gebhart/patrepeval huggingface dataset:
Modelling the P2Y purinoceptor using rhodopsin as template. (1995)

The P2Y1 purinoceptor cloned from chick brain (Webb, T. et al (1993) FEBS Lett., 324, 219-225) is a 362 amino acid, 41 kDa protein. To locate residues tentatively involved in ligand recognition a molecular model of the P2Y purinoceptor has been constructed. The model was based on the primary sequence and structural homology with the G-protein coupled photoreceptor rhodopsin, in analogy to the method proposed by Ballesteros and Weinstein ((1995) Meth. Neurosci. 25, 366-428). Transmembrane helices were constructed from the amino acid sequence, minimized individually, and positioned in a helical bundle. The helical bundle was then minimized using the Amber forcefield in Discover (BIOSYM Technologies) to obtain the final model. Several residues that have been shown to be critical in ligand binding in other GPCRs are conserved in the P2Y1 purinoceptor. According to our model the side chains of these conserved residues are facing the internal cleft in which ligand binding likely occurs. The model also suggests four basic residues (H121 in TM3, H266 and K269 in TM6 and R299 in TM7) near the extracellular surface that might be involved in ligand binding. These basic residues might be essential in coordinating the triphosphate chain of the endogenous ligand adenosine 5'-triphosphate (ATP). Potential binding sites for agonists have been explored by docking several derivatives (including newly synthesized N6-derivatives) into the model. The N6-phenylethyl substituent is tolerated pharmacologically, and in our model this substituent occupies a region predominantly defined by aromatic residues such as F51 (TM1), Y100 (TM2) and F120 (TM3). The dimethylated analogue of ATP, N6,N6-dimethyl-adenosine 5'-triphosphate, is less well tolerated pharmacologically, and our model predicts that the attenuated activity is due to interference with hydrogen bonding capacity to Q296 (TM7).
Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection (2013)

These results help clarify the spectrum of serum-neutralizing activity induced by HIV-1 infection and that should be possible to elicit with vaccines. Importantly, most people appear capable of making low to moderate titres of broadly neutralizing antibodies. Additional studies of these relatively common responses might provide insights for practical and feasible vaccine designs.
Properties of the extracellular calcium binding module of the proteoglycan testican (1997)

The extracellular calcium-binding (EC) module of human testican (115 residues) was obtained in native form by recombinant production in mammalian cell culture and thus shown to represent an independently folding domain. This module showed a large loss in alpha-helix upon calcium depletion. Apparently only one of the two EF hands binds calcium, with a moderate affinity (Kd =68 microM) about 100-fold lower than in the homologous BM-40 protein. No clear evidence was obtained for collagen binding, indicating that EC modules found in different proteins may not share similar functions.
Objective Measurement of Music Quality Using Inter-Band Relationship Analysis (2011)

This paper describes and evaluates an objective measurement that grades the quality of a complex musical signal. The authors have previously identified a potential correlation between inter-band dynamics and the subjective quality of produced music excerpts. This paper describes the previously presented Inter-Band Relationship (IBR) descriptor and extends this work by conducting more thorough testing with real-world music excerpts and a greater number of listening subjects. A high degree of correlation is observed between the Mean Subject Scores (MSS) and the objective IBR descriptor suggesting it could be used as an additional model output variable (MOV) to describe produced music quality. The method lends itself to real-time implementation and therefore can be exploited within mixing, mastering and monitoring tools.
Chemoselective enzymatic hydrolysis of aliphatic and alicyclic nitriles (1992)

Mild and selective hydrolysis of aliphatic and alicyclic nitriles leading to carboxylic acids and amides was achieved under neutral conditions by an immobilized enzyme preparation from Rhodococcus sp. This method is particularly useful for the transformation of compounds containing other acid- or base-sensitive groups.
Allosteric Agonist Modulators (2007)

This article discusses a model to describe the effects of molecules that bind to a site on the receptor separate from that of the endogenous agonist to actively produce receptor signals (direct agonism). In addition, these molecules also modify the biological responses of the endogenous agonist (either potentiation or antagonism). The effects of such compounds in high-throughput screening assays are described as well as their effects on the dose-response curves to conventional agonists.
A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1 (1997)

Pbx1 is a homeodomain transcription factor that has the ability to form heterodimers with homeodomain proteins encoded by the homeotic selector (Hox) gene complexes and increase their DNA-binding affinity and specificity. A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development. In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A. The E2A-Pbx1 fusion protein should therefore activate transcription of genes normally regulated by Pbx1. We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1. We show that E2A-Pbx1 can directly activate transcription of a novel member of the fibroblast growth factor family of intercellular signalling molecules, FGF-15. The FGF-15 gene is expressed in a regionally restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and patterning within specific regions of the embryonic brain, spinal cord and sensory organs.
Transfection by human oncogenes: Concomitant induction of tumorigenicity and tumor‐associated membrane alterations (1985)

NIH 3T3 cells were transfected with DNA derived from human bladder carcinoma, colon carcinoma and HL60 promyelocytic leukemia cells. The transfectants were examined for the presence of human oncogenes in relation to tumorigenic potential and composition of surface-located fucosyl glycopeptides by gel filtration, Concanavalin-A-binding and high-performance liquid chromatography. All transfectants, harboring 3 different human cellular ras genes, appeared to be tumorigenic in nude mice and displayed characteristically altered glycopeptides. The surface glycopeptides were consistently changed to higher apparent molecular weight due to enrichment in higher-branched sialic-acid-containing glycopeptides. Similar alterations have been found previously in virally- and chemically-transformed cells in vitro and tumors raised in vivo, and were designated as cancer-related or tumor-associated glycopeptides. Revertants derived from HL60-DNA-induced transfectants, which had lost the transfected human N-ras oncogene, simultaneously lost their tumorigenic potential and expression of cancer-related membrane glycopeptides. In addition, spontaneous transformants, exhibiting morphology and growth patterns indistinguishable from those of tumor-DNA-induced transfectants, neither contained transferred human DNA sequences nor expressed cancer-related glycopeptides. Nevertheless these cells were capable, after prolonged latency periods, of inducing tumors in nude mice. Cells derived from such tumors constantly displayed cancer-related glycopeptides on their surface, suggesting selection of tumorigenic cells from spontaneous transformants during passage in nude mice. In one of these tumors at least, an endogenous mouse ras-gene appeared to be activated. The results indicate a close correlation between the presence of activated ras-oncogenes in the genome of the transfected cells, the tumorigenic potential of these cells and the expression of surface-located cancer-related glycopeptides. The data suggest that functions provided by human ras-oncogenes contribute to the alteration of membrane glycopeptides on tumor cells.
Automated Curriculum Learning for Neural Networks (2017)

We introduce a method for automatically selecting the path, or syllabus, that a neural network follows through a curriculum so as to maximise learning efficiency. A measure of the amount that the network learns from each data sample is provided as a reward signal to a nonstationary multi-armed bandit algorithm, which then determines a stochastic syllabus. We consider a range of signals derived from two distinct indicators of learning progress: rate of increase in prediction accuracy, and rate of increase in network complexity. Experimental results for LSTM networks on three curricula demonstrate that our approach can significantly accelerate learning, in some cases halving the time required to attain a satisfactory performance level.
Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury (1990)

An increase in extracellular K+ concentration ([K+]c) of the rat hippocampus following fluid-percussion concussive brain injury was demonstrated with microdialysis. The role of neuronal discharge was examined with in situ administration of 0.1 mM tetrodotoxin, a potent depressant of neuronal discharges, and of 0.5 to 20 mM cobalt, a blocker of Ca++ channels. While a small short-lasting [K+]c increase (1.40- to 2.15-fold) was observed after a mild insult, a more pronounced longer-lasting increase (4.28- to 5.90-fold) was induced without overt morphological damage as the severity of injury rose above a certain threshold (unconscious for 200 to 250 seconds). The small short-lasting increase was reduced with prior administration of tetrodotoxin but not with cobalt, indicating that neuronal discharges are the source of this increase. In contrast, the larger longer-lasting increase was resistant to tetrodotoxin and partially dependent on Ca++, suggesting that neurotransmitter release is involved. In order to test the hypothesis that the release of the excitatory amino acid neurotransmitter glutamate mediates this increase in [K+]c, the extracellular concentration of glutamate ([Glu]c) was measured along with [K+]c. The results indicate that a relatively specific increase in [Glu]c (as compared with other amino acids) was induced concomitantly with the increase in [K+]c. Furthermore, the in situ administration of 1 to 25 mM kynurenic acid, an excitatory amino acid antagonist, effectively attenuated the increase in [K+]c. A dose-response curve suggested that a maximum effect of kynurenic acid is obtained at a concentration that substantially blocks all receptor subtypes of excitatory amino acids. These data suggest that concussive brain injury causes a massive K+ flux which is likely to be related to an indiscriminate release of excitatory amino acids occurring immediately after brain injury.
Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents (1999)

Mismatch DNA repair deficiency is associated with resistance to certain major groove alkylating agents including methylating agents and cisplatin. We have now studied the relevance of mismatch repair alterations to the cytotoxicity induced by drugs which alkylate N3 adenines in the minor groove of DNA. We have used the mismatch repair defective human colocarcinoma cell line HCT-116 which has a mutation in the hMLH1 gene, and a subline where hMLH1 expression is restored by chromosome 3 transfer (HCT-116+ch3). We have tested three alkylating minor groove binders (tallimustine, carzelesin and CC1065) and one non-covalent minor groove binder (PNU 151807). The HCT-116+ch3 subline was more sensitive than the parental line to the treatment with the three alkylating minor groove binders, while the non-alkylating compound had a similar activity in both cell lines. Further support for mismatch repair being involved in sensitivity of the minor groove alkylators is that two cisplatin-resistant sublines of the human ovarian adenocarcinoma cell line A2780 (A2780/CP70 and A2780/MCP-1) are defective in hMLH1 expression and are more resistant to these agents than the parental mismatch repair proficient cells. Furthermore, the restoration of hMLH1 activity in the A2780/CP70 cell line, by introduction of chromosome 3, was associated with an increased sensitivity to the three alkylating minor groove binders. Again, the non-covalent minor groove binder was equally effective in mismatch repair deficient and proficient clones. The data indicate that mismatch repair deficiency mediated by loss of hMLH1 expression is associated not only with drug-resistance to major groove binders, but also to minor groove binders. However, loss of mismatch repair does not mediate resistance to the non-covalent minor groove binder PNU 151807.
Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein (2005)

In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein alpha-synuclein (alphaS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, alphaS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric alphaS assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerization and aggregation. The autoinhibitory conformations fluctuate in the range of nanoseconds to micro-seconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and/or temperature increase, conditions that induce aggregation in vitro, release this inherent tertiary structure, leading to a completely unfolded conformation that associates readily. Stabilization of the native, autoinhibitory structure of alphaS constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.
Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. (1988)

To survive and proliferate in pure culture, human melanocytes require basic fibroblast growth factor (bFGF) and cAMP. Without these factors, even in the presence of serum, the cells die. Melanocytes cultured in the presence of keratinocytes, however, survive for weeks without added bFGF and cAMP. We show here that the growth factor for melanocytes produced by human keratinocytes is bFGF because its activity can be abolished by neutralizing antibodies to bFGF and by a bFGF synthetic peptide that inhibits the binding of the growth factor to its receptor. The melanocyte mitogen in keratinocytes is cell associated and increases after irradiation with ultraviolet B. Northern blots reveal bFGF gene transcripts in keratinocytes but not melanocytes. These studies demonstrate that bFGF elaborated by keratinocytes in vitro sustains melanocyte growth and survival, and they suggest that keratinocyte-derived bFGF is the natural growth factor for normal human melanocytes in vivo.
Fabrication and Characteristics of Pyroelectric IR Sensor Using $1.6{\mu}m$ P(VDF/TrFE) thin film (2001)

A pyroelectric senior using P(VDF/TrFE) film for sensing materials has been fabricated and evaluated with other commercial pyroelectric sensors that use ceramic materials for sensing. The device was mounted in a TO-5 housing to detect infrared light of wavelength. The NEP (noise equivalent power) and specific detectivity of the device were and respectively under emission energy of respectively. These result shows a better characteristics than other commercial pyroelectric sensors NEP and .
Composition of N-linked carbohydrates from ovalbumin and co-purified glycoproteins (2000)

Analysis of commercial samples of chicken ovalbumin by reversed-phase high performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) showed the presence of several other co-purifying glycoproteins. These were isolated, subjected to tryptic digestion, and two of them were identified as ovomucoid and chicken riboflavin binding-protein following database matching of the peptide masses obtained by MALDI. The N-linked glycans were released from the glycoproteins and their structures were examined by MALDI-MS in combination with exoglycosidase digestion. Ovalbumin was found to be glycosylated mainly with high-mannose and hybrid structures, consistent with profiles obtained on the intact glycoprotein by electrospray. The other glycoproteins contained mainly larger, complex glycans with up to five antennae, many of which had earlier been associated with ovalbumin.
An Analysis of the Arrangement of Neurons in the Cingulate Cortex of Schizophrenic Patients (1987)

A series of computer-assisted stereomorphometric analyses of the spatial arrangements of neurons and glia in postmortem cerebral cortex specimens has been developed and applied to both control subjects and schizophrenic patients. The data suggest that the anterior cingulate cortex of schizophrenic patients may contain domains or aggregates of neurons, particularly in layer II, which are smaller in size and separated by wider distances than those observed in the control group. Verification of the inferences made from the computer-generated data has been obtained by direct microscopic visualization and measurement of neuronal aggregates of layer II in Nissl-stained cingulate specimens from the control and schizophrenic groups. Statistical correction of the data, using multivariate statistics, for effects of age, hypoxia, postmortem interval, fixation, and neuroleptic exposure does not eliminate the differences in size and separation of neuronal aggregates in layer II of schizophrenic patients. The possible relevance of these findings to our understanding of schizophrenic symptomatology is discussed.
Pediatric renovascular hypertension (1996)

Renovascular disease is a frequent cause of severe hypertension in children and may result in significant morbidity or mortality. Most children presenting with renovascular hypertension have few if any symptoms, but devastating neurologic injury and congestive heart failure are still too often observed. Several new radiographic techniques have been used to detect renovascular lesions, but none has yet demonstrated consistently superior results when compared with intra-arterial digital subtraction angiography. Renal venous renin sampling, duplex ultrasonography, and captopril-enhanced renal scintigraphy may be useful diagnostic adjuncts. Therapeutic objectives include cure of hypertension and restoration or preservation of renal function. At many institutions, percutaneous transluminal angioplasty has become the treatment of choice for patients with renal transplant artery stenosis and discrete, nonostial stenoses caused by fibromuscular dysplasia. More extensive lesions generally respond well to surgical correction. Chronic pharmacologic therapy is reserved for patients who do not respond to angioplasty or in cases in which the location or extent of involvement of the renal arterial system precludes surgical revascularization. Nephrectomy is usually reserved for kidneys that have minuscule function of irreparable vascular anomalies. An individualized approach to therapy is increasingly emphasized.
Analysis of the expression, distribution and function of cyclin dependent kinase 5 (cdk5) in developing cerebellar macroneurons (1997)

ABSTRACT Cultures of cerebellar macroneurons were used to study the expression, activity, subcellular localization, and function of cdk5 during neuronal morphogenesis. The results obtained indicate that in non-polarized neurons cdk5 is restricted to the cell body but as soon as polarity is established it becomes highly concentrated at the distal tip of growing axons where it associates with microtubules and the subcortical cytoskeleton. In addtion, we show that laminin, an extracellular matrix molecule capable of stimulating axonal extension and promoting MAP1b phosphorylation (DiTella et al., 1996), accelerates the redistribution of cdk5 to the axonal tip and dramatically increases its activity. Finally, our results indicate that cdk5 suppression by antisense oligonucleotide treatment selectively reduces axonal elongation and decreases the phosphorylation status of MAP1b, as well as its binding to microtubules. Taken collectively, our observations suggest that cdk5 may serve as an important regulatory linker between enviromental signals (e.g. laminin) and constituents of the intracellular machinery (e.g. MAP1b) involved in axonal formation.
Aldose Reductase and AGE–RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging rats (2010)

Summary Aging is inevitably accompanied by gradual and irreversible innate endothelial dysfunction. In this study, we tested the hypothesis that accentuation of glucose metabolism via the aldose reductase (AR) pathway contributes to age‐related vascular dysfunction. AR protein and activity levels were significantly increased in aged vs. young aortic homogenates from Fischer 344 rats. Immunostaining revealed that the principal site of increased AR protein was the aortic endothelium as well as smooth muscle cells. Studies revealed that endothelial‐dependent relaxation (EDR) in response to acetylcholine was impaired in aged rats compared to young rats and that treatment with the AR inhibitor (ARI) zopolrestat significantly improved EDR in aged rats. Methylglyoxal (MG), a key precursor of advanced glycation endproducts (AGEs), was significantly increased in the aortas of aged rats vs. young rats. Consistent with central roles for AR in generation of MG in aging, ARI treatment significantly reduced MG levels in aged rat aorta to those in young rats. Treatment of aged rats with soluble(s) RAGE, a soluble form of the chief signal transduction receptor for AGEs, RAGE, significantly improved EDR in aged rats, thus establishing the contribution of age‐related increases in AGEs to endothelial dysfunction. These findings reveal that significant increases in AR expression and activity in aged rat vasculature linked to endothelial dysfunction may be mitigated, at least in part, via ARI and that aging‐linked increased flux via AR generates AGEs; species which transduce endothelial injury consequent to their interaction with RAGE. These data demonstrate for the first time that AR mediates aging‐related vascular dysfunction, at least in part, via RAGE.