genetic abnormalities. Introduction of a wild-type p53 complementary DNA expression vector into lung cancer cell lines carrying either a homozygous deletion (NCI-H358) or a missense mutation (NCI-H23) in the p53 gene greatly suppressed tumor cell growth. In contrast, p53 expression vectors bearing lung cancer derived mutations affecting single amino acids had lost this growth suppressing ability.
Localization of Mesenchymal Cells in Adult Mouse Thymus: Their Abnormal Distribution in Mice With Disorganization of Thymic Medullary Epithelium (2008)

Thymic mesenchymal cells are known to be important for the development of the early fetal thymus into a functionally mature organ supporting T cell differentiation. We examined the expression of mesenchymal markers: pan-mesenchymal marker ER-TR7, desmin, alpha-smooth muscle actin (alpha-SMA), and alpha- and beta-chain of platelet-derived growth factor receptor (PDGFRalpha, PDGFRbeta) in thymi of normal adult mice. Desmin and ER-TR7 revealed specific staining in the capsule, septa, and perivascular cells. Most perivascular cells highly expressed PDGFRbeta at the same levels as desmin. Low expression of PDGFRalpha was detected in the capsule, intralobular septa, and some perivascular cells of normal adult thymi. alpha-SMA, used to identify vascular smooth muscle cells, was detectable on arterioles and some large venules but not on capillaries. Thus, desmin, PDGFRalpha, and PDGFRbeta were localized in the capsule, septa, and perivascular cells in thymus of adult mouse, although there were differences in the expression level among these markers. On the other hand, the expression of mesenchymal markers was detectable in the region of the thymic medullary epithelium of lymphotoxin beta receptor-deficient mice and plt/plt mice, indicating that mesenchymal cells were abnormally localized in the region. These results suggest that disorganization of the medullary epithelium may be accompanied by aberrant distribution of mesenchyme in adult mouse thymus.
Low peak-to-average power ratio for next generation cellular systems with generalized frequency division multiplexing (2013)

With the Internet of Things on the horizon, novel services will impose new challenges upon future cellular systems. One key parameter that influences the energy efficiency is peak-to-average power ratio (PAPR). PAPR is particularly revelant for cheap mass market terminals. In the most recent cellular standard, Long Term Evolution, different waveforms are used in downlink and uplink transmission, to address the issue of nonlinear distortions as a consequence of high PAPR. In this work, generalized frequency division multiplexing (GFDM) is explored as a possible, non-orthogonal waveform for next generation cellular systems. Particular focus lies on the PAPR properties of the generated waveform. First, various filtered multi-carrier techniques, including OFDM, SC-FDE and GFDM, are presented in an unified framework. Second, the PAPR of those schemes is compared in an uplink multiple access scenario. The results show that a non-orthogonal waveform brings additional degrees of freedom, which can be beneficial.
Identifizierung, Bewertung und Anerkennung von non-formal und informell erworbenen Kompetenzen in Österreich (2005)

Wenn es um die Herangehensweise an die Frage der Ermittlung, Bewertung und Anerkennung nicht formaler Kompetenzen geht, so verhält sich Österreich eher zögerlich. Sowohl die bildungspolitische Diskussion als auch die Bildungspraxis sind in diesem Land stark auf Zertifizierung ausgerichtet. Als Ansätze der Zertifizierung nicht formal erworbener Kenntnisse stellt der Autor die "Ausnahmsweise Zulassung zur Lehrabschlussprüfung" (aLAP) und die Berufsreifeprüfung (BRP) dar. Dass es aber auch projektbezogene Ansätze für "weiche" Formen der Sichtbarmachung nicht formal bzw. informell erworbener Kenntnisse gibt, wird mit drei aktuellen Beispielen verdeutlicht: Projekt "Kompetenzerwerb im Freiwilligen Engagement", Vocational Qualification Transfer-System (VQTS), Elemente des Tarifvertrags "Forschungs-KV". (DIPF/Kie.)
Putative reaction mechanism of heterologously expressed octopine dehydrogenase from the great scallop, Pecten maximus (L) (2007)

cDNA for octopine dehydrogenase (ODH) from the adductor muscle of the great scallop, Pecten maximus, was cloned using 5'- and 3'-RACE. The cDNA comprises an ORF of 1197 nucleotides and the deduced amino acid sequence encodes a protein of 399 amino acids. ODH was heterologously expressed in Escherichia coli with a C-terminal penta His-tag. ODH-5His was purified to homogeneity using metal-chelate affinity chromatography and Sephadex G-100 gel filtration. Recombinant ODH had kinetic properties similar to those of wild-type ODH isolated from the scallop's adductor muscle. Site-directed mutagenesis was used to elucidate the involvement of several amino acid residues for the reaction catalyzed by ODH. Cys148, which is conserved in all opine dehydrogenases known to date, was converted to serine or alanine, showing that this residue is not intrinsically important for catalysis. His212, Arg324 and Asp329, which are also conserved in all known opine dehydrogenase sequences, were subjected to site-directed mutagenesis. Modification of these residues revealed their importance for the catalytic activity of the enzyme. Conversion of each of these residues to alanine resulted in strong increases in K(m) and decreases in k(cat) values for pyruvate and L-arginine, but had little effect on the K(m) and k(cat) values for NADH. Assuming a similar structure for ODH compared with the only available structure of a bacterial opine dehydrogenase, these three amino acids may function as a catalytic triad in ODH similar to that found in lactate dehydrogenase or malate dehydrogenase. The carboxyl group of pyruvate is then stabilized by Arg324. In addition to orienting the substrate, His212 will act as an acid-base catalyst by donating a proton to the carbonyl group of pyruvate. The acidity of this histidine is further increased by the proximity of Asp329.
Homing of mucosal leukocytes to joints. Distinct endothelial ligands in synovium mediate leukocyte-subtype specific adhesion. (1997)

Inflammation and infection of the gut can be followed by reactive arthritis at a distant joint. Leukocyte recruitment into synovium is essential for this process, but nothing is known about the endothelial adhesion molecules in synovial membrane which direct the homing of activated, gut-derived leukocytes to joints. Here we analyzed the expression of the known endothelial adhesion molecules in inflamed synovium and their function in binding of mucosal leukocytes. Intercellular adhesion molecule-1 (ICAM-1/CD54) and vascular adhesion protein-1 (VAP-1) were most prominently expressed in synovial vessels. All other adhesion molecules were found at lower levels in inflamed synovia, except mucosal addressin which was absent. Binding of macrophages isolated from lamina propria of the gut to synovial endothelium was almost entirely P-selectin-dependent. In contrast, small intestinal lymphocytes and immunoblasts both relied mainly on VAP-1 in recognition of synovial vessels. Thus, endothelial P-selectin and VAP-1 mediate binding of mucosal effector cells to synovium in a leukocyte subtype-selective manner. Antiadhesive therapy against these inducible molecules should ablate the pathogenetic cascade leading to inappropriate homing of leukocytes to joints in arthritis.
CDC20 and CDH1 : A Family of Substrate-Specific Activators of APC-Dependent Proteolysis (1997)

Proteolysis mediated by the anaphase-promoting complex (APC) triggers chromosome segregation and exit from mitosis, yet its regulation is poorly understood. The conserved Cdc20 and Cdh1 proteins were identified as limiting, substrate-specific activators of APC-dependent proteolysis. CDC20 was required for the degradation of the APC substrate Pds1 but not for that of other APC substrates, such as Clb2 and Ase1. Conversely, cdh1Delta mutants were impaired in the degradation of Ase1 and Clb2 but not in that of Pds1. Overexpression of either CDC20 or CDH1 was sufficient to induce APC-dependent proteolysis of the appropriate target in stages of the cell cycle in which substrates are normally stable.
The Bile Acid Taurochenodeoxycholate Activates a Phosphatidylinositol 3-Kinase-dependent Survival Signaling Cascade (2000)

Liver injury during cholestasis reflects a balance between the effects of toxic and nontoxic bile acids. However, the critical distinction between a toxic and nontoxic bile acid remains subtle and unclear. For example, the glycine conjugate of chenodeoxycholate (GCDC) induces hepatocyte apoptosis, whereas the taurine conjugate (TCDC) does not. We hypothesized that the dissimilar cellular responses may reflect differential activation of a phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway. In the bile acid-transporting McNtcp.24 rat hepatoma cell line, TCDC, but not GCDC, stimulated PI3K activity. Consistent with this observation, inhibition of PI3K rendered TCDC cytotoxic, and constitutive activation of PI3K rendered GCDC nontoxic. Both Akt and the atypical protein kinase C isoform zeta (PKCzeta) have been implicated in PI3K-dependent survival signaling. However, TCDC activated PKCzeta, but not Akt. Moreover, inhibition of PKCzeta converted TCDC into a cytotoxic agent, whereas overexpression of wild-type PKCzeta blocked GCDC-induced apoptosis. We also demonstrate that TCDC activated nuclear factor kappaB (NF-kappaB) in a PI3K- and PKCzeta-dependent manner. Moreover, inhibition of NF-kappaB by an IkappaB super-repressor rendered TCDC cytotoxic, suggesting that NF-kappaB is also necessary to prevent the cytotoxic effects of TCDC. Collectively, these data suggest that some hydrophobic bile acids such as TCDC activate PI3K-dependent survival pathways, which prevent their otherwise inherent toxicity.
Construction of a clonable, infectious, and tumorigenic mouse mammary tumor virus provirus and a derivative genetic vector. (1988)

Molecular genetic studies of mouse mammary tumor virus (MMTV) have been hampered by the difficulty of cloning proviruses of milk-borne strains because of inhibitory sequences located in the gag gene. To surmount this barrier we have constructed a hybrid MMTV provirus composed of clonable 5' sequences (encompassing gag) from an endogenous MMTV provirus of C3H mice (Mtv-1) and 3' sequences from the milk-borne strain of MMTV in C3H mice, MMTV(C3H). Virions produced from XC cells transfected with this hybrid provirus are infectious in cell culture and tumorigenic in BALB/cJ mice. A vector derived from this provirus, containing the neomycin phosphotransferase gene (neo) and origins of replication from simian virus 40 and pBR322, is capable of transferring G418 resistance by virus infection in cell culture when supplied with viral proteins from either MMTV(C3H) or the hybrid MMTV. Expression of both hybrid and vector proviruses is inducible by dexamethasone in infected cells.
Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN (2009)

The metabolic disorders that predispose patients to NASH (non-alcoholic steatohepatitis) include insulin resistance and obesity. Repeated hypoxic events, such as occur in obstructive sleep apnoea syndrome, have been designated as a risk factor in the progression of liver disease in such patients, but the mechanism is unclear, in particular the role of hypoxia. Therefore we studied the influence of hypoxia on the development and progression of steatohepatitis in an experimental mouse model. Mice with a hepatocellular-specific deficiency in the Pten (phosphatase and tensin homologue deleted on chromosome 10) gene, a tumour suppressor, were exposed to a 10% O2 (hypoxic) or 21% O2 (control) atmosphere for 7 days. Haematocrit, AST (aspartate aminotransferase), glucose, triacylglycerols (triglycerides) and insulin tolerance were measured in blood. Histological lesions were quantified. Expression of genes involved in lipogenesis and mitochondrial beta-oxidation, as well as FOXO1 (forkhead box O1), hepcidin and CYP2E1 (cytochrome P450 2E1), were analysed by quantitative PCR. In the animals exposed to hypoxia, the haematocrit increased (60+/-3% compared with 50+/-2% in controls; P<0.01) and the ratio of liver weight/body weight increased (5.4+/-0.2% compared with 4.7+/-0.3% in the controls; P<0.01). Furthermore, in animals exposed to hypoxia, steatosis was more pronounced (P<0.01), and the NAS [NAFLD (non-alcoholic fatty liver disease) activity score] (8.3+/-2.4 compared with 2.3+/-10.7 in controls; P<0.01), serum AST, triacylglycerols and glucose were higher. Insulin sensitivity decreased in mice exposed to hypoxia relative to controls. The expression of the lipogenic genes SREBP-1c (sterol-regulatory-element-binding protein-1c), PPAR-gamma (peroxisome-proliferator-activated receptor-gamma), ACC1 (acetyl-CoA carboxylase 1) and ACC2 (acetyl-CoA carboxylase 2) increased significantly in mice exposed to hypoxia, whereas mitochondria beta-oxidation genes [PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and CPT-1 (carnitine palmitoyltransferase-1)] decreased significantly. In conclusion, the findings of the present study demonstrate that hypoxia alone aggravates and accelerates the progression of NASH by up-regulating the expression of lipogenic genes, by down-regulating genes involved in lipid metabolism and by decreasing insulin sensitivity.
Enhanced flexor tendon healing through controlled delivery of PDGF‐BB (2009)

A fibrin/heparin-based delivery system was used to provide controlled delivery of platelet derived growth factor BB (PDGF-BB) in an animal model of intrasynovial flexor tendon repair. We hypothesized that PDGF-BB, administered in this manner, would stimulate cell proliferation and matrix remodeling, leading to improvements in the sutured tendon's functional and structural properties. Fifty-six flexor digitorum profundus tendons were injured and repaired in 28 dogs. Three groups were compared: (1) controlled delivery of PDGF-BB using a fibrin/heparin-based delivery system; (2) delivery system carrier control; and (3) repair- only control. The operated forelimbs were treated with controlled passive motion rehabilitation. The animals were euthanized at 7, 14, and 42 days, at which time the tendons were assessed using histologic (hyaluronic acid content, cellularity, and inflammation), biochemical (total DNA and reducible collagen crosslink levels), and biomechanical (gliding and tensile properties) assays. We found that cell activity (as determined by total DNA, collagen crosslink analyses, and hyaluronic acid content) was accelerated due to PDGF-BB at 14 days. Proximal interphalangeal joint rotation and tendon excursion (i.e., tendon gliding properties) were significantly higher for the PDGF-BB-treated tendons compared to the repair-alone tendons at 42 days. Improvements in tensile properties were not achieved, possibly due to suboptimal release kinetics or other factors. In conclusion, PDGF-BB treatment consistently improved the functional but not the structural properties of sutured intrasynovial tendons through 42 days following repair.
Fabrication of multilayered microfluidic 3D polymer packages (2005)

The realization of microfluidic packages by stacking and bonding several layers of microstructured polymer films opens up the potential of creating complex three-dimensional microfluidic structures based on relatively simple two-dimensional manufacturing processes. Whereas a multitude of microstructuring techniques have been developed, packaging and bonding technologies for multilayer microfluidic devices are still underrepresented. Bulk bonding processes like thermal diffusion bonding fit well into a lab environment, but feature extensive bonding times. With increasing fluidic complexity, bonding technologies that enable selective bonding and sealing at pre-selected areas (e.g. around channel walls or process chambers) are required. Selective bonding technologies enable a localized heat generation exactly at the desired bond position and thus significantly reduce the risk of structure deformation and channel clogging. In this paper, experimental results for a variety of bulk and selective bonding methods are reported and compared. Surface modification of polymers and lasers welding of polymer sheets are identified as suitable technologies for integration with high-throughput production environments.
Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells (2013)

Hematopoietic stem and progenitor cells, as well as nucleated erythroblasts and megakaryocytes, reside preferentially in adult marrow microenvironments whereas other blood cells readily cross the endothelial barrier into the circulation. Because the nucleus is the largest organelle in blood cells, we hypothesized that (i) cell sorting across microporous barriers is regulated by nuclear deformability as controlled by lamin-A and -B, and (ii) lamin levels directly modulate hematopoietic programs. Mass spectrometry-calibrated intracellular flow cytometry indeed reveals a lamin expression map that partitions human blood lineages between marrow and circulating compartments (P = 0.00006). B-type lamins are highly variable and predominate only in CD34(+) cells, but migration through micropores and nuclear flexibility in micropipette aspiration both appear limited by lamin-A:B stoichiometry across hematopoietic lineages. Differentiation is also modulated by overexpression or knockdown of lamins as well as retinoic acid addition, which regulates lamin-A transcription. In particular, erythroid differentiation is promoted by high lamin-A and low lamin-B1 expression whereas megakaryocytes of high ploidy are inhibited by lamin suppression. Lamins thus contribute to both trafficking and differentiation.
Synthesis and properties of polyurethanes derived from diaminodianhydroalditols (1986)

Abstract The readily accessible 1,4:3,6‐dianhydroalditols with D‐gluco‐ ( 1 ), L‐ido‐ ( 5 ) and D‐mannoconfigurations ( 6 ) were efficiently transformed into the 2,5‐diamino‐1,4:3,6‐dianhydro‐2,5‐dideoxyalditols with D‐gluco‐ ( 10 ), D‐manno‐ ( 13 ), and L‐ido‐configuration ( 16 ). Interfacial polycondensation of these chiral heterocyclic diamines as well as ethylene‐ and tetramethylene diamine with the bis(chloroformate) 3 derived from 1,4:3,6‐dianhydro‐D‐sorbitol gave the polyurethanes 17 to 21 . Their number‐average molecular weights were determined to be M̄ n ≈ 3000 corresponding to an average degree of polymerisation P̄ n ≈ 20. Inherent viscosities were measured, and 1 H NMR spectroscopy as well as DSC gave informations about the molecular structure and some polymer properties.
Critical Role of Endothelial Notch1 Signaling in Postnatal Angiogenesis (2006)

Notch receptors are important mediators of cell fate during embryogenesis, but their role in adult physiology, particularly in postnatal angiogenesis, remains unknown. Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow recovery and postnatal neovascularization in response to hindlimb ischemia in haploinsufficient global or endothelial-specific Notch1(+/-) mice, but not Notch4(-/-) mice, were impaired compared with wild-type mice. The expression of vascular endothelial growth factor (VEGF) in response to ischemia was comparable between wild-type and Notch mutant mice, suggesting that Notch1 is downstream of VEGF signaling. Treatment of endothelial cells with VEGF increases presenilin proteolytic processing, gamma-secretase activity, Notch1 cleavage, and Hes-1 (hairy enhancer of split homolog-1) expression, all of which were blocked by treating endothelial cells with inhibitors of phosphatidylinositol 3-kinase/protein kinase Akt or infecting endothelial cells with a dominant-negative Akt mutant. Indeed, inhibition of gamma-secretase activity leads to decreased angiogenesis and inhibits VEGF-induced endothelial cell proliferation, migration, and survival. Overexpression of the active Notch1 intercellular domain rescued the inhibitory effects of gamma-secretase inhibitors on VEGF-induced angiogenesis. These findings indicate that the phosphatidylinositol 3-kinase/Akt pathway mediates gamma-secretase and Notch1 activation by VEGF and that Notch1 is critical for VEGF-induced postnatal angiogenesis. These results suggest that Notch1 may be a novel therapeutic target for improving angiogenic response and blood flow recovery in ischemic limbs.