gebhart/patrepeval huggingface dataset:
Glycoprotein Ibα Promoter Drives Megakaryocytic Lineage-Restricted Expression After Hematopoietic Stem Cell Transduction Using a Self-Inactivating Lentiviral Vector (2007)

Megakaryocytic (MK) lineage is an attractive target for cell/gene therapy approaches, aiming at correcting platelet protein deficiencies. However, MK cells are short-lived cells, and their permanent modification requires modification of hematopoietic stem cells with an integrative vector such as a lentiviral vector. Glycoprotein (Gp) IIb promoter, the most studied among the MK regulatory sequences, is also active in stem cells. To strictly limit transgene expression to the MK lineage after transduction of human CD34(+) hematopoietic cells with a lentiviral vector, we looked for a promoter activated later during MK differentiation. Human cord blood, bone marrow, and peripheral-blood mobilized CD34(+) cells were transduced with a human immunodeficiency virus-derived self-inactivating lentiviral vector encoding the green fluorescent protein (GFP) under the transcriptional control of GpIbalpha, GpIIb, or EF1alpha gene regulatory sequences. Both GpIbalpha and GpIIb promoters restricted GFP expression (analyzed by flow cytometry and immunoelectron microscopy) in MK cells among the maturing progeny of transduced cells. However, only the GpIbalpha promoter was strictly MK-specific, whereas GpIIb promoter was leaky in immature progenitor cells not yet engaged in MK cell lineage differentiation. We thus demonstrate the pertinence of using a 328-base-pair fragment of the human GpIbalpha gene regulatory sequence, in the context of a lentiviral vector, to tightly restrict transgene expression to the MK lineage after transduction of human CD34(+) hematopoietic cells. Disclosure of potential conflicts of interest is found at the end of this article.
Mutation of SAC1, an Arabidopsis SAC Domain Phosphoinositide Phosphatase, Causes Alterations in Cell Morphogenesis, Cell Wall Synthesis, and Actin Organization (2005)

SAC (for suppressor of actin) domain proteins in yeast and animals have been shown to modulate the levels of phosphoinositides, thereby regulating several cellular activities such as signal transduction, actin cytoskeleton organization, and vesicle trafficking. Nine genes encoding SAC domain-containing proteins are present in the Arabidopsis thaliana genome, but their roles in plant cellular functions and plant growth and development have not been characterized. In this report, we demonstrate the essential roles of one of the Arabidopsis SAC domain proteins, AtSAC1, in plant cellular functions. Mutation of the AtSAC1 gene in the fragile fiber7 (fra7) mutant caused a dramatic decrease in the wall thickness of fiber cells and vessel elements, thus resulting in a weak stem phenotype. The fra7 mutation also led to reduced length and aberrant shapes in fiber cells, pith cells, and trichomes and to an alteration in overall plant architecture. The AtSAC1 gene was found to be expressed in all tissues in elongating organs; however, it showed predominant expression in vascular tissues and fibers in nonelongating parts of stems. In vitro activity assay demonstrated that AtSAC1 exhibited phosphatase activity toward phosphatidylinositol 3,5-biphosphate. Subcellular localization studies showed that AtSAC1 was colocalized with a Golgi marker. Truncation of the C terminus by the fra7 mutation resulted in its localization in the cytoplasm but had no effect on phosphatase activity. Furthermore, examination of the cytoskeleton organization revealed that the fra7 mutation caused the formation of aberrant actin cables in elongating cells but had no effect on the organization of cortical microtubules. Together, these results provide genetic evidence that AtSAC1, a SAC domain phosphoinositide phosphatase, is required for normal cell morphogenesis, cell wall synthesis, and actin organization.
Mechanism of the Quorum-Quenching Lactonase (AiiA) fromBacillus thuringiensis. 1. Product-Bound Structures (2008)

Enzymes capable of hydrolyzing N-acyl- l-homoserine lactones (AHLs) used in some bacterial quorum-sensing pathways are of considerable interest for their ability to block undesirable phenotypes. Most known AHL hydrolases that catalyze ring opening (AHL lactonases) are members of the metallo-beta-lactamase enzyme superfamily and rely on a dinuclear zinc site for catalysis and stability. Here we report the three-dimensional structures of three product complexes formed with the AHL lactonase from Bacillus thuringiensis. Structures of the lactonase bound with two different concentrations of the ring-opened product of N-hexanoyl- l-homoserine lactone are determined at 0.95 and 1.4 A resolution and exhibit different product configurations. A structure of the ring-opened product of the non-natural N-hexanoyl- l-homocysteine thiolactone at 1.3 A resolution is also determined. On the basis of these product-bound structures, a substrate-binding model is presented that differs from previous proposals. Additionally, the proximity of the product to active-site residues and observed changes in protein conformation and metal coordination provide insight into the catalytic mechanism of this quorum-quenching metalloenzyme.
N-Substituted 9β-Methyl-5-(3-hydroxyphenyl)morphans Are Opioid Receptor Pure Antagonists (1998)

The inhibition of radioligand binding and [35S]GTPgammaS functional assay data for N-methyl- and N-phenethyl-9beta-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) show that these compounds are pure antagonists at the micro, delta, and kappa opioid receptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked in a conformation comparable to an equatorial group of a piperidine chair conformation, this information provides very strong evidence that opioid antagonists can interact with opioid receptors in this conformation. In addition, it suggests that the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist operates via a phenyl equatorial piperidine chair conformation. Importantly, the close relationship between the 4-(3-hydroxyphenyl)piperidines and 5-(3-hydroxyphenyl)morphan antagonists shows that the latter class of compound provides a rigid platform on which to build a novel series of opioid antagonists.
Consensus Paper of the WFSBP Task Force on Biological Markers of Dementia: The role of CSF and blood analysis in the early and differential diagnosis of dementia (2005)

Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.
Membrane transport of natural folates and antifolate compounds in murine L1210 leukemia cells: role of carrier- and receptor-mediated transport systems. (1991)

L1210-B73 cells, variants of L1210 cells grown in medium containing nanomolar concentrations of folates, express a membrane associated folate binding protein (mFBP) in addition to the classical reduced folate/methotrexate carrier (RF/MTX-carrier) present in L1210 cells grown in standard high folate medium (G. Jansen et al., Cancer Res., 49: 1959-1963, 1989). In this study we used L1210-B73 and L1210 cells as a model system to study the affinity of the RF/MTX-carrier and the mFBP for the natural folate compounds folic acid and 5-formyltetrahydrofolate (5-CHO-THF), as well as a number of antifolate compounds. Furthermore we studied the contribution of the RF/MTX-carrier and the mFBP in membrane transport of these (anti)folates, and finally we analyzed the role of the mFBP and RF/MTX-carrier in the cytotoxic effects of the antifolates. The antifolates used were either inhibitors of dihydrofolate reductase, including methotrexate (MTX) and 10-ethyl-10-deazaaminopterin (10-EdAM), or two folate-based inhibitors of thymidylate synthase, N10-propargyl-5,8-dideazafolic acid (CB3717) and 2-deamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI-198,583). The affinity of the RF/MTX-carrier for natural and antifolate compounds declined in the order 10-EdAM greater than or equal to ICI-198,583 greater than or equal to 5-CHO-THF greater than MTX much greater than CB3717 much greater than folic acid. The mFBP exhibited a high binding affinity for CB3717 and ICI-198,583 but a poor binding affinity for MTX and 10-EdAM. Binding affinities of the mFBP decreased in the order CB3717 greater than or equal to folic acid = ICI-198,583 greater than or equal to 5-CHO-THF much greater than MTX = 10-EdAM. Over 24 h, at 25 nM, [3H]folic acid uptake in L1210-B73 cells was found to proceed for more than 98% via the mFBP. Uptake of [3H]-5-CHO-THF, at 50 nM extracellular concentration, occurred via both the mFBP (81%) and the RF/MTX-carrier (19%). With respect to antifolates, the mFBP in L1210-B73 cells contributed for less than 30% in the uptake of [3H]MTX but was the predominant route (92%) in the uptake of [3H]ICI-198,583. Results from affinity and membrane transport observations were consistent with growth inhibition studies on L1210-B73 cells demonstrating that the mFBP played only a minor role in the cytotoxic effects of MTX or 10-EdAM. On the other hand, L1210-B73 cells were significantly more sensitive to CB3717 (220-fold) and ICI-198,583 (10-fold) than parental L1210 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
An Implementation of an Electronic Diary (1989)

This paper describes an implementation of a personal information system - an electronic diary. Specific emphasis is placed on the design and development of a humanised interface to the diary. This electronic diary is based on the bifocal diary proposed by Spence and some modifications and improvements have been introduced to make the system more suitable for implementation on a personal computer. The concept of this humanized interface can also be applied to any database system which is of sequential nature such as telephone directories and library cataloguing systems.
Changes in excitability of motor cortical circuitry in primary restless legs syndrome (1999)

The supraspinal inhibitory system is impaired in pRLS.
One‐stop clinic for assessment of risk for trisomy 21 at 11–14 weeks: a prospective study of 15 030 pregnancies (2002)

Screening for trisomy 21 by a combination of maternal age, fetal NT and maternal serum biochemistry at 11-14 weeks can be provided in an OSCAR setting and is associated with a detection rate of about 90% for a false-positive rate of 5%.
Mapping of Cotton-Melon Aphid Resistance in Melon (2001)

Resistance to cotton-melon aphid ( Aphis gossypii Glover) segregated as a single dominant gene in a melon ( Cucumis melo L.) mapping population derived from the cross `Top Mark' × PI 414723. Sixty-four F 2 -derived F 3 families were used to map the aphid resistance locus, Vat , with respect to randomly amplified polymorphic DNA (RAPD) and restriction fragment length polymorphism (RFLP) markers. RFLP markers NBS-2 and AC-39 flanked Vat at distances of 3.1 cM and 6.4 cM, respectively. NBS-2 is homologous to the nucleotide binding site-leucine-rich repeat (NBS-LRR) superfamily of plant resistance genes. Another homolog of this superfamily, NBS-5, was positioned ≈16.8 cM from Vat , raising the possibility that Vat resides in a cluster of NBS-LRR paralogs. RFLP marker AC-8, which has similarity to plant lipoxygenases, was positioned at ≈5.5 cM from Vat . Monogenic resistance to A. gossypii has been identified in two sources of melon germplasm, Indian accession PI 371795 (progenitor of PI 414723) and Korean accession PI 161375. To test for an allelic relation between the genes controlling aphid resistance in these two distinct germplasm sources, melon plants of a backcross population from a cross between two resistant lines having Indian- or Korean-derived resistance were infested with aphids. At least 90 out of 92 segregating progeny were aphid resistant, suggesting that the same resistance gene, Vat, is present in both sources of melon germplasm.
Prostate cancer in systemic lupus erythematosus (2011)

Our research objective was to estimate prostate cancer risk in systemic lupus erythematosus (SLE), relative to the age-matched general population. A progressive literature review was performed to identify SLE cohort studies with cancer registry linkage for cancer ascertainment. Data were pooled from four studies of large SLE cohorts who met these criteria. The total number of prostate cancers observed was derived by pooling the incident cases across all studies. The total expected number of prostate, derived from applying appropriate general population cancer incidence data to the observed number of patient-years of follow-up for each study, was similarly determined. The parameter of interest was the standardized incidence ratio (SIR), the ratio of observed to expected malignancies. The four studies together provided a pool of 6,068 male SLE patients observed for a total of 38,186 patient-years (mean 6.3 years). Within these subjects, 80 prostate cancers were observed. In each contributing study, the number of cancers expected far exceeded that observed. The pooled SIR estimate for prostate cancer risk in males with SLE, compared to the general population, was 0.72 (95% CI 0.57, 0.89). These data suggest a decreased risk of prostate cancer in SLE; more definite conclusions require additional data. As alterations in androgen pathways can potentially alter prostate risk, a lower risk of prostate cancer in SLE could possibly be due to low hypoadrenergic states which some believe may occur in men with SLE; underlying genetic factors could also be at play. Further study of these issues in large cohorts is needed.
A High-Resolution Root Spatiotemporal Map Reveals Dominant Expression Patterns (2007)

Transcriptional programs that regulate development are exquisitely controlled in space and time. Elucidating these programs that underlie development is essential to understanding the acquisition of cell and tissue identity. We present microarray expression profiles of a high-resolution set of developmental time points within a single Arabidopsis root and a comprehensive map of nearly all root cell types. These cell type-specific transcriptional signatures often predict previously unknown cellular functions. A computational pipeline identified dominant expression patterns that demonstrate transcriptional similarity between disparate cell types. Dominant expression patterns along the root's longitudinal axis do not strictly correlate with previously defined developmental zones, and in many cases, we observed expression fluctuation along this axis. Both robust co-regulation of gene expression and potential phasing of gene expression were identified between individual roots. Methods that combine these profiles demonstrate transcriptionally rich and complex programs that define Arabidopsis root development in both space and time.
Cortical neuropathological and neurochemical substrates of Alzheimer's and Parkinson's diseases. (1987)

Whilst the neuropathological correlates of Alzheimer type dementia--cortical neurofibrillary tangles and senile plaques--are well defined, the prevalence of these cortical abnormalities in Parkinson's disease and their relation to dementia is unclear. In a series of 46 consecutive cases of clinically and pathologically established Parkinson's disease the prevalence of mild Alzheimer-type pathology (exceeding the normal but not as extensive as in Alzheimer's disease) was increased 2 to 3 fold compared with an age-matched control group, although there was no obvious relation to the presence or severity of dementia. In a subgroup of Parkinsonian cases (both demented and non-demented), examined neurochemically, there were both similarities (decreased choline acetyltransferase, nicotinic and serotonergic S 1 receptor activities) and distinctions (increased muscarinic receptor binding--particularly to the "L" subtype, and normal serotonergic S 2, somatostatin, and D-aspartate binding together with normal levels of an endogenous nicotine binding inhibitor) compared with a group of cases with Alzheimer's disease. Amongst the various pathological and chemical indices examined, only presynaptic cholinergic markers (including the number of Meynert neurons) and S 1 receptor binding were related to dementia in Parkinson's disease. It is suggested that whilst coincidental classical Alzheimer's disease is infrequent in Parkinson's disease (5% in the present series) Alzheimer's disease itself is distinguished from Parkinson's disease by the formation of numerous neocortical neurofibrillary tangles and a reduction in glutamate uptake, serotonergic S 2 receptors and possibly in endogenous nicotine binding inhibitor.
Metabolic Inactivation of Resolvin E1 and Stabilization of Its Anti-inflammatory Actions (2006)

The resolvins (Rv) are lipid mediators derived from omega-3 polyunsaturated fatty acids that act within a local inflammatory milieu to stop leukocyte recruitment and promote resolution. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an oxygenase product derived from omega-3 eicosapentaenoic acid that displays potent anti-inflammation/pro-resolution actions in vivo. Here, we determined whether oxidoreductase enzymes catalyze the conversion of RvE1 and assessed the biological activity of the RvE1 metabolite. With NAD+ as a cofactor, recombinant 15-hydroxyprostaglandin dehydrogenase acted as an 18-hydroxyl dehydrogenase to form 18-oxo-RvE1. In the murine lung, dehydrogenation of the hydroxyl group at carbon 18 position to form 18-oxo-RvE1 represented the major initial metabolic route for RvE1. At a concentration where RvE1 potently reduced polymorphonuclear leukocyte (PMN) recruitment in zymosan-induced peritonitis, 18-oxo-RvE1 was devoid of activity. In human neutrophils, carbon 20 hydroxylation of RvE1 was the main route of conversion. An RvE1 analog, i.e. 19-(p-fluorophenoxy)-RvE1, was synthesized that resisted rapid metabolic inactivation and proved to retain biological activity reducing PMN infiltration and pro-inflammatory cytokine/chemokine production in vivo. These results established the structure of a novel RvE1 initial metabolite, indicating that conversion of RvE1 to the oxo product represents a mode of RvE1 inactivation. Moreover, the designed RvE1 analog, which resisted further metabolism/inactivation, could be a useful tool to evaluate the actions of RvE1 in complex disease models.
ASC: an associative-computing paradigm (1994)

Today's increased computing speeds allow conventional sequential machines to effectively emulate associative computing techniques. We present a parallel programming paradigm called ASC (ASsociative Computing), designed for a wide range of computing engines. Our paradigm has an efficient associative-based, dynamic memory-allocation mechanism that does not use pointers. It incorporates data parallelism at the base level, so that programmers do not have to specify low-level sequential tasks such as sorting, looping and parallelization. Our paradigm supports all of the standard data-parallel and massively parallel computing algorithms. It combines numerical computation (such as convolution, matrix multiplication, and graphics) with nonnumerical computing (such as compilation, graph algorithms, rule-based systems, and language interpreters). This article focuses on the nonnumerical aspects of ASC.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
TNF-alpha in CRPS and ‘normal’ trauma – Significant differences between tissue and serum (2010)

Posttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha we investigated tissue (skin) and serum concentrations in three different patient groups: patients with osteoarthritis and planned surgery, with acute traumatic upper limb bone fracture waiting for surgery, and with CRPS I. Thirty patients (10 in each group) were recruited. Mean CRPS duration was 36.1 ± 8.1 weeks (range 8- 90 weeks). Skin punch biopsies were taken at the beginning of the surgery in osteoarthritis and fracture patients and from the affected side in CRPS patients. Blood samples were taken before the respective procedures. Skin and serum TNF-alpha levels were quantified by ELISA. Compared to patients with osteoarthritis, skin TNF-alpha was significantly elevated in CRPS (p<0.001) and fracture patients (p<0.04). Skin TNF-alpha in CRPS patients was higher than in patients with acute bone fracture (p<0.02). In contrast, serum TNF-alpha values were the same in osteoarthritis and CRPS, and lower in fracture patients (p<0.03). Our results indicate a local but not systemic increase of TNF-alpha in CRPS patients. This increase persists for months after limb trauma and may offer the opportunity for targeted treatment.
Enzymatically deacylated Neisseria lipopolysaccharide (LPS) inhibits murine splenocyte mitogenesis induced by LPS (1991)

Acyloxyacyl hydrolase is a leukocyte enzyme that selectively removes the secondary acyl chains from the lipid A moiety of gram-negative bacterial lipopolysaccharides (LPS). As predicted by the reported contribution of secondary acyl chains to the bioactivities of lipid A analogs, enzymatic deacylation of Salmonella typhimurium Rc LPS substantially reduces its potency in the dermal Shwartzman reaction and in several in vitro assays that measure responses of human endothelial cells and neutrophils, whereas the potency of this LPS for inducing murine splenocyte mitogenesis is affected much less. In the experiments described here, we studied the impact of acyloxyacyl hydrolysis on the bioactivities of several LPS that differ from Salmonella LPS in carbohydrate and lipid A structures. Deacylated LPS from Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, and S. typhimurium were similarly reduced in potency in the Limulus lysate test (30- to 60-fold reduction in potency relative to the corresponding mock-treated LPS), and the ability of all of these deacylated LPS to stimulate neutrophil adherence to human endothelial cells was reduced by a factor of 100 or more. For LPS from E. coli, H. influenzae, and Pseudomonas aeruginosa, the impact of deacylation on spleen cell mitogenesis was also similar to that observed for S. typhimurium LPS: deacylation reduced potency by less than 15-fold. Unexpectedly, the potency of Neisseria LPS in the murine splenocyte mitogenicity test was reduced over 100-fold by deacylation, and deacylated Neisseria LPS could block the mitogenic activity of Neisseria and Salmonella LPS. These studies indicate that the contribution of secondary acyl chains to the bioactivities of a given LPS cannot be predicted with confidence from the reported structure-activity relationships of lipid A or from the behavior of other deacylated LPS.