gebhart/patrepeval huggingface dataset:
New liquid crystalline di- and tetra-acrylates for network formation (2001)

New liquid crystalline diacrylates and tetra-acrylates containing four to six aromatic rings were synthesized and characterized, and their mesophase behaviour was investigated. They are designed to be used in combination with chiral molecules to form cholesteric mesophases which can be crosslinked by photopolymerization. The acrylates presented exhibit broad mesophase ranges since mesogenic moieties longer than three are employed. Most diacrylates show no isotropization, due to premature thermal polymerization above 180°C. Additionally, liquid crystalline dipropionates were synthesized as reference compounds which cannot be crosslinked, and selected examples of these exhibit isotropization temperatures as high as 238°C prior to thermal degradation. Substituents at the mesogenic moiety have a great influence on the mesophase characteristics. Bulky substituents such as the tert-butyl group, induce a nematic mesophase, whereas compounds with small substituents (e.g. OCH3) or unsubstituted molecules also exhibit smectic phases. Tetra-acrylates with unsubstituted and substituted mesogenic units feature nematic mesophases only as a result of the additional spacers attached. Here isotropization was observed without polymerization at temperatures around 120-160°C.
E-Mail-Marketing (2003)

Nein, gleich vorneweg: E-Mail-Marketing ist nicht gleichzusetzen mit der Zusendung unerwünschter Werbemails! E-Mail-Marketing, richtig verstanden und eingesetzt, ist ein smartes und effizientes Werbetool, das aus dem modernen Kommunikationsmix nicht mehr wegzudenken ist. Und es hat viele Vorteile: E-Mail-Marketing ist schnell, individuell, ortsunabhängig und effektiv. E-Mail-Marketing bedeutet Zwei-Wege-Kommunikation und Kundenorientierung. Und noch mehr Lob: Die notwendige technische Infrastruktur lässt sich rasch und kostengünstig einführen, durch verschiedene Formate lassen sich unterschiedlichste Ziele verfolgen, die Auswertung kann zeitnah erfolgen und ermöglicht schnelle Optimierungen. E-Mail-Marketing funktioniert als eigenständiges Instrument und als Bestandteil integrierter Kampagnen. Der Kreativität sind bei der Gestaltung und Konzeption kaum Grenzen gesetzt, und es eröffnen sich neue Möglichkeiten des Dialogs mit dem Kunden.
Spontaneous Development of Psoriasis in a New Animal Model Shows an Essential Role for Resident T Cells and Tumor Necrosis Factor-α (2004)

Psoriasis is a common T cell-mediated autoimmune disorder where primary onset of skin lesions is followed by chronic relapses. Progress in defining the mechanism for initiation of pathological events has been hampered by the lack of a relevant experimental model in which psoriasis develops spontaneously. We present a new animal model in which skin lesions spontaneously developed when symptomless prepsoriatic human skin was engrafted onto AGR129 mice, deficient in type I and type II interferon receptors and for the recombination activating gene 2. Upon engraftment, resident human T cells in prepsoriatic skin underwent local proliferation. T cell proliferation was crucial for development of a psoriatic phenotype because blocking of T cells led to inhibition of psoriasis development. Tumor necrosis factor-alpha was a key regulator of local T cell proliferation and subsequent disease development. Our observations highlight the importance of resident T cells in the context of lesional tumor necrosis factor-alpha production during development of a psoriatic lesion. These findings underline the importance of resident immune cells in psoriasis and will have implications for new therapeutic strategies for psoriasis and other T cell-mediated diseases.
Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain‐induced cardiovascular differentiation (2006)

Growing stem cells are subjected to mechanical forces, which may initiate differentiation programs. Mechanical strain stimulated cardiovascular differentiation of mouse embryonic stem (ES) cells as evaluated by quantification of contracting cardiac foci and capillary areas, respectively. Mechanical strain rapidly elevated intracellular reactive oxygen species (ROS). After 24 h up-regulation of NADPH oxidase subunits p22-phox, p47-phox, p67-phox, and Nox-4 as well as Nox-1 and Nox-4 mRNA was observed. In parallel, mechanical strain increased hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) mRNA and protein as well as MEF2C and GATA-4 mRNA, which are involved in cardiovascular development. Furthermore, phosphorylation of extracellular-regulated kinase 1,2 (ERK1,2), p38, and c-jun N-terminal kinase (c-Jun NH2-terminal kinase (JNK)) was observed. Stimulation of cardiovascular commitment, HIF-1alpha, VEGF, and MEF2C expression as well as MAPK activation were abolished by free radical scavengers, whereas GATA-4 expression was increased. Cardiomyogenesis was inhibited by the p38 inhibitor SB203580, the ERK1,2 inhibitor UO126, and the JNK inhibitor SP600125. Vasculogenesis/angiogenesis was blunted following inhibition of ERK1,2 and JNK, whereas p38 inhibition was ineffective. Our data outline a role of ROS as mechanotransducing molecules in mechanical strain-stimulated cardiovascular differentiation of ES cells, and point toward a microenvironment of elevated ROS required for signaling cascades initiating cardiovascular differentiation programs.
Optimality of Mutation and Selection in Germinal Centers (2010)

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the approximately 100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understanding of the functions of germinal centers.
RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells (2015)

The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination. In addition, previous experiments in budding yeast have shown that the same activity of Rad54 removes Rad51 from undamaged sites on chromosomes; mutants lacking Rad54 accumulate nonrepair-associated complexes that can block growth and lead to chromosome loss. Here, we show that human RAD54 also promotes the dissociation of RAD51 from dsDNA and not ssDNA. We also show that translocase depletion in tumor cell lines leads to the accumulation of RAD51 on chromosomes, forming complexes that are not associated with markers of DNA damage. We further show that combined depletion of RAD54L and RAD54B and/or artificial induction of RAD51 overexpression blocks replication and promotes chromosome segregation defects. These results support a model in which RAD54L and RAD54B counteract genome-destabilizing effects of direct binding of RAD51 to dsDNA in human tumor cells. Thus, in addition to having genome-stabilizing DNA repair activity, human RAD51 has genome-destabilizing activity when expressed at high levels, as is the case in many human tumors.
Floral Induction of Vegetative Plants Supplied a Purified Fraction of Deoxyribonucleic Acid from Stems of Flowering Plants (1977)

It has been found that floral induced stems of flowering tobacco (Nicotiana tabacum cv. Wis. 38) plants contain large amounts of rapidly renaturing DNA, whereas noninduced stems of vegetative plants contain only small amounts. In addition, it has been shown that the striking qualitative difference in DNA between stems of flowering and vegetative plants mimics the over-all quantitative difference in DNA content (on a fresh weight basis). Therefore, the extra DNA in stems of flowering plants seems, at least in part, to represent preferential synthesis of rapidly renaturing DNA.Rapidly renatured DNA (flowering plants) has been purified (cesium chloride gradients) from heated-cooled DNA solution and under noninductive conditions has been tested for floral activity. It has been found that when rapidly renatured DNA in buffer solution is supplied to axillary vegetative buds of vegetative plants and then the axillary buds are defoliated every 4th day for 12 days, the treated buds change into flower buds. On the other hand, control axillary buds supplied buffer solution alone remain vegetative.In stem segments from flowering plants, the concept, discussed in previous reports, that indole-3-acetic acid may modify in vitro bud expression by directly affecting DNA synthesis has been reviewed. On the basis of this report, the concept is elaborated by proposing here that indole-3-acetic acid may act partially in bud expression by directly suppressing synthesis of rapidly renaturing DNA.
Conformationally Constrained Butyrophenones with Affinity for Dopamine (D1, D2, D4) and Serotonin (5-HT2A, 5-HT2B, 5-HT2C) Receptors:  Synthesis of Aminomethylbenzo[b]furanones and Their Evaluation as Antipsychotics (2000)

A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D(1), D(2), D(4)) and serotonin receptors (5-HT(2A), 5-HT(2B), 5-HT(2C)), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT(2A) receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)p iperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs.
A Stoichiometric Aromatic CH Borylation Catalyzed by Iridium( I )/2,2′‐Bipyridine Complexes at Room Temperature (2002)

Room-temperature CH borylation using a stoichiometric amount of arenes and bis(pinacolato)diboron (pin2B2) is efficiently catalyzed by iridium(I) complexes generated from [{Ir(OMe)(cod)}2] (cod=1,5-cyclooctadiene) and 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) in hexane, and provides the corresponding arylboronates in excellent yields [Eq. (1)].
Replacement of interleukin-2 (IL-2)-generated mitogenic signals by a mink cell focus-forming (MCF) or xenotropic virus-induced IL-9-dependent autocrine loop: implications for MCF virus-induced leukemogenesis (1994)

In earlier studies, we have shown that superinfection of an interleukin-2 (IL-2)-dependent, Moloney murine leukemia virus (MoMuLV)-induced rat T-cell lymphoma line (4437A) with mink cell focus-forming (also called polytropic) murine retroviruses induces rapid progression to IL-2-independent growth. In this report, we present evidence that the vast majority (> 90%) of the IL-2-independent lines established from polytropic or xenotropic virus-infected 4437A cells carry provirus insertions in the 3' untranslated region of the IL-9 receptor gene (Gfi-2 [for growth factor independence-2]/IL-9R). Prior to superinfection, the cells express neither IL-9 nor IL-9R. Following superinfection and provirus insertion in the Gfi-2/IL-9R locus, the cells express high levels of mRNA transcripts with a truncated 3' untranslated region which are predicted to encode the normal IL-9R protein product. The same IL-2-independent cells also express IL-9 which is induced by an insertional mutagenesis-independent mechanism. The establishment of an IL-9-dependent autocrine loop was sufficient to render the cells IL-2 independent, as suggested by the finding that 4437A cells, expressing a stably transfected Gfi-2/IL-9R construct, do not require IL-2 when maintained in IL-9-containing media. Additional experiments designed on the basis of these results showed that IL-9 gene expression is induced rapidly following the infection of 4437A cells by polytropic or xenotropic viruses and occurs in the absence of selection for IL-2-independent growth. Taken together, these data suggest that infection of 4437A cells by mink cell focus-forming or xenotropic viruses induces the expression of IL-9, which in turn rapidly selects the cells expressing the IL-9 receptor through an insertional mutagenesis-dependent mechanism. Given that both the polytropic and xenotropic viruses can induce the IL-9-dependent autocrine loop, the reduced ability of the xenotropic viruses to rapidly induce IL-2 independence in culture and tumors in animals is likely to be the result of their lower growth rates.
SURGICAL DECOMPRESSION OF BRANCH RETINAL VEIN OCCLUSION VIA ARTERIOVENOUS CROSSING SHEATHOTOMY: A Prospective Review of 15 Cases (1999)

Surgical decompression of BRVO via A/V crossing sheathotomy is a technically feasible procedure that can result in rapid reperfusion of the retina. Resolution of macular hemorrhage, edema, and ischemia may improve visual prognosis in patients with this common retinal vascular disorder.
Polymorphisms in RET and Its Coreceptors and Ligands as Genetic Modifiers of Multiple Endocrine Neoplasia Type 2A (2006)

Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series.
Dual roles of Wnt signaling during chondrogenesis in the chicken limb (2000)

Long bones of the appendicular skeleton are formed from a cartilage template in a process known as endochondral bone development. Chondrocytes within this template undergo a progressive program of differentiation from proliferating to postmitotic prehypertrophic to hypertrophic chondrocytes, while mesenchymal cells immediately surrounding the early cartilage template form the perichondrium. Recently, members of the Wnt family of secreted signaling molecules have been implicated in regulating chondrocyte differentiation. We find that Wnt-5a, Wnt-5b and Wnt-4 genes are expressed in chondrogenic regions of the chicken limb: Wnt-5a is expressed in the perichondrium, Wnt-5b is expressed in a subpopulation of prehypertrophic chondrocytes and in the outermost cell layer of the perichondrium, and Wnt-4 is expressed in cells of the joint region. Misexpression experiments demonstrate that two of these Wnt molecules, Wnt-5a and Wnt-4, have opposing effects on the differentiation of chondrocytes and that these effects are mediated through divergent signaling pathways. Specifically, Wnt-5a misexpression delays the maturation of chondrocytes and the onset of bone collar formation, while Wnt-4 misexpression accelerates these two processes. Misexpression of a stabilized form of beta-catenin also results in accelerated chondrogenesis, suggesting that a beta-catenin/TCF-LEF complex is involved in mediating the positive regulatory effect of Wnt-4. A number of the genes involved in Wnt signal tranduction, including two members of the Frizzled gene family, which are believed to encode Wnt-receptors, show very dynamic and distinct expression patterns in cartilaginous elements of developing chicken limbs. Misexpression of putative dominant-negative forms of the two Frizzled proteins results in severe shortening of the infected cartilage elements due to a delay in chondrocyte maturation, indicating that an endogenous Wnt signal does indeed function to promote chondrogenic differentiation.
Pharmacokinetics of sulbactam and ampicillin intravenously applied in combination to healthy volunteers and patients. Determination of the ratio of the two drugs in serum and in various tissues. (1988)

The pharmacokinetics of sulbactam, a new beta-lactamase inhibitor, and ampicillin were investigated in 9 healthy volunteers and 125 patients. The two drugs were administered intravenously in combination (Unacid). Each subject received 1 g sulbactam and 2 g ampicillin. The two drugs showed a similar pharmacokinetic profile in humans. Relevant pharmacokinetic parameters were calculated using a 2-compartment model on the basis of the serum and urine concentrations determined in healthy volunteers. The ratio of sulbactam to ampicillin was found to be nearly constant (approx. 1:2), both in the blood, in several tissues and at various time points. The two compounds apparently penetrated well into the myometrium, renal cortex and medulla, the gall bladder wall, the tonsils and the cutis of the skin. The sulbactam/ampicillin ratios in the bile ranged from 1:3 to 1:13 over 2 h after the infusion. The concentrations of the two compounds measured in the various fluids and tissues of the body reached levels which are effective against beta-lactamase producing bacteria. The similar pharmacokinetics of sulbactam and ampicillin in humans are considered an essential prerequisite for the therapeutic efficacy of such a combination product.
Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload (2011)

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders.
ASIC design system for radiation environments (2002)

A complete radiation hardened ASIC design system, under development by a three company team is described. The compiler approach design system, with radiation hardness tunable library cells, allows the designer to concentrate on the circuit design rather than the details of hardness affecting geometry layout. The designer must be aware of the hardness requirements and the limitations of the available compilable process technologies, but is not burdened with the transistor level design techniques to achieve the hardness desired.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Genome-Wide Survey of SNP Variation Uncovers the Genetic Structure of Cattle Breeds (2009)

The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans.
Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture (2004)

The transthyretin (TTR) amyloidoses are human diseases in which the misfolded TTR protein aggregates in tissues with subsequent visceral, peripheral, and autonomic nerve dysfunction. Recent reports have stressed the importance of oligomeric intermediates as major cytotoxic species in various forms of amyloidogenesis. We have examined the cytotoxic effects of several quaternary structural states of wild-type and variant TTR proteins on cells of neural lineage. TTR amyloid fibrils and soluble aggregates >100 kDa were not toxic. Incubation of TTR under the conditions of the cell assay and analysis by size-exclusion chromatography and SDS/PAGE reveal that monomeric TTR or relatively small, rapidly formed aggregates of a maximum size of six subunits were the major cytotoxic species. Small molecules that stabilize the native tetrameric state were shown to prevent toxicity. The studies are consistent with a model in which the misfolded TTR monomer rapidly aggregates to form transient low molecular mass assemblies (<100 kDa) that are highly cytotoxic in tissue culture.