gebhart/patrepeval huggingface dataset:
Structural and Biologic Characterization of Pegylated Recombinant IFN- α 2b (2001)

The type I interferon-alpha (IFN-alpha) family is a family of natural small proteins that have clinically important anti-infective and antitumor activity. We have developed a semisynthetic protein-polymer conjugate of IFN-alpha2b (Intron A) by attaching a 12,000-Da monomethoxypolyethylene glycol (PEG-12000) polymer to the protein. PEG conjugation is thought to increase the serum half-life and thereby prolong patient exposure to IFN-alpha2b without altering the biologic potency to the protein. Matrix-assisted laser desorption ionization/mass spectrometry (MALDI-MS), high-performance size exclusion chromatography (HPSEC), circular dichroism (CD) analysis and tryptic digestion peptide analysis of PEG Intron demonstrated that the IFN-alpha2b protein was approximately 95% monopegylated and that the primary, the secondary, and the tertiary structures were unaltered. Pegylation did not affect the epitope recognition of antibodies used for Intron A quantitation. An extensive analysis of the pegylated positional isomers revealed that approximately 50% of PEG Intron was monopegylated on the His(34) residue of the IFN-alpha2b protein. The highest antiviral activity of the pegylated positional isomers for PEG Intron was associated with the His(34) pegylated isomer. The specific activity for PEG Intron in an antiviral cytopathic protection assay was 28%, relative to Intron A. However, the potency of PEG Intron, defined as bioactivity independent of protein concentration, was comparable to Intron A at both the molecular and cellular levels in a battery of in vitro assays. Equivalent units of PEG Intron and Intron A were indistinguishable for the induction of several key IFN-induced genes, including 2',5'-oligoadenylate synthetase (2',5'-OAS) and protein kinase R (PKR), in Molt 4 cells. The antiviral dose-response curves revealed that there were no significant differences between PEG Intron and Intron A. This demonstrated that the introduction of more IFN-alpha2b protein associated with equivalent unit dosing of PEG Intron did not create any antagonism or agonism in the antiviral assay. In assays for the immune response, PEG Intron and Intron A displayed comparable potency for both natural-killer (NK) and lymphokine-activated killer (LAK) cell cytolytic activity and for the induction of class I major histocompatibility protein. These results demonstrate that PEG Intron maintains an in vitro biologic potency profile for both antiviral and immunotherapeutic activity that is highly comparable to that of Intron A.
Frequency‐dependent selection of reflexes by pudendal afferents in the cat (2006)

Activation of urethral or genital afferents of the pudendal nerve can elicit or inhibit micturition, and low frequency stimulation of the compound pudendal nerve (PN) is known to produce a continence response. The present study demonstrates that PN stimulation also can elicit a micturition-like response and that the response to PN stimulation is dependent on stimulation frequency. We measured the changes in bladder pressure and external urethral sphincter (EUS) electroneurogram (ENG) evoked by PN stimulation before and up to 16 h after spinal cord transection (SCT) in cats anaesthetized with alpha-chloralose. Low frequency (10 Hz) stimulation elicited a continence-like response, including inhibition of the bladder and activation of the EUS, but mid-frequency (33 Hz) stimulation produced a micturition-like response, including excitation of the bladder without activation of the EUS. The dependence of the response on stimulus frequency was linked to interpulse interval as the same number of pulses at 10, 33 and 100 Hz produced different responses. Stimulation of the PN at 33 Hz produced bladder contractions before and 8 h after SCT provided the bladder contained a minimum volume of fluid. Only mid-range frequency stimulation with sufficient stimulus train duration produced a reduction in EUS ENG activity before and after SCT. In addition to a continence-like response, PN stimulation can also elicit a micturition-like response, and this response is dependent on stimulation frequency, stimulus train duration, and bladder volume. The ability to control the two principal functions of the bladder by pudendal nerve stimulation is an exciting prospect for neurorehabilitation.
Neural prosthetic control signals from plan activity (2003)

The prospect of assisting disabled patients by translating neural activity from the brain into control signals for prosthetic devices, has flourished in recent years. Current systems rely on neural activity present during natural arm movements. We propose here that neural activity present before or even without natural arm movements can provide an important, and potentially advantageous, source of control signals. To demonstrate how control signals can be derived from such plan activity we performed a computational study with neural activity previously recorded from the posterior parietal cortex of rhesus monkeys planning arm movements. We employed maximum likelihood decoders to estimate movement direction and to drive finite state machines governing when to move. Performance exceeded 90% with as few as 40 neurons.
Butyrophilin controls milk fat globule secretion (2006)

The molecular mechanism underlying milk fat globule secretion in mammary epithelial cells ostensibly involves the formation of complexes between plasma membrane butyrophilin and cytosolic xanthine oxidoreductase. These complexes bind adipophilin in the phospholipid monolayer of milk secretory granules, the precursors of milk fat globules, enveloping the nascent fat globules in a layer of plasma membrane and pinching them off the cell. However, using freeze-fracture immunocytochemistry, we find these proteins in locations other than those previously inferred. Significantly, butyrophilin in the residual plasma membrane of the fat globule envelope is concentrated in a network of ridges that are tightly apposed to the monolayer derived from the secretory granule, and the ridges coincide with butyrophilin labeling in the globule monolayer. Therefore, we propose that milk fat globule secretion is controlled by interactions between plasma membrane butyrophilin and butyrophilin in the secretory granule phospholipid monolayer rather than binding of butyrophilin-xanthine oxidoreductase complexes to secretory granule adipophilin.
Heterogeneous Memory Enhanced Multimodal Attention Model for Video Question Answering (2019)

In this paper, we propose a novel end-to-end trainable Video Question Answering (VideoQA) framework with three major components: 1) a new heterogeneous memory which can effectively learn global context information from appearance and motion features; 2) a redesigned question memory which helps understand the complex semantics of question and highlights queried subjects; and 3) a new multimodal fusion layer which performs multi-step reasoning by attending to relevant visual and textual hints with self-updated attention. Our VideoQA model firstly generates the global context-aware visual and textual features respectively by interacting current inputs with memory contents. After that, it makes the attentional fusion of the multimodal visual and textual representations to infer the correct answer. Multiple cycles of reasoning can be made to iteratively refine attention weights of the multimodal data and improve the final representation of the QA pair. Experimental results demonstrate our approach achieves state-of-the-art performance on four VideoQA benchmark datasets.
Visualization of growth factor receptor sites in rat forebrain (1988)

It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of [125I]EGF and [125I]IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that [125I]EGF sites are mostly found in the rat forebrain during brain development. On the other hand, [125I]IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.
Exploring the Structure of Human Defensive Responses from Judgments of Threat Scenarios (2015)

How humans react to threats is a topic of broad theoretical importance, and also relevant for understanding anxiety disorders. Many animal threat reactions exhibit a common structure, a finding supported by human evaluations of written threat scenarios that parallel patterns of rodent defensive behavior to actual threats. Yet the factors that underlie these shared behavioral patterns remain unclear. Dimensional accounts rooted in Darwin's conception of antithesis explain many defensive behaviors. Across species, it is also clear that defensive reactions depend on specific situational factors, a feature long emphasized by psychological appraisal theories. Our study sought to extend prior investigations of human judgments of threat to a broader set of threats, including natural disasters, threats from animals, and psychological (as opposed to physical) threats. Our goal was to test whether dimensional and specific patterns of threat evaluation replicate across different threat classes. 85 healthy adult subjects selected descriptions of defensive behaviors that indicated how they would react to 29 threatening scenarios. Scenarios differed with respect to ten factors, e.g., perceived dangerousness or escapability. Across scenarios, we correlated these factor ratings with the pattern of defensive behaviors subjects endorsed. A decision tree hierarchically organized these correlation patterns to successfully predict each scenario's most common reaction, both for the original sample of subjects and a separate replication group (n = 22). At the top of the decision tree, degree of dangerousness interacted with threat type (physical or psychological) to predict dimensional approach/avoidance behavior. Subordinate nodes represented specific defensive responses evoked by particular contexts. Our ecological approach emphasizes the interplay of situational factors in evoking a broad range of threat reactions. Future studies could test predictions made by our results to help understand pathological threat processing, such as seen in anxiety disorders, and could begin to test underlying neural mechanisms.
Treatment of the Cancer Anorexia-Cachexia Syndrome: A Critical Reappraisal (2003)

Cancer anorexia-cachexia syndrome (CACS) is a combination of anorexia, tissue wasting, weight loss and poor performance status. Some CACS symptoms are due to a macrophage production of TNF and IL-1, while the metabolic effects are mainly explained by the release of IL-6 from tumor cells. Clinical treatment of CACS involves progestational agents (medroxyprogesterone acetate, MPA, megestrol acetate, MA) for long term treatment. The use of prokinetic agents (like metoclopramide) is recommended, especially if patients need concomitant opioid treatment for pain; if otherwise indicated, corticosteroids are useful for short periods. The administration of artificial nutrition should be individualized following the clinical condition of the patient and possibly taking into account the wishes of the patient. The practical evaluation criteria of the drugs employed for CACS are based on weight increase and appetite stimulation. Hence, a new approach to the mechanism of action of MPA, MA and of other agents is urgently needed.
Effect of insulin-like growth factor-1 on the responses to and recognition of hypoglycemia in humans. A comparison with insulin. (1993)

Recombinant human insulin-like growth factor-1 (rhIGF-1) lowers blood glucose in humans but its effect on counterregulatory responses has not been established. We therefore compared infusions of rhIGF-1 (0.7 micrograms/kg per min) and insulin (0.8 mU/kg.min) for 120 min in 10 healthy volunteers (glucose allowed to fall freely). With both, glucose fell rapidly because of stimulation of glucose uptake and suppression of hepatic glucose production. Despite similar plasma glucose nadirs (2.6 +/- 0.1 vs. 2.7 +/- 0.1 mM), the glucagon response was absent (P < 0.005), growth hormone release was attenuated (P < 0.03), and norepinephrine levels were increased (P < 0.05) by rhIGF-1 compared with insulin. Absent glucagon responses were associated with a blunting of the rebound increase in glucose production (P < 0.05 vs. insulin). After stopping the infusions, glucose recovery was delayed with rhIGF-1 (P < 0.001 vs. insulin). To further evaluate the effects of rhIGF-1 during a standard hypoglycemic stimulus, eight additional healthy subjects received rhIGF-1 or insulin while glucose was clamped at 2.8 mM. Again the rise in glucagon during insulin-induced hypoglycemia was totally abolished by rhIGF-1. Growth hormone responses were delayed, whereas increases in norepinephrine, heart rate, and symptomatic awareness of hypoglycemia were greater with rhIGF-1 compared with insulin (P < 0.05). It was concluded that rhIGF-1 suppression of glucagon release during hypoglycemia impairs glucose recovery. Paradoxically, awareness of hypoglycemia is enhanced with rhIGF-1 in part due to stimulation of the sympathetic activity.
Renal tubular effects of endothelin-B receptor signaling: its role in cardiovascular homeostasis and extracellular volume regulation (2000)

The role of the endothelin-B receptor in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. One potential depressor mechanism of endothelin-B activation is through the promotion of natriuresis and diuresis in the renal tubule. Recent studies demonstrate that rodents genetically deficient for the endothelin-B exhibit sodium-dependent hypertension due to an absence of tonic inhibition of the epithelial sodium channel in the distal nephron. These studies suggest that the predominant role of endothelin-B receptors in the basal physiologic state may be to regulate renal sodium excretion relative to the level of oral salt intake.
Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady‐state dose (2002)

The cis-OH-perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.
A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis (2014)

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat-human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1-treated primary human lung fibroblasts and transforming growth factor-β1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model-human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease.
Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors (2010)

Intestinal cells are constantly produced from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate into one of the four principal cell types. Signalling pathways, including the Notch signalling pathway, coordinate these differentiation processes and their deregulation may cause cancer. Pharmacological inhibition through γ-secretase inhibitors or genetic inactivation of the Notch signalling pathway results in the complete loss of proliferating crypt progenitors due to their conversion into post-mitotic goblet cells. The basic helix-loop-helix transcription factor Math1 is essential for intestinal secretory cell differentiation. Because of the critical roles of both Math1 and Notch signalling in intestinal homeostasis and neoplastic transformation, we sought to determine the genetic hierarchy regulating the differentiation of intestinal stem cells into secretory cells. In this paper, we demonstrate that the conversion of intestinal stem cells into goblet cells upon inhibition of the Notch signalling pathway requires Math1.
Expression of staphylococcal enterotoxin C1 in Escherichia coli (1987)

The structural gene encoding staphylococcal enterotoxin C1 was cloned into Escherichia coli and localized on a 1.5-kilobase HindIII-ClaI DNA fragment by subcloning. The toxin was partially purified from E. coli clones and shown to be immunologically identical to enterotoxin C1 from Staphylococcus aureus. The cloned toxin also had the same molecular weight (26,000) and charge heterogeneity as staphylococcus-derived enterotoxin. Toxins from both sources were equally biologically active.
Yield-reliability modeling: experimental verification and application to burn-in reduction (2003)

An integrated yield-reliability model is verified using burn-in data from 77,000 microprocessor units manufactured by IBM Microelectronics. The model is based on the fact that defects over semiconductor wafers are not randomly distributed, but have a tendency to cluster. It is shown that this fact can be exploited to produce die of varying reliability by sorting die into bins based on how many of their neighbors test faulty. Die that test good at wafer probe, yet come from regions with many faulty die, have a higher incidence of infant mortality failure than die from regions with few faulty die. The yield-reliability model is used to predict the fraction of good die in each bin following wafer probing as well as the fraction of failures in each bin following stress testing (e.g. burn-in). Results show excellent agreement between model predictions and observed data.
Temporal Noise Shaping, Qualtization and Coding Methods in Perceptual Audio Coding: A Tutorial Introduction (1999)

Perceptual audio coding has become an important key technology for many types of multimedia services these days. This paper provides a brief tutorial introduction into a number of issues as they arise in todayOs low bitrate audio coders. After discussing the Temporal Noise Shaping technology in the first part of this paper, the second part will focus on the large number of possible choices for the quantization and coding methods for perceptual audio coding along with examples of real-world systems using these approaches.
Alpha-glucan phosphorylase from Escherichia coli. Cloning of the gene, and purification and characterization of the protein. (1988)

By using a synthetic oligonucleotide probe identical to a part of the gene for the Escherichia coli major outer membrane lipoprotein, we have cloned a gene from E. coli chromosomal DNA. However, the cloned gene was not one of the lipoprotein genes. The amino acid sequence deduced from its nucleotide sequence shows extensive similarities instead to alpha-glucan phosphorylase (EC 2.4.1.1). The gene, glgP, is located immediately downstream from glgA, the gene for glycogen synthase. The glgP gene was inserted into pUC9 vector and expressed in the presence of the lac inducer. The gene product was purified to apparent homogeneity as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In all chromatographies, the protein was eluted accompanied by a low phosphorylase activity. The final preparation showed phosphorolytic activity to various alpha-glucans, although the specific activity was extremely low compared to other alpha-glucan phosphorylases under the standard assay conditions. Its enzymatic activity, however, increased almost linearly as the concentration of glucan increased, reaching a value comparable with those of other phosphorylases. The amino acid sequence deduced was compared with those of alpha-glucan phosphorylases from other sources.
Synthesis of Glycoconjugate Vaccines for Candida albicans Using Novel Linker Methodology (2005)

[reaction: see text] The cell wall phosphomannan of Candida species is a complex N-linked glycoprotein with a glycan chain that contains predominantly alpha-linked mannose residues. However, it is the minor beta-mannan component of the phosphomannan of clinically important Candida strains that provides immunological protection in animal models of fungal disease and hence holds promise as a component of conjugate vaccines. This important antigen occurs in different forms linked to the alpha-mannan backbone via a phosphodiester bond (acid-labile beta-mannan) or directly via a glycosidic bond. To reproducibly synthesize and evaluate conjugate vaccines, a robust method for the synthesis of the different oligosaccharide epitopes is required. Here, we report the gram-scale syntheses of both types of epitopes by an approach that utilizes glucosyl trichloroacetimidate donor 2 to first create a beta-glucopyranoside linkage and then epimerizes the C-2 center via an oxidation-reduction sequence that provides an efficient multigram scale route to the beta-mannopyranosides 5, 8, and 15. Reaction of glycosides 16-18 with homobifunctional adipic acid p-nitrophenyl diesters in dry DMF gave the corresponding half esters in good yields, and of sufficient stability to permit chromatographic purification. Subsequent conjugation with BSA and tetanus toxiod (TT) under mild conjugation conditions afforded the corresponding tri- and tetrasaccharide neoglycoproteins with good efficiency. The conjugation method is also applicable to the coupling of small amounts (mg) of larger oligosaccharides with different proteins.
Mucin-type O-Glycosylation during Development (2013)

Mucin-type O-glycosylation is an evolutionarily conserved protein modification present on membrane-bound and secreted proteins. Aberrations in O-glycosylation are responsible for certain human diseases and are associated with disease risk factors. Recent studies have demonstrated essential roles for mucin-type O-glycosylation in protein secretion, stability, processing, and function. Here, we summarize our current understanding of the diverse roles of mucin-type O-glycosylation during eukaryotic development. Appreciating how this conserved modification operates in developmental processes will provide insight into its roles in human disease and disease susceptibilities.