gebhart/patrepeval huggingface dataset:
Epidermal Growth Factor Receptor Fate Is Controlled by Hrs Tyrosine Phosphorylation Sites That Regulate Hrs Degradation (2006)

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is an endosomal protein essential for the efficient sorting of activated growth factor receptors into the lysosomal degradation pathway. Hrs undergoes ligand-induced tyrosine phosphorylation on residues Y329 and Y334 downstream of epidermal growth factor receptor (EGFR) activation. It has been difficult to investigate the functional roles of phosphoHrs, as only a small proportion of the cellular Hrs pool is detectably phosphorylated. Using an HEK 293 model system, we found that ectopic expression of the protein Cbl enhances Hrs ubiquitination and increases Hrs phosphorylation following cell stimulation with EGF. We exploited Cbl's expansion of the phosphoHrs pool to determine whether Hrs tyrosine phosphorylation controls EGFR fate. In structure-function studies of Cbl and EGFR mutants, the level of Hrs phosphorylation and rapidity of apparent Hrs dephosphorylation correlated directly with EGFR degradation. Differential expression of wild-type versus Y329,334F mutant Hrs in Hrs-depleted cells revealed that one or both tyrosines regulate ligand-dependent Hrs degradation, as well as EGFR degradation. By modulating Hrs ubiquitination, phosphorylation, and protein levels, Cbl may control the composition of the endosomal sorting machinery and its ability to target EGFR for lysosomal degradation.
Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes (2019)

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%-40% for HPS. Puumala virus (PUUV) is the most common HFRS-causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell-mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.
Single base pair mutation analysis by PNA directed PCR clamping (1993)

A novel method that allows direct analysis of single base mutation by the polymerase chain reaction (PCR) is described. The method utilizes the finding that PNAs (peptide nucleic acids) recognize and bind to their complementary nucleic acid sequences with higher thermal stability and specificity than the corresponding deoxyribooligonucleotides and that they cannot function as primers for DNA polymerases. We show that a PNA/DNA complex can effectively block the formation of a PCR product when the PNA is targeted against one of the PCR primer sites. Furthermore, we demonstrate that this blockage allows selective amplification/suppression of target sequences that differ by only one base pair. Finally we show that PNAs can be designed in such a way that blockage can be accomplished when the PNA target sequence is located between the PCR primers.
Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors (2004)

Oncogenic mutations in ras genes frequently occur in patients with myeloid disorders, and in these patients erythropoiesis is often affected. Previously, we showed that expression of oncogenic H-ras in purified mouse primary fetal liver erythroid progenitors blocks terminal erythroid differentiation and supports erythropoietin (Epo)-independent proliferation. As a first step in understanding the underlying molecular mechanisms we examined the signaling pathways downstream of Ras in primary erythroid cells. We found that 3 major pathways are abnormally activated by oncogenic H-ras: Raf/ERK (extracellular signal-regulated kinase), phosphatidyl inositol 3 (PI3)-kinase/Akt, and RalGEF/RalA. However, only constitutive activation of the MEK (MAPK [mitogen-activated protein kinase]/ERK kinase)/ERK pathway alone could recapitulate all of the effects of oncogenic H-ras expression in blocking erythroid differentiation and inducing Epo-independent proliferation. Although expression of a constitutively active Akt kinase (ca.Akt) in erythroid progenitors does not significantly affect erythroid differentiation in the presence of Epo, coexpression of ca.Akt together with a constitutively active MEK causes prolonged Epo-independent proliferation of erythroid progenitors in addition to a block in differentiation. Moreover, the effects of oncogenic H-ras expression on primary erythroid cells are blocked by the addition of U0126, a specific inhibitor of MEK1 and MEK2, allowing normal terminal erythroid proliferation and differentiation. Our data suggest that the interruption of constitutive MEK/ERK signaling is a potential therapeutic strategy to correct impaired erythroid differentiation in patients with myeloid disorders.
The nucleotype, the natural karyotype and the ancestral genome. (1996)

New knowledge of synteny and collinearity promises to unify genetics and to affect our perception of higher order genome structure. This exciting new synthetic approach emphasizes genomic similarities rather than diversity. Two other aspects of genomic form and organisation, offering potentially unifying concepts in genome studies are: the nucleotype, and the natural karyotype. Genome size varies greatly between eukaryotes, and shows many strikingly precise correlations with phenotypic characters, independent of information encoded in DNA. Such nucleotypic correlations, based on biophysical absolutes, apply to all species, irrespective of genome size or chromosome number, and set limits on the range of phenotypes which can be expressed by genic control. Thus, knowledge of nucleotypic effects has considerable predictive value which can help to unify our understanding of genomes. Other studies of reconstructed nuclei have shown that: (1) the basic haploid genome exists as a real structural unit in nuclear architecture; while (2) the mean spatial arrangement of its heterologues also exists as a natural karyotype which is predictable using a simple model. Recently reported conceptual alignments of the maize genomes, which reflect the circularized ancestral grass genome, show interesting similarities with the orders of centromeres in their natural karyotypes predicted by the Bennett model. The basis of this phenomenon (if repeated in other species), and of selection which retains the ancestral genome form despite changes in basic chromosome number, may need to be explained. Perhaps the overall 3-D structure of the genome has some critical functional significance, essential for development. If so, a knowledge of this common structure would further unify our understanding of genomes and their evolution.
Correction for intensity falloff in surface coil magnetic resonance imaging (1988)

A method has been developed to compensate for sensitivity variation in surface coil images. An algorithm to derive the surface coil profile by acquiring a crude body coil image of the region under study is presented and tested using a homogeneous phantom. Practical application is demonstrated on images of a tomato and rabbit acquired with a 2 T 33-cm bore magnetic resonance imager/spectrometer.
Chemical modification of acyl-CoA:cholesterol-O-acyltransferase. 1. Identification of acyl-CoA:cholesterol O-acyltransferase subtypes by differential diethyl pyrocarbonate sensitivity (1988)

Acyl-CoA:cholesterol O-acyltransferase (EC 2.3.1.26) (ACAT) catalyzes the intracellular synthesis of cholesteryl esters from cholesterol and fatty acyl-CoA at neutral pH. Despite the probable pathophysiologic role of ACAT in vascular cholesteryl ester accumulation during atherogenesis, its mechanism of action and its regulation remain to be elucidated because the enzyme polypeptide has never been identified or purified. Present chemical modification results identify two distinct tissue types of ACAT, based on marked differences in reactivity of an active-site histidine residue toward diethyl pyrocarbonate (DEP) and acetic anhydride. The apparent Ki of the DEP-sensitive ACAT subtype, typified by aortic ACAT, was 40 microM, but the apparent Ki of the DEP-resistant ACAT subtype, typified by liver ACAT, was 1500 microM, indicating a 38-fold difference in sensitivity to DEP. Apparent Ki's of aortic and liver ACAT for inhibition by acetic anhydride were also discordant (less than 500 microM and greater than 5 mM, respectively). On the basis of the reversibility of inhibition by hydroxylamine, a neutral pKa for maximal modification, and acetic anhydride protection against DEP inactivation, DEP and acetic anhydride appear to modify a common histidine residue. Oleoyl-CoA provided partial protection against inactivation by DEP and acetic anhydride, suggesting that the modified histidine is at or near the active site of ACAT. Systematic investigation of ACAT activity from 14 different organs confirmed the existence of 2 subtypes of ACAT on the basis of their different reactivities toward DEP and acetic anhydride.(ABSTRACT TRUNCATED AT 250 WORDS)
Old Friends in New Constellations - the Hematopoetic Growth Factors G-CSF, GMCSF, and EPO for the Treatment of Neurological Diseases (2008)

Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.
Exacerbation of Noise-Induced Hearing Loss in Mice Lacking the Glutamate Transporter GLAST (2000)

Acoustic overstimulation is one of the major causes of hearing loss. Glutamate is the most likely candidate neurotransmitter for afferent synapses in the peripheral auditory system, so it was proposed that glutamate excitotoxicity may be involved in noise trauma. However, there has been no direct evidence that noise trauma is caused by excessive release of glutamate from the inner hair cells (IHCs) during sound exposure because studies have been hampered by powerful glutamate uptake systems in the cochlea. GLAST is a glutamate transporter highly expressed in the cochlea. Here we show that after acoustic overstimulation, GLAST-deficient mice show increased accumulation of glutamate in perilymphs, resulting in exacerbation of hearing loss. These results suggest that GLAST plays an important role in keeping the concentration of glutamate in the perilymph at a nontoxic level during acoustic overstimulation. These findings also provide further support for the hypothesis that IHCs use glutamate as a neurotransmitter.
Prototype Selection for Composite Nearest Neighbor Classifiers TITLE2 (1996)

Combining the predictions of a set of classifiers has been shown to be an effective way to create composite classifiers that are more accurate than any of the component classifiers. Increased accuracy has been shown in a variety of real-world applications, ranging from protein sequence identification to determining the fat content of ground meat. Despite such individual successes, the answers are not known to fundamental questions about classifier combination, such as ``Can classifiers from any given model class be combined to create a composite classifier with higher accuracy?'''' or ``Is it possible to increase the accuracy of a given classifier by combining its predictions with those of only a small number of other classifiers?''''. The goal of this dissertation is to provide answers to these and closely related questions with respect to a particular model class, the class of nearest neighbor classifiers. We undertake the first study that investigates in depth the combination of nearest neighbor classifiers. Although previous research has questioned the utility of combining nearest neighbor classifiers, we introduce algorithms that combine a small number of component nearest neighbor classifiers, where each of the components stores a small number of prototypical instances. In a variety of domains, we show that these algorithms yield composite classifiers that are more accurate than a nearest neighbor classifier that stores all training instances as prototypes. The research presented in this dissertation also extends previous work on prototype selection for an independent nearest neighbor classifier. We show that in many domains, storing a very small number of prototypes can provide classification accuracy greater than or equal to that of a nearest neighbor classifier that stores all training instances. We extend previous work by demonstrating that algorithms that rely primarily on random sampling can effectively choose a small number of prototypes.
Finding the Optimal Social Trust Path for the Selection of Trustworthy Service Providers in Complex Social Networks (2011)

Online Social networks have provided the infrastructure for a number of emerging applications in recent years, e.g., for the recommendation of service providers or the recommendation of files as services. In these applications, trust is one of the most important factors in decision making by a service consumer, requiring the evaluation of the trustworthiness of a service provider along the social trust paths from a service consumer to the service provider. However, there are usually many social trust paths between two participants who are unknown to one another. In addition, some social information, such as social relationships between participants and the recommendation roles of participants, has significant influence on trust evaluation but has been neglected in existing studies of online social networks. Furthermore, it is a challenging problem to search the optimal social trust path that can yield the most trustworthy evaluation result and satisfy a service consumer's trust evaluation criteria based on social information. In this paper, we first present a novel complex social network structure incorporating trust, social relationships and recommendation roles, and introduce a new concept, Quality of Trust (QoT), containing the above social information as attributes. We then model the optimal social trust path selection problem with multiple end-to-end QoT constraints as a Multiconstrained Optimal Path (MCOP) selection problem, which is shown to be NP-Complete. To deal with this challenging problem, we propose a novel Multiple Foreseen Path-Based Heuristic algorithm MFPB-HOSTP for the Optimal Social Trust Path selection, where multiple backward local social trust paths (BLPs) are identified and concatenated with one Forward Local Path (FLP), forming multiple foreseen paths. Our strategy could not only help avoid failed feasibility estimation in path selection in certain cases, but also increase the chances of delivering a near-optimal solution with high quality. The results of our experiments conducted on a real data set of online social networks illustrate that MFPB-HOSTP algorithm can efficiently identify the social trust paths with better quality than our previously proposed H_OSTP algorithm that outperforms prior algorithms for the MCOP selection problem.
Vitamin D Status Affects Strength Gains in Older Adults Supplemented With a Combination of β‐Hydroxy‐β‐Methylbutyrate, Arginine, and Lysine (2011)

The nutrient cocktail of HMB/ARG/LYS alone was effective in increasing muscle mass regardless of vitamin D status, but accompanying strength increases were observed only when participants also had adequate vitamin D status indicating a synergistic effect between the HMB/ARG/LYS and vitamin D.
Darstellung und Eigenschaften des Chinaaldehyds (1962)

Abstract Chinaaldehyd (IV) wird in 4 Schritten aus Chinasäure in 75‐proz. Ausbeute dargestellt. Als α‐Hydroxyaldehyd bildet er eine dimere Form, als λ‐Hydroxyaldehyd bildet er Lactolide und normale Acetale nebeneinander, und in der „Aldehydammoniak”︁‐Verbindung sind offene Aldehyd‐Form und Cyclohalbacetal‐Form im gleichen Molekül vereinigt.
Structure of concentrated nanoemulsions (2005)

We use extreme shear to create a dispersion of nanoscale droplets of silicone oil in an immiscible water phase containing an anionic surfactant sodium dodecylsulfate. Using centrifugal size fractionation, we obtain nanoemulsions having a well-defined average radius of a=75 nm. We measure the structure of concentrated nanoemulsions over a wide range of volume fractions, 0<phi<0.6, using small angle neutron scattering, and we determine the structure factor S(q) of disordered glassy dispersions of uniform deformable droplets interacting through screened surface charge repulsions. Although the low-q behavior of S(q,phi) resembles that predicted for hard spheres, the height of the primary peak does not. Instead, it exhibits a maximum as phi is increased. This difference cannot be explained solely by the droplet size polydispersity and is likely related to the deformability of the droplets that have been locked into a glassy structure.
Enhanced selective gene delivery to neural stem cells in vivo by an adeno-associated viral variant (2015)

Neural stem cells (NSCs) are defined by their ability to self-renew and to differentiate into mature neuronal and glial cell types. NSCs are the subject of intense investigation, owing to their crucial roles in neural development and adult brain function and because they present potential targets for gene and cell replacement therapies following injury or disease. Approaches to specifically genetically perturb or modulate NSC function would be valuable for either motivation. Unfortunately, most gene delivery vectors are incapable of efficient or specific gene delivery to NSCs in vivo. Vectors based on adeno-associated virus (AAV) present a number of advantages and have proven increasingly successful in clinical trials. However, natural AAV variants are inefficient in transducing NSCs. We previously engineered a novel AAV variant (AAV r3.45) capable of efficient transduction of adult NSCs in vitro. Here, to build upon the initial promise of this variant, we investigated its in vitro and in vivo infectivity. AAV r3.45 was more selective for NSCs than mature neurons in a human embryonic stem cell-derived culture containing a mixture of cell types, including NSCs and neurons. It was capable of more efficient and selective transduction of rat and mouse NSCs in vivo than natural AAV serotypes following intracranial vector administration. Delivery of constitutively active β-catenin yielded insights into mechanisms by which this key regulator modulates NSC function, indicating that this engineered AAV variant can be harnessed for preferential modulation of adult NSCs in the hippocampus. The capacity to rapidly genetically modify these cells might greatly accelerate in vivo investigations of adult neurogenesis.
Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta (2008)

The main disorders of human pregnancy are rooted in defective placentation. Normal placental development depends on proliferation, differentiation, and fusion of cytotrophoblasts to form and maintain an overlying syncytiotrophoblast. There is indirect evidence that the insulin-like growth factors (IGFs), which are aberrant in pregnancy disorders, are involved in regulating trophoblast turnover, but the processes that control human placental growth are poorly understood. Using an explant model of human first-trimester placental villus in which the spatial and ontological relationships between cell populations are maintained, we demonstrate that cytotrophoblast proliferation is enhanced by IGF-I/IGF-II and that both factors can rescue cytotrophoblast from apoptosis. Baseline cytotrophoblast proliferation ceases in the absence of syncytiotrophoblast, although denuded cytotrophoblasts can proliferate when exposed to IGF and the rate of cytotrophoblast differentiation/fusion and, consequently, syncytial regeneration, increases. Use of signaling inhibitors suggests that IGFs mediate their effect on cytotrophoblast proliferation/syncytial formation through the MAPK pathway, whereas effects on survival are regulated by the phosphoinositide 3-kinase pathway. These results show that directional contact between cytotrophoblast and syncytium is important in regulating the relative amounts of the two cell populations. However, IGFs can exert an exogenous regulatory influence on placental growth/development, suggesting that manipulation of the placental IGF axis may offer a potential therapeutic route to the correction of inadequate placental growth.
Synthesis, DNA-binding properties and cytotoxic activity of flavin-oligopyrrolecarboxamide and flavin-oligoimidazolecarboxamide conjugates. (1998)

The aim of this study was to develop novel series of photosensitizer-DNA minor groove binder hybrids composed of a flavin (isoalloxazine) chromophore linked to a moiety related to netropsin or distamycin. Three series (Fla-Pyr, Fla-Gly-Pyr and Fla-Gly-Im) were synthesized which differ by the number and the nature of the heterocyclic nuclei in the oligopeptide units, the nature of the linker and its anchoring position on the flavin. In terms of DNA binding and DNA specificity, satisfactory data are obtained in the Fla-Pyr and Fla-Gly-Pyr series; in terms of photo-induced cytotoxicity, the results are disappointing. The present study allows us to draw the following structure-activity relationships: (i) substitution of the flavin nucleus in either the N3 or the N10 position does not affect the activity; (ii) tris-pyrrolic hybrids are more efficient than bis- and tetra-pyrrolic analogs; (iii) the presence of a glycin in the linking chain does not suppress the DNA binding properties or the cytotoxic activities of the hybrids; and (iv) the replacement of the pyrrole nuclei by imidazoles has a drastic effect since it results in the loss of DNA affinity and cytotoxicity.