gebhart/patrepeval huggingface dataset:
Drug-Mediated Targeted Disruption of Multiple Protein Activities Through Functional Inhibition of the Hsp90 Chaperone Complex (2007)

Hsp90 is an evolutionarily conserved and ubiquitously expressed molecular chaperone that mainly modulates, along with a group of co-chaperones, the general platform of protein folding and prevents the nonspecific aggregation of misfolded or unfolded proteins. In the voluminous Hsp90 clientele, a large variety of important regulatory proteins can be identified, including many whose deregulation may lead to cancer initiation and progression, such as the oncogenic clients pp60(v-src), Bcr-Abl, mutated p53, ErbB2 (Her-2), Akt, Flt3, HIF-1alpha and B-Raf. Therefore, inhibition of Hsp90 function offers the prospect of simultaneously disrupting multiple signaling pathways directly implicated in the development of malignant phenotypes. During the last few years, there has been a major focus on the development of Hsp90 specific inhibitors. This started with the discovery that certain natural products could specifically disrupt Hsp90 chaperone activities. The benzoquinone ansamycin antibiotic geldanamycin and its less toxic derivative 17-AAG have been shown to possess strong anti-proliferative and apoptotic activity in cancer cells, whereas 17-AAG has demonstrated potent anti-tumor activity in several human xenograft models, including breast, prostate and colon cancer. In an effort to overcome difficulties with drug toxicity and solubility, a number of novel bioengineered 17-AAG analogues, such as 17-DMAG and IPI-504, and small-molecule inhibitors, including purine and pyrazole derivatives, have emerged from rational drug design followed by high-throughput screening approaches. 17-AAG was the leader inhibitor to enter and successfully complete phase I clinical trials, thus demonstrating that Hsp90 constitutes a valid drug target for cancer therapy. This review includes information on the current model of ternary interactions between Hsp90, client proteins and a vast array of co-chaperones followed by a list of characteristic inhibitors and ongoing clinical trials reported thus far.
Interaction of a Receptor Tyrosine Kinase, EGF-R, with Caveolins (1997)

Caveolin, a 21-24-kDa integral membrane protein, is a principal component of caveolae membranes. We and others have suggested that caveolin functions as a scaffolding protein to organize and concentrate certain caveolin-interacting signaling molecules within caveolae membranes. In this regard, it has been shown that a 20-amino acid membrane-proximal region of the cytosolic NH2-terminal domain of caveolin is sufficient to mediate the interaction of caveolin with signaling proteins, namely G-proteins, Src-like kinases, eNOS, and H-Ras. This caveolin-derived protein domain has been termed the caveolin-scaffolding domain. Binding of the caveolin-scaffolding domain functionally suppresses the activity of G-protein alpha subunits, eNOS, and Src-like kinases, suggesting that caveolin binding may also play a negative regulatory role in signal transduction. Here, we report the direct interaction of caveolin with a growth factor receptor, EGF-R, a known caveolae-associated receptor tyrosine kinase. Two consensus caveolin binding motifs have been previously defined using phage display technology. One of these motifs is present within the conserved kinase domains of most known receptor tyrosine kinases (termed region IX). We now show that this caveolin binding motif within the kinase domain of the EGF-R can mediate the interaction of the EGF-R with the scaffolding domains of caveolins 1 and 3 but not with caveolin 2. In addition, the scaffolding domains of caveolins 1 and 3 both functionally inhibit the autophosphorylation of the EGF-R kinase in vitro. Importantly, this caveolin-mediated inhibition of the EGF-R kinase could be prevented by the addition of an EGF-R-derived peptide that (i) contains a well conserved caveolin binding motif and (ii) is located within the kinase domain of the EGF-R and most known receptor tyrosine kinases. Similar results were obtained with protein kinase C, a serine/threonine kinase, suggesting that caveolin may function as a general kinase inhibitor. The implications of our results are discussed within the context of caveolae-mediated signal transduction. In this regard, caveolae-coupled signaling might explain how linear signaling pathways can branch and interconnect extensively, forming a signaling module or network.
Human photoreceptor topography (1990)

We have measured the spatial density of cones and rods in eight whole-mounted human retinas, obtained from seven individuals between 27 and 44 years of age, and constructed maps of photoreceptor density and between-individual variability. The average human retina contains 4.6 million cones (4.08-5.29 million). Peak foveal cone density averages 199,000 cones/mm2 and is highly variable between individuals (100,000-324,000 cones/mm2). The point of highest density may be found in an area as large as 0.032 deg2. Cone density falls steeply with increasing eccentricity and is an order of magnitude lower 1 mm away from the foveal center. Superimposed on this gradient is a streak of high cone density along the horizontal meridian. At equivalent eccentricities, cone density is 40-45% higher in nasal compared to temporal retina and slightly higher in midperipheral inferior compared to superior retina. Cone density also increases slightly in far nasal retina. The average human retina contains 92 million rods (77.9-107.3 million). In the fovea, the average horizontal diameter of the rod-free zone is 0.350 mm (1.25 degrees). Foveal rod density increases most rapidly superiorly and least rapidly nasally. The highest rod densities are located along an elliptical ring at the eccentricity of the optic disk and extending into nasal retina with the point of highest density typically in superior retina (5/6 eyes). Rod densities decrease by 15-25% where the ring crosses the horizontal meridian. Rod density declines slowly from the rod ring to the far periphery and is highest in nasal and superior retina. Individual variability in photoreceptor density differs with retinal region and is similar for both cones and rods. Variability is highest near the fovea, reaches a minimum in the midperiphery, and then increases with eccentricity to the ora serrata. The total number of foveal cones is similar for eyes with widely varying peak cone density, consistent with the idea that the variability reflects differences in the lateral migration of photoreceptors during development. Two fellow eyes had cone and rod numbers within 8% and similar but not identical photoreceptor topography.
Spatio-temporal motion estimation for disease discrimination in cardiac echo videos (2008)

In this paper we present a method of simultaneous registration of an entire sequence of frames of an echocardiographic sequence. In our approach, each echo frame is modeled using a probability density function, and registration problem between all pairs of echo frames is formulated as the problem of matching probability densities. An information-theoretic criterion called the Jensen-Renyi divergence is used to measure the distance between the probability density functions. The Renyipsilas Quadratic entropy results in a closed- form solution for the registration problem. Once the echo frames are registered, temporal trajectories of corresponding feature points in successive frames can be used to derive average velocity curves which have been shown to be useful for disease discrimination. To evaluate our technique for echo motion estimation for disease discrimination, we tested on a data set including cardiac echo from 21 patients of varying diseases. The data set includes a total of 72 complete cardiac cycles and contains 1612 frames. We compare our approach against two competing motion detection techniques, optical flow and Demons algorithm, on the same data set, and our motion detector performs best in terms of the separation between different diseases.
MANIFESTATION AND OUTCOME OF SEVERE MALARIA IN CHILDREN IN NORTHERN GHANA (2004)

The symptoms of severe malaria and their contribution to mortality were assessed in 290 children in northern Ghana. Common symptoms were severe anemia (55%), prostration (33%), respiratory distress (23%), convulsions (20%), and impaired consciousness (19%). Age influenced this pattern. The fatality rate was 11.2%. In multivariate analysis, circulatory collapse, impaired consciousness, hypoglycemia, and malnutrition independently predicted death. Children with severe malaria by the current World Health Organization (WHO) classification, but not by the previous one (1990), showed relatively mild clinical manifestations and a low case fatality rate (3.2%). In hospitalized children with severe malaria in northern Ghana, severe anemia is the leading manifestation, but itself does not contribute to mortality. In this region, malnutrition and circulatory collapse were important predictors of fatal malaria. The current WHO criteria serve well in identifying life-threatening disease, but also include rather mild cases that may complicate the allocation of immediate care in settings with limited resources.
Identification of a specific interleukin 1 inhibitor in the urine of febrile patients. (1984)

The urine of febrile patients has been found to contain high concentrations of an inhibitor of interleukin 1 (IL-1)-induced thymocyte proliferation. The inhibitor is specific for IL-1 and does not block the effects of interleukin 2 (IL-2) or phytohemagglutin (PHA) on thymocytes, and it is not nonspecifically toxic for these cells. IL-1 inhibitor can be found in the urine of normal individuals and afebrile patients, but is present in increased concentrations in the urine of patients with fever of diverse etiologies. Preliminary physicochemical characterization indicates that the inhibitor is a 20-40-kdalton protein.
Neurodegenerative Disorders and Nanoformulated Drug Development (2009)

Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders.
DBC2 , a candidate for a tumor suppressor gene involved in breast cancer (2002)

A previously uncharacterized gene, DBC2 (deleted in breast cancer), was cloned from a homozygously deleted region at human chromosome 8p21. DBC2 contains a highly conserved RAS domain and two putative protein interacting domains. Our analyses indicate that DBC2 is the best candidate tumor suppressor gene from this region. It lies within the epicenter of the deletions and is homozygously deleted in 3.5% (7/200) of breast tumors. Mutation analysis of DBC2 led to discovery of two instances of somatic missense mutations in breast tumor specimens, whereas no missense mutations were found in other candidates from the region. Unlike other genes in the region, expression of DBC2 is often extinguished in breast cancer cells or tissues. Moreover, our functional analysis revealed that DBC2 expression in breast cancer cells lacking DBC2 transcripts causes growth inhibition. By contrast, expression of a somatic mutant discovered in a breast cancer specimen does not suppress the growth of breast cancer cells.
Minireview: Glucagon-Like Peptides Regulate Cell Proliferation and Apoptosis in the Pancreas, Gut, and Central Nervous System (2004)

Gut peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut peptides, exemplified by glucagon-like peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances beta-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of beta-cell mass and enhanced resistance to beta-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these peptides in human subjects with diabetes and intestinal disorders, respectively.
The Oncogene eIF4E Reprograms the Nuclear Pore Complex to Promote mRNA Export and Oncogenic Transformation (2012)

The eukaryotic translation initiation factor eIF4E is a potent oncogene that promotes the nuclear export and translation of specific transcripts. Here, we have discovered that eIF4E alters the cytoplasmic face of the nuclear pore complex (NPC), which leads to enhanced mRNA export of eIF4E target mRNAs. Specifically, eIF4E substantially reduces the major component of the cytoplasmic fibrils of the NPC, RanBP2, relocalizes an associated nucleoporin, Nup214, and elevates RanBP1 and the RNA export factors, Gle1 and DDX19. Genetic or pharmacological inhibition of eIF4E impedes these effects. RanBP2 overexpression specifically inhibits the eIF4E mRNA export pathway and impairs oncogenic transformation by eIF4E. The RanBP2 cytoplasmic fibrils most likely slow the release and/or recycling of critical export factors to the nucleus. eIF4E overcomes this inhibitory mechanism by indirectly reducing levels of RanBP2. More generally, these results suggest that reprogramming the NPC is a means by which oncogenes can harness the proliferative capacity of the cell.
Carbohydrate‐mediated cell adhesion in cancer metastasis and angiogenesis (2004)

Malignant transformation is associated with abnormal glycosylation, resulting in the synthesis and expression of altered carbohydrate determinants including sialyl Lewisa and sialyl Lewisx. The sialyl Lewisa and sialyl Lewisx determinants appear in the sera of patients with cancer, and are extensively utilized for serum diagnosis of cancers in Japan. Sialyl Lewisa and sialyl Lewisx are involved in selectin-mediated adhesion of cancer cells to vascular endothelium, and these determinants are thought to be closely associated with hematogenous metastasis of cancers. Recent progress in this area includes the following: 1. Substantial increases in solid clinical statistics that further confirm the contribution of these determinants in the progression of a wide variety of cancers; 2. Elucidation of the ligand specificity of the three family members of selectins and evaluation of the roles of these molecules in cancer cell adhesion; and 3. Advances in the study of the mechanism that leads to the enhanced expression of the sialyl Lewis(a/x) determinants in malignant cells. These recent results have confirmed that these determinants are not merely markers for cancers, but are functionally implicated in the malignant behavior of cancer cells. The results also suggested that the increase of these determinants in malignant cells is an inevitable consequence of the malignant transformation of cells. Considerable new knowledge has also been accumulated regarding the therapeutic implications for suppression of hematogenous metastasis targeting this cell adhesion system.
CD4+,CD28? T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems (2001)

Patients with RA have an expanded and unusual subset of CD4 T cells that infiltrates the tissue lesions and is characterized by a deficiency of CD28, the expression of CD8-alphaalpha homodimers, and the expression of several types of HLA class I-recognizing NK receptors. CD4 T cells bearing NK receptors can bridge functions of the innate and adaptive immune systems, such as responsiveness to specific antigen, rapid release of interferon-gamma, cytotoxicity, independence from classic costimulatory pathways, and integration of multiple activating and inhibitory signals to control effector functions.
Outlier resistant adaptive matched filtering (2002)

Robust adaptive matched filtering (AMF) whereby outlier data vectors are censored from the covariance matrix estimate is considered in a maximum likelihood estimation (MLE) setting. It is known that outlier data vectors whose steering vector is highly correlated with the desired steering vector, can significantly degrade the performance of AMF algorithms such as sample matrix inversion (SMI) or fast maximum likelihood (FML). Four new algorithms that censor outliers are presented which are derived via approximation to the MLE solution. Two algorithms each are related to using the SMI or the FML to estimate the unknown underlying covariance matrix. Results are presented using computer simulations which demonstrate the relative effectiveness of the four algorithms versus each other and also versus the SMI and FML algorithms in the presence of outliers and no outliers. It is shown that one of the censoring algorithms, called the reiterative censored fast maximum likelihood (CFML) technique is significantly superior to the other three censoring methods in stressful outlier scenarios.
Overexpression of Lactobacillus casei d -Hydroxyisocaproic Acid Dehydrogenase in Cheddar Cheese (2004)

Metabolism of aromatic amino acids by lactic acid bacteria is an important source of off-flavor compounds in Cheddar cheese. Previous work has shown that alpha-keto acids produced from Trp, Tyr, and Phe by aminotransferase enzymes are chemically labile and may degrade spontaneously into a variety of off-flavor compounds. However, dairy lactobacilli can convert unstable alpha-keto acids to more-stable alpha-hydroxy acids via the action of alpha-keto acid dehydrogenases such as d-hydroxyisocaproic acid dehydrogenase. To further characterize the role of this enzyme in cheese flavor, the Lactobacillus casei d-hydroxyisocaproic acid dehydrogenase gene was cloned into the high-copy-number vector pTRKH2 and transformed into L. casei ATCC 334. Enzyme assays confirmed that alpha-keto acid dehydrogenase activity was significantly higher in pTRKH2:dhic transformants than in wild-type cells. Reduced-fat Cheddar cheeses were made with Lactococcus lactis starter only, starter plus L. casei ATCC 334, and starter plus L. casei ATCC 334 transformed with pTRKH2:dhic. After 3 months of aging, the cheese chemistry and flavor attributes were evaluated instrumentally by gas chromatography-mass spectrometry and by descriptive sensory analysis. The culture system used significantly affected the concentrations of various ketones, aldehydes, alcohols, and esters and one sulfur compound in cheese. Results further indicated that enhanced expression of d-hydroxyisocaproic acid dehydrogenase suppressed spontaneous degradation of alpha-keto acids, but sensory work indicated that this effect retarded cheese flavor development.
Cytokine-Activated Endothelium Recruits Osteoclast Precursors (2001)

Osteoclast precursors reach sites of osteoclast formation and remodelling via the vasculature and are therefore destined to encounter endothelium before migrating to the bone surface. Here we investigated the hypothesis that endothelium may be involved in the regulation of osteoclast precursor recruitment to sites of bone resorption. Osteoclast precursors in human peripheral blood were identified by their ability to form mature osteoclasts in 21-day cultures supplemented with RANKLigand, M-CSF, 1,25(OH)(2)-vitamin D(3), dexamethasone and prostaglandin E(2). Under control conditions few osteoclast precursors adhered to endothelial cells (the human bone marrow-derived endothelial cell line BMEC-1). However, BMEC-1 cells treated with the resorption stimulating cytokines IL-1beta and TNFalpha depleted the PBMC population of all osteoclast precursors. These results provide the first evidence that osteoclast precursors can adhere to endothelium and suggest that endothelium could play an important role in the recruitment of osteoclast precursors to sites of bone resorption.
Properties of a 4Pi confocal fluorescence microscope (1992)

In a 4Pi confocal fluorescence microscope two opposing microscope objective lenses were used to illuminate a fluorescent object from both sides and to collect the fluorescence emissions on both sides. Constructive interference of either the illumination wave fronts in the common focus or the detection wave fronts in the common detector pinhole resulted in an axial resolution approximately four times higher than that in a confocal fluorescence microscope. A precise 4Pi confocal fluorescence microscope that uses simultaneous illumination was built. The full width at half-maximum of the depth discrimination was determined experimentally to be approximately 110 nm when lenses with a numerical aperture of 1.4, an excitation of 633 nm, and detection of approximately 725 nm were used.