gebhart/patrepeval huggingface dataset:
Neutralizing anti‐interferon‐α antibodies and response to treatment in patients with Ph+ chronic myeloid leukaemia sequentially treated with recombinant (α2a) and lymphoblastoid interferon‐α (1996)

Neutralizing anti-IFN alpha antibodies (nIFN alpha Abs) occur in a significant proportion of patients with hairy cell leukaemia, hepatitis or solid tumours treated with recombinant IFN alpha (IFN alpha 2a or IFN alpha 2b), but information on their incidence in chronic myeloid leukaemia (CML) is scanty and their clinical relevance is not yet completely defined. By using an IFN alpha antiviral neutralization bioassay, the frequency of nIFN alpha 2a Abs was evaluated in 67Ph+ CML patients during IFN alpha 2a therapy at doses ranging from 6 to 9 MU/d. 15 patients (22%) developed nIFN alpha 2a Abs (titre ranging from 1:40 to 1:20480) and 11/15 (73%) were haematologically and/or karyotypically unresponsive to treatment. 52 patients did not develop antibodies and 11 of them (21%) were unresponsive. The negative relationship between the positivity for nIFN alpha 2a Abs and the response to treatment was highly significant (P = 0.0001). In nine nIFN alpha 2a Abs positive patients, treatment was changed from recombinant IFN alpha 2a to lymphoblastoid IFN alpha (IFN alpha-ly), at the same dose and schedule. After 9 months of IFN alpha-ly treatment a haematological response was achieved in 4/7 cases who were non-responsive to prior IFN alpha 2a therapy and was maintained in the other two patients previously responsive to IFN alpha 2a. However, no karyotypic response was observed. This data shows that a significant proportion of Ph+ CML patients receiving treatment with IFN alpha 2a can develop neutralizing antibodies and that these antibodies are associated with a loss of IFN alpha 2a efficacy. Changing the patients to treatment with lymphoblastoid IFN alpha may restore haematological response but it is not likely to induce a karyotypic response.
Identification and preliminary characterization of protein-cysteine farnesyltransferase. (1990)

Ras proteins must be isoprenylated at a conserved cysteine residue near the carboxyl terminus (Cys-186 in mammalian Ras p21 proteins) in order to exert their biological activity. Previous studies indicate that an intermediate in the mevalonate pathway, most likely farnesyl pyrophosphate, is the donor of this isoprenyl group. Inhibition of mevalonate synthesis reverts the abnormal phenotypes induced by the mutant RAS2Val-19 gene in Saccharomyces cerevisiae and blocks the maturation of Xenopus oocytes induced by an oncogenic Ras p21 protein of human origin. These results have raised the possibility of using inhibitors of the mevalonate pathway to block the transforming properties of ras oncogenes. Unfortunately, mevalonate is a precursor of various end products essential to mammalian cells, such as dolichols, ubiquinones, heme A, and cholesterol. In this study, we describe an enzymatic activity(ies) capable of catalyzing the farnesylation of unprocessed Ras p21 proteins in vitro at the correct (Cys-186) residue. This farnesylating activity is heat-labile, requires Mg2+ or Mn2+ ions, is linear with time and with enzyme concentration, and is present in all mammalian cell lines and tissues tested. Gel filtration analysis of a partially purified preparation of protein farnesyltransferase revealed two peaks of activity at 250-350 kDa and 80-130 kDa. Availability of an in vitro protein farnesyltransferase assay should be useful in screening for potential inhibitors of ras oncogene function that will not interfere with other aspects of the mevalonate pathway.
Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions (2012)

Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.
Repression of c-Kit and Its Downstream Substrates by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation (2005)

Stem cell factor (SCF), erythropoietin (Epo), and GATA-1 play an essential role(s) in erythroid development. We examined how these proteins interact functionally in G1E cells, a GATA-1(-) erythroblast line that proliferates in an SCF-dependent fashion and, upon restoration of GATA-1 function, undergoes GATA-1 proliferation arrest and Epo-dependent terminal maturation. We show that SCF-induced cell cycle progression is mediated via activation of the Src kinase/c-Myc pathway. Restoration of GATA-1 activity induced G1 cell cycle arrest coincident with repression of c-Kit and its downstream effectors Vav1, Rac1, and Akt. Sustained expression of each of these individual signaling components inhibited GATA-1-induced cell cycle arrest to various degrees but had no effects on the expression of GATA-1-regulated erythroid maturation markers. Chromatin immunoprecipitation analysis revealed that GATA-1 occupies a defined Kit gene regulatory element in vivo, suggesting a direct mechanism for gene repression. Hence, in addition to its well-established function as an activator of erythroid genes, GATA-1 also participates in a distinct genetic program that inhibits cell proliferation by repressing the expression of multiple components of the c-Kit signaling axis. Our findings reveal a novel aspect of molecular cross talk between essential transcriptional and cytokine signaling components of hematopoietic development.
Titanium complexes of amidophosphinimide ligands (2009)

The tripodal phosphines MeC(CH(2)NMe)(3)P and N(CH(2)CH(2)NMe)(3)P were converted to the corresponding phosphinimines and the corresponding Ti-complexes MeC(CH(2)NMe)(3)PNTiCpCl(2) and N(CH(2)CH(2)NMe)(3)PNTiCpCl(2) were prepared. These species were also alkylated to give the corresponding dimethyl derivatives. Preliminary attempts to utilize these species in the polymerization of ethylene with MAO as the activator resulted in all but negligible activity. An alternative synthetic approach utilizing the bis-phosphinimine (CH(2)(Me)NPtBu(2))(2) was developed to prepare (CH(2)(Me)NP(tBu(2))NSiMe(3))(2), (CH(2)(Me)NP(tBu(2))NH)(2) and subsequently [(CH(2)(Me)NP(tBu(2))N)(2)]Ti(NMe(2))(2) , [(CH(2)(Me)NP(tBu(2))N)(2)]TiCl(2) and [(CH(2)(Me)NP(tBu(2))N)(2)]TiMe(2). For comparison purposes the related species [tBu(2)(Me(2)N)PN](2)TiCl(2) and [tBu(2)(Me(2)N)PN](2)TiMe(2) were also prepared. Compounds, using 2 equiv. of [Ph(3)C][B(C(6)F(5))(4)] as the activator, resulted in moderate to good polymerization activities.
Transformational Silicon Electronics (2014)

In today's traditional electronics such as in computers or in mobile phones, billions of high-performance, ultra-low-power devices are neatly integrated in extremely compact areas on rigid and brittle but low-cost bulk monocrystalline silicon (100) wafers. Ninety percent of global electronics are made up of silicon. Therefore, we have developed a generic low-cost regenerative batch fabrication process to transform such wafers full of devices into thin (5 μm), mechanically flexible, optically semitransparent silicon fabric with devices, then recycling the remaining wafer to generate multiple silicon fabric with chips and devices, ensuring low-cost and optimal utilization of the whole substrate. We show monocrystalline, amorphous, and polycrystalline silicon and silicon dioxide fabric, all from low-cost bulk silicon (100) wafers with the semiconductor industry's most advanced high-κ/metal gate stack based high-performance, ultra-low-power capacitors, field effect transistors, energy harvesters, and storage to emphasize the effectiveness and versatility of this process to transform traditional electronics into flexible and semitransparent ones for multipurpose applications.
Towards An Adaptive Mail Classifier (2002)

We introduce a technique based on data mining algorithms for classifying incoming messages, as a basis for an overall architecture for maintenance and management of e-mail messages. We exploit clustering techniques for grouping structured and unstructured information extracted from e-mail messages in an unsupervised way, and exploit the resulting algorithm in the process of folder creation (and maintenance) and e-mail redirection. Some initial experimental results show the effectiveness of the technique, both from an efficiency and a quality-of-results viewpoint.
Toxin-Labeled Monoclonal Antibodies (2001)

To arm monoclonal antibodies (MAbs) with the power to kill malignant cells, they have been connected to toxins to create chimeric proteins called immunotoxins. Conventional immunotoxins contain a MAb chemically conjugated to a toxin which is mutated or chemically modified to minimize binding to normal cells. Examples include anti-B4-blocked ricin, targeting CD5, and RFB4-deglycosylated ricin A chain, targeting CD22. Conventional immunotoxins are capable of inducing responses in patients with hematologic malignancies, with dose-limiting toxicities being vascular leak syndrome, thrombocytopenia, and hepatic damage. Newer immunotoxins contain a recombinant ligand, either the variable domains (Fv) of a MAb, or a growth factor, fused to a truncated bacterial toxin. Bacterial toxins commonly used for this purpose include diphtheria toxin and Pseudomonas exotoxin. DAB389lL2 (Ontak) is a recently approved growth factor fusion toxin containing human interleukin-2 and diphtheria toxin and is effective in chemotherapy-resistant cutaneous T-cell lymphoma. Anti-Tac(Fv)-PE38 (LMB-2) and RFB4(dsFv)-PE38 (BL22) are two recombinant immunotoxins, targeting CD25 and CD22, respectively, in which Fvs of MAbs targeting these antigens are fused to truncated Pseudomonas exotoxin. Both LMB-2 and BL22 have exhibited clinical activity in patients with hematologic malignancies, with less vascular leak syndrome and probably less immunogenicity than the larger conventional immunotoxin conjugates. New recombinant immunotoxins are currently being engineered and developed to target other hematologic and solid tumor antigens.
Improvement of an Isolation Medium for Actinomycetes (2011)

By comparing differences among the effects of several isolation mediums on soil actinomycetes, we attempted to find a isolation medium that could result in actionomycetes with high diversity. Soil samples were isolated by the dilution plateing method, and genomic DNA was extracted using phenol-chloroform method. After amplification by 16S rDNA PCR, PCR products were sequenced and undertaken phylogenetic analysis in order to determine the ownership of isolates. The results showed that the isolated strains belonged to 15 genuses; as for the established medium in the present paper, ZSSE was easier to isolate rare actiomycetes with rich diversity, and could replace routine agars such as Gause`s No.1, HV and ISP5; CHV was easier to isolate micromonospora.
Valence-Specific Effects ofBDNFVal66Met Polymorphism on Dopaminergic Stress and Reward Processing in Humans (2014)

Brain-derived neurotrophic factor (BDNF) levels in dopaminergic (DA) cells within the ventral tegmental area (VTA)/nucleus accumbens (NAc) circuitry appear to be a candidate mechanism for the neuroadaptive changes that follow stress and reward responses in animal models. However, the role of the BDNF gene variants in responses to salient cues through DA neurotransmission in humans remains unexplored. Here, we studied the effect of the common functional BDNF Val(66)Met (rs6265) polymorphism on rewarding experiences in the striatum and DA-mediated responses to stress. Seventy-two healthy controls were genotyped for the BDNF Val(66)Met polymorphism and underwent the monetary incentive delay task during an functional magnetic resonance imaging (fMRI) session. Forty-nine of them also underwent a sustained pain challenge with and without placebo administration with potential analgesic properties during PET measures of DA D2/3-receptor-mediated neurotransmission. Neuroimaging results revealed a significant effect of BDNF (Met(66) carriers > Val/Val) on brain responses during the anticipation of monetary losses, baseline D2/3 receptor availability, and pain-stress-induced DA release in the NAc. Conversely, BDNF Met(66) carriers showed no activation in response to monetary gains and a blunted DA response to the analgesic placebo in the NAc. These results provide initial human evidence regarding the effect of the BDNF Val(66)Met polymorphism on DA-mediated responses to stress, its cognitive regulation by positive expectations, and the anticipatory responses to monetary gains and losses in the VTA-NAc pathway. Our results are of relevance to the neurobiology of stress and reward interactions and the pathophysiology of stress-related disorders.
Reduced polyphenol oxidase gene expression and enzymatic browning in potato (Solanum tuberosum L.) with artificial microRNAs (2014)

StuPPO1 to StuPPO4 genes contributed to browning reactions in tuber tissues but their effect was not equal. Different PPO genes may be regulated independently reflecting their diversified functions. Our results show that amiRNAs can be used to suppress closely related members of highly conserved multi-gene family. This approach also suggests a new strategy for breeding low-browning crops using small DNA inserts.
Autoimmunity, T‐cells and STAT‐4 in the pathogenesis of chronic obstructive pulmonary disease (2004)

There is not much doubt that cigarette smoking is the main trigger for the development of chronic obstructive pulmonary disease (COPD). However, the mechanisms by which cigarettes produce the disease have been elusive. The consideration of new ideas could bring new insights. The paper by DI STEFANO et al. [1] in this issue of the European Respiratory Journal invites me to revisit a previously stated hypothesis
Steam as turbine blade coolant: Experimental data generation (1995)

Steam as a coolant is a possible option to cool blades in high temperature gas turbines. However, to quantify steam as a coolant, there exists practically no experimental data. This work deals with an attempt to generate such data and with the design of an experimental setup used for the purpose. Initially, in order to guide the direction of experiments, a preliminary theoretical and empirical prediction of the expected experimental data is performed and is presented here. This initial analysis also compares the coolant properties of steam and air.
Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys (1991)

Prefrontostriatal connections were investigated in rhesus monkeys using the autoradiographic technique to examine whether there are systematic relationships with regard to the architectonic organization of the prefrontal cortex. On the basis of progressive laminar elaboration, the different regions of the prefrontal cortex can be grouped into two architectonic trends. The dorsal trend, which begins in the medial proisocortical areas, can be followed through the dorsolateral prefrontal cortex, culminating in the dorsal arcuate region. The ventral trend, which originates in the orbital proisocortex, can be traced through the inferior prefrontal convexity to the ventral arcuate region. The results show that the main connections from the prefrontal cortex to the striatum are to the head and body of the caudate nucleus. These connections are topographically organized. Medial and dorsal prefrontal areas project predominantly to the dorsal and central portion of the head and body of the caudate nucleus, whereas orbital and inferior prefrontal areas are related mainly to the ventral and central portion. Moreover, prefrontostriatal connections have a medial-lateral topography. Medial and orbital prefrontal areas project medially in the head and body of the caudate nucleus, whereas the dorsal and ventral arcuate regions project laterally, adjacent to the internal capsule. The prefrontal regions above and below the principal sulcus project mainly to the intermediate sector of the head and body of the nucleus. However, there appears to be some degree of overlap of corticostriatal projections from the dorsal and ventral prefrontal regions, as well as within each trend. Relatively minor projections are directed to the putamen as well as to the tail of the caudate nucleus from certain subregions of the prefrontal cortex. Thus the distribution of prefrontostriatal connections seems to reflect the architectonic organization of the prefrontal cortex. Possible functional aspects of prefrontostriatal connectivity are considered in the light of behavioral and physiological studies.
THE MAMMALIAN LOW-DENSITY LIPOPROTEIN RECEPTOR FAMILY (1999)

The low-density lipoprotein (LDL) receptor (LDL-R) family consists of cell-surface receptors that recognize extracellular ligands and internalize them for degradation by lysosomes. The LDL-R is the prototype of this family, which also contains very-low-density lipoprotein receptors (VLDL-R), apolipoprotein E receptor 2, LRP, and megalin. The family members contain four major structural modules: the cysteine-rich complement-type repeats, epidermal growth factor precursor-like repeats, a transmembrane domain, and a cytoplasmic domain. Each structural module serves distinct and important functions. These receptors bind several structurally dissimilar ligands. It is proposed that instead of a primary sequence, positive electrostatic potential in different ligands constitutes a receptor binding domain. This family of receptors plays crucial roles in various physiologic functions. LDL-R plays an important role in cholesterol homeostasis. Mutations cause familial hypercholesterolemia and premature coronary artery disease. LDL-R-related protein plays an important role in the clearance of plasma-activated alpha 2-macroglobulin and apolipoprotein E-enriched lipoproteins. It is essential for fetal development and has been associated with Alzheimer's disease. Megalin is the major receptor in absorptive epithelial cells of the proximal tubules and an antigenic determinant for Heymann nephritis in rats. Mutations in a chicken homolog of VLDL-R cause female sterility and premature atherosclerosis. This receptor is not expressed in liver tissue; however, transgenic expression of VLDL-R in liver corrects hypercholesterolemia in experiment animals, which suggests that it can be a candidate for gene therapy for various hyperlipidemias. The functional importance of individual receptors may lie in their differential tissue expression. The regulation of expression of these receptors occurs at the transcriptional level. Expression of the LDL-R is regulated by intracellular sterol levels involving novel membrane-bound transcription factors. Other members of the family are not regulated by sterols. All the members are, however, regulated by hormones and growth factors, but the mechanisms of regulation by hormones have not been elucidated. Studies of these receptors have provided important insights into receptor structure-function and mechanisms of ligand removal and catabolism. It is anticipated that increased knowledge about the LDL-R family members will open new avenues for the treatment of many disorders.
Protein damage and degradation by oxygen radicals. IV. Degradation of denatured protein. (1987)

Proteolytic degradation of oxidatively damaged [3H] bovine serum albumin [( 3H]BSA) was studied during incubation with cell-free erythrocyte extracts and a wide variety (14) of purified proteases. [3H]BSA was pretreated by exposure (60Co radiation) to the hydroxyl radical (.OH), the superoxide anion radical (O2-), or the combination of .OH + O2- + oxygen. Treated (and untreated) samples were dialyzed and then incubated with erythrocyte extract or proteases for measurements of proteolytic susceptibility (release of acid-soluble counts). Both .OH and .OH + O2- + caused severalfold increases in proteolytic susceptibility (with extract and proteases), but O2- alone had no effect. Proteolytic susceptibility reached a maximum at 15 nmol of .OH/nmol of BSA and declined thereafter. In contrast, proteolytic susceptibility was still increasing at an .OH + O2-/BSA molar ratio of 100 (50% .OH + 50% O2-). Degradation in erythrocyte extracts was conducted by a novel ATP- and Ca2+-independent pathway, with maximal activity at pH 7.8. Inhibitor profiles indicate that this pathway may involve metalloproteases and serine proteases. Comparisons of proteolytic susceptibility with multiple modifications to BSA primary, secondary, and tertiary structure revealed a high correlation (r = 0.98) with denaturation/increased hydrophobicity by low concentrations of .OH. Covalent aggregation reactions (BSA cross-linking) may explain the declining proteolytic susceptibility observed at .OH/BSA molar ratios greater than 20. Protein denaturation may also have caused the increased proteolytic susceptibility induced by .OH + O2- + O2, but no simple correlation could be obtained. Results with .OH + O2- + O2 appear to have been complicated by direct BSA fragmentation reactions involving (.OH-induced) protein radicals and oxygen. These data indicate a direct and quantitative relationship between protein damage by oxygen radicals and increased proteolytic susceptibility. Oxidative denaturation may exemplify a simple, yet effective inherent mechanism for intracellular proteolysis.
Two distinct knockout approaches highlight a critical role for p53 in rat development (2012)

Gene targeting in embryonic stem cells (ESCs) has become the principal technology for generating knockout models. Although numerous studies have predicted that the disruption of p53 leads to increased developmental anomalies and malignancies, most p53 knockout mice develop normally. Therefore, the role of p53 in animal development was examined using rat knockout models. Conventionally generated homozygous KO males developed normally, whereas females rarely survived due to neural tube defects. Mutant chimeras generated via blastocyst injection with p53-null ESCs exhibited high rates of embryonic lethality in both sexes. This phenotype could be observed in one month by the use of zinc-finger nucleases. The p53-null ESCs were resistant to apoptosis and differentiation, and exhibited severe chromosome instabilities in the chimera-contributed cells, suggesting an essential role for p53 in maintaining ESC quality and genomic integrity. These results demonstrate that p53 functions as a guardian of embryogenesis in the rats.