gebhart/patrepeval huggingface dataset:
Reduced retinal function in amyloid precursor protein‐over‐expressing transgenic mice via attenuating glutamate‐N‐methyl‐d‐aspartate receptor signaling (2008)

Here, we examined whether amyloid-beta (Abeta) protein participates in cell death and retinal function using three types of transgenic (Tg) mice in vivo [human mutant amyloid precursor protein (APP) Tg (Tg 2576) mice, mutant presenilin-1 (PS-1) knock-in mice, and APP/PS-1 double Tg mice]. ELISA revealed that the insoluble form of Abeta(1-40) was markedly accumulated in the retinas of APP and APP/PS-1, but not PS-1 Tg, mice (vs. wild-type mice). In APP Tg and APP/PS-1 Tg mice, immunostaining revealed accumulations of intracellular Abeta(1-42) in retinal ganglion cells and in the inner and outer nuclear layers. APP Tg and APP/PS-1 Tg, but not PS-1 Tg, mice had less NMDA-induced retinal damage than wild-type mice, and the reduced damage in APP/PS-1 Tg mice was diminished by the pre-treatment of N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, a gamma-secretase inhibitor. Furthermore, the number of TUNEL-positive cells was significantly less in ganglion cell layer of APP/PS-1 Tg mice than PS-1 Tg mice 24 h after NMDA injection. The phosphorylated form of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha), but not total CaMKIIalpha or total NMDA receptor 1 (NR1) subunit, in total retinal extracts was decreased in non-treated retinas of APP/PS-1 Tg mice (vs. wild-type mice). CaMKIIalpha and NR2B proteins, but not NR1, in retinal membrane fraction were significantly decreased in APP/PS-1 Tg mice as compared with wild-type mice. The NMDA-induced increase in p-CaMKIIalpha in the retina was also lower in APP/PS-1 Tg mice than in wild-type mice. In electroretinogram and visual-evoked potential recordings, the implicit time to each peak from a light stimulus was prolonged in APP/PS-1 mice versus wild-type mice. Hence, Abeta may impair retinal function by reducing activation of NMDA-receptor signaling pathways.
A nonvolatile nanoelectromechanical memory element utilizing a fabric of carbon nanotubes (2005)

Manufacturability of electronic devices based on carbon nanotubes (CNT) generally depends on the ability to manipulate and control individual structures at the molecular level. A novel technique has been developed to overcome this hurdle, allowing CNT-based nano-electromechanical devices to be fabricated directly on existing production CMOS fabrication lines. The first demonstration of this technique has resulted in a CNT nonvolatile memory element. This unique approach relies on the deposition and lithographic patterning of a 1-2 nm thick fabric of nanotubes which retain their molecular-scale electromechanical characteristics, even when patterned with 180 nm feature sizes. Individual patches of this CNT fabric can be elastically deformed by electro-static attraction to metal electrodes, creating a pair of stable nonvolatile states around the equilibrium of two molecular-level forces: an attractive van der Waals force and the restoring tensile strain within the deformed fabric. A CMOS-compatible fabrication process for these devices has been developed and demonstrated which is free from metallic or material contaminants and particulates. Because these nonvolatile memory elements are created in an all thin-film process, they can be monolithically integrated directly within existing CMOS circuitry to facilitate addressing and readout. Design considerations and preliminary device switching characteristics are presented.
ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis (2015)

The integrated stress response (ISR) is a critical mediator of cancer cell survival, and targeting the ISR inhibits tumor progression. Here, we have shown that activating transcription factor 4 (ATF4), a master transcriptional effector of the ISR, protects transformed cells against anoikis - a specialized form of apoptosis - following matrix detachment and also contributes to tumor metastatic properties. Upon loss of attachment, ATF4 activated a coordinated program of cytoprotective autophagy and antioxidant responses, including induced expression of the major antioxidant enzyme heme oxygenase 1 (HO-1). HO-1 upregulation was the result of simultaneous activation of ATF4 and the transcription factor NRF2, which converged on the HO1 promoter. Increased levels of HO-1 ameliorated oxidative stress and cell death. ATF4-deficient human fibrosarcoma cells were unable to colonize the lungs in a murine model, and reconstitution of ATF4 or HO-1 expression in ATF4-deficient cells blocked anoikis and rescued tumor lung colonization. HO-1 expression was higher in human primary and metastatic tumors compared with noncancerous tissue. Moreover, HO-1 expression correlated with reduced overall survival of patients with lung adenocarcinoma and glioblastoma. These results establish HO-1 as a mediator of ATF4-dependent anoikis resistance and tumor metastasis and suggest ATF4 and HO-1 as potential targets for therapeutic intervention in solid tumors.
2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia (2000)

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, gamma-globin synthesis ratio, complete blood count, and chemistry were measured. The average gamma-globin synthesis relative to non-alpha-globin synthesis prior to therapy was 3.19% +/- 1.43% and increased to 13.66% +/- 4.35% after treatment. HbF increased from 3.55% +/- 2.47% to 13.45% +/- 3.69%. F cells increased from 21% +/- 14.8% to 55% +/- 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% +/- 1.61% to 2.6% +/- 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% +/- 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.
RNase S complex bearing arginine-rich peptide and anti-HIV activity (2004)

Basic peptide-mediated protein delivery into living cells is becoming recognized as a potent approach for the understanding of cellular mechanisms and drug delivery. We have prepared the conjugates of the S-peptide (1-15) derived from RNase S with membrane-permeable basic peptides, octaarginine and the human immunodeficient virus (HIV)-1 Rev (34-50). The RNase S complexes, formed among these S-peptide (1-15)-basic peptide conjugates and the S-protein and having a dissociation constant in the range of 10(-5) M, efficiently penetrated into the HeLa cells. These RNase S complexes exerted an anti-HIV replication activity. The time-of-drug-addition assay suggested that the site of action for these complexes would reside in the stages between the viral entry into the cells and reverse transcription. The present study exemplified the applicability of the arginine-rich peptides to the intracellular targeting of non-covalent protein complexes and supramolecular assemblies for the research in chemical and cellular biology.
Rapid Polymerase Chain Reaction Assay to Detect Variation in the Extent of Gene‐specific Damage between Cisplatin‐ or VP‐16‐resistant and Sensitive Lung Cancer Cell Lines (1994)

We previously established a rapid and facile polymerase chain reaction (PCR)-stop assay for quantitation of specific gene damage in very small numbers of cells. The present study investigated whether the PCR-stop assay was able to detect variation in the extent of DNA damage in transcribed active genes between cisplatin- or VP-16-resistant and sensitive cells. The assay demonstrated that about twice as much genetic damage occurs in PC-9 cells than in cisplatin-resistant PC-9/CDDP cells following cisplatin exposure and about 4.6 times more damage occurs in H69 than in VP-16-resistant H69/VP cells following VP-16 exposure. These results show that DNA damage, as detected by PCR-stop assay, correlates with cytotoxicity. In conclusion, the PCR-stop assay could be useful in detecting variation in DNA damage in specific genes.
Multistep signaling requirements for pituitary organogenesis in vivo (1998)

During development of the mammalian pituitary gland specific hormone-producing cell types, critical in maintaining homeostasis, emerge in a spatially and temporally specific fashion from an ectodermal primordium. We have investigated the molecular basis of generating diverse pituitary cell phenotypes from a common precursor, providing in vivo and in vitro evidence that their development involves three sequential phases of signaling events and the action of a gradient at an ectodermal boundary. In the first phase, the BMP4 signal from the ventral diencephalon, expressing BMP4, Wnt5a, and FGF8, represents a critical dorsal neuroepithelial signal for pituitary organ commitment in vivo. Subsequently, a BMP2 signal emanates from a ventral pituitary organizing center that forms at the boundary of a region of oral ectoderm in which Shh expression is selectively excluded. This BMP2 signal together with a dorsal FGF8 signal, appears to create opposing activity gradients that are suggested to generate overlapping patterns of specific transcription factors underlying cell lineage specification events, whereas Wnt4 is needed for the expansion of ventral pituitary cell phenotypes. In the third phase, temporally specific loss of the BMP2 signal is required to allow terminal differentiation. The consequence of these sequential organ and cellular determination events is that each of the hormone-producing pituitary cell types-gonadotropes, thyrotropes, somatotropes, lactotropes, corticotropes, and melanotropes-appear to be determined, in a ventral-to-dorsal gradient, respectively.
Efficient Estimation of Mutual Information for Strongly Dependent\n Variables (2014)

We demonstrate that a popular class of nonparametric mutual information (MI)\nestimators based on k-nearest-neighbor graphs requires number of samples that\nscales exponentially with the true MI. Consequently, accurate estimation of MI\nbetween two strongly dependent variables is possible only for prohibitively\nlarge sample size. This important yet overlooked shortcoming of the existing\nestimators is due to their implicit reliance on local uniformity of the\nunderlying joint distribution. We introduce a new estimator that is robust to\nlocal non-uniformity, works well with limited data, and is able to capture\nrelationship strengths over many orders of magnitude. We demonstrate the\nsuperior performance of the proposed estimator on both synthetic and real-world\ndata.\n
Room Temperature Ionic Liquids from 20 Natural Amino Acids (2005)

We first succeeded in synthesizing ionic liquids from 20 natural amino acids. Amino acid ionic liquids dissolved native amino acids, despite water-free conditions. Furthermore, these ionic liquids are soluble in various organic solvents, such as chloroform. Effects of acidity, hydrogen bonding ability, and steric factors on the properties of these ionic liquids were analyzed as the function of side groups.
Reconstitution of membrane proteins: sequential incorporation of integral membrane proteins into preformed lipid bilayers (1987)

Several integral membrane proteins can be inserted sequentially into preformed unilamellar vesicles (ULV's) composed of dimyristoylphosphatidylcholine (DMPC) and cholesterol in a gel phase. Thus, proteoliposomes of DMPC, cholesterol, and bacteriorhodopsin from Halobacterium halobium rapidly incorporate UDPglucuronosyltransferase (EC 2.4.1.17) from pig liver microsomes, cytochrome oxidase from beef heart mitochondria, and additional bacteriorhodopsin, added sequentially. This process of spontaneous incorporation can be regulated to produce complex artificial membranes that contain phospholipids and proteins at ratios (mol/mol) equivalent to what is found in biological membranes. The ability of the lipid-protein bilayers to incorporate additional integral membrane proteins is not affected by annealing of the proteoliposomes at 37 degrees C nor by the order of addition of the proteins. Bacteriorhodopsin-containing vesicles formed by the sequential addition of integral membrane proteins demonstrate light-driven proton pumping. Therefore, they have retained a vesicular structure. Vesicles containing one or two different proteins will fuse with each other at 21 degrees C or with ULV's devoid of proteins. Incorporation of bacteriorhodopsin or UDPglucuronosyltransferase into proteoliposomes containing DMPC, with or without cholesterol as impurity, also occurs above the phase transition for DMPC. The presence of a protein in a liquid-crystalline bilayer provides the necessary condition for promoting the spontaneous incorporation of other membrane proteins into preformed bilayers.
Depletion forces in colloidal mixtures (2000)

Depletion forces are accounted for by a contraction of the description of colloidal mixtures based on the integral equations theory of simple liquids. The applicability of this treatment is illustrated for binary mixtures of hard spheres, in the bulk and near a hard wall. The Asakura and Oosawa potential is obtained as the dilute limit of our equations. At higher concentrations the depletion potential has an oscillatory behavior and becomes more long ranged. If charge is put on the small particles there are energy-driven depletion forces in addition to those of entropic origin, which result in repulsive interaction at contact.
Brush‐First Synthesis of Core‐Photodegradable Miktoarm Star Polymers via ROMP: Towards Photoresponsive Self‐Assemblies (2013)

This report describes the synthesis of miktoarm brush‐arm star polymers (BASPs) from branched and linear norbornene‐terminated macromonomers (MMs) via the brush‐first ring‐opening metathesis polymerization (ROMP) method. First, a polystyrene (PS)‐ branch ‐poly(lactic acid) (PLA) MM is synthesized via a combination of atom transfer radical polymerization (ATRP), tin(II)‐mediated ring opening polymerization, and copper‐catalyzed azide‐alkyne cycloaddition reactions. Graft‐through ROMP of this MM followed by in situ cross‐linking with a photo‐cleavable bis‐norbornene derivative provided nanoscopic BASPs with photodegradable cores and a precise 1:1 PS:PLA arm composition. Three‐miktoarm BASPs are prepared in an analogous manner via copolymerization of the same PS ‐branch‐ PLA MM with a poly(ethylene glycol) (PEG) MM prior to cross‐linking. Intramolecular phase segregation of these miktoarm BASPs is characterized by transmission electron microscopy (TEM); a UV‐induced structural rearrangement from three‐faced Janus particles to micelles is observed. image
Effect of Molecular Weight on the Exponential Growth and Morphology of Hyaluronan/Chitosan Multilayers:  A Surface Plasmon Resonance Spectroscopy and Atomic Force Microscopy Investigation (2005)

The layer-by-layer growth of multilayer assemblies of two polysaccharides, the polyanion hyaluronan (HA) and the polycation chitosan (CH), was investigated using atomic force microscopy (AFM) and surface plasmon resonance (SPR) spectroscopy, with primary emphasis on the effect of the polysaccharide molecular weights on the film thickness and surface morphology. The HA/CH multilayers exhibit an exponential increase of the optical film thickness with the number of deposited bilayers. We show that the multilayer thickness at a given stage depends on the size of both CH, the diffusing polyelectrolyte, and HA, the non-diffusing species. Assemblies (12 bilayers) of high molecular weight polysaccharides (HA, 360,000; CH, 160,000) were twice as thick (approximately 900 nm vs approximately 450 nm) as those obtained with low molecular weight polymers (HA, 30,000; CH, 31,000), as assessed by AFM scratch tests. The exponential growth rate is the same for the high and low molecular weight pairs; the larger film thicknesses observed by SPR and by AFM arising from an earlier onset of the steep exponential growth phase in the case of the high molecular weight pair. In all cases, isolated islets form during the deposition of the first CH layer onto the underlying HA. Upon further film growth, individual islets coalesce into larger vermiculate features. The transition from distinct islands to vermiculate structures depends on the molecular weights of the polysaccharides and the lower molecular weight construct presents larger worm-like surface domains than the high molecular weight pair.
Antiangiogenic proteins require plasma fibronectin or vitronectin for in vivo activity (2003)

Fragmentation of various extracellular matrix and blood proteins generates antiangiogenic substances that are physiological regulators of angiogenesis. Some of these compounds are in clinical trials as inhibitors of tumor angiogenesis. Anastellin, an antiangiogenic protein fragment derived from fibronectin, was unable to inhibit matrigel plug angiogenesis in mice that lack plasma fibronectin. Anastellin was fully active in mice that are null for vitronectin, which, like fibronectin, is a major adhesion protein in the blood. An antiangiogenic form of antithrombin showed the opposite pattern. The activity of endostatin was impaired in both fibronectin- and vitronectin-deficient mice. These results suggest a shared mechanism of action for antiangiogenic factors derived from extracellular matrix and plasma proteins: these factors form complexes with adhesion proteins in plasma to create an active antiangiogenic substance.
Intrinsic remediation of trichloroethene driven by tetraalkoxysilanes as co‐contaminants: Results of microcosm and field studies (2003)

Abstract Biological reduction of trichloroethene (TCE), driven by the transformation products of tetraalkoxysilanes, was investigated in seasonal field monitorings and anaerobic groundwater microcosms. Under anaerobic conditions, tetraalkoxysilanes such as tetrabutoxysilane (TBOS) and tetrakis(2‐ethylbutoxy)silane (TKEBS) are abiotically hydrolyzed to their corresponding alcohols, 1‐butanol and 2‐ethylbutanol, respectively, and silicic acid. These alcohols are then fermented by subsurface microorganisms to their corresponding acids and hydrogen, which likely serves as the ultimate electron donor facilitating reductive dechlorination of TCE. At Site 300, Lawrence Livermore National Laboratory (LLNL), California, tetraalkoxysilanes are present along with TCE as subsurface contaminants. Intrinsic transformation of TCE to cis‐dichloroethene (c‐DCE) was observed at this site, and this was promoted by the transformation products of these tetraalkoxysilanes. Efficient transformation of high concentrations of TCE (150–300 mg/l aqueous concentration) was observed in anaerobic microcosms constructed with groundwater from this site. The lack of transformation of c‐DCE to vinyl chloride (VC) and ethene in the microcosms is consistent with studies of the microbial community in the site groundwater reported by Lowe et al. ( 2002 ). © 2003 Wiley Periodicals, Inc.
Characterization of High Oxygen:Tetraethylorthosilicate Ratio Plasma‐Enhanced Chemical Vapor Deposited Films (1996)

An investigation was conducted to characterize film properties of oxygen‐rich tetraethylorthosilicate (TEOS) films deposited by single‐wafer plasma‐enhanced chemical vapor deposition. By increasing the oxygen:TEOS gas ratio from 1:1 to 4:1 and maintaining a reduced gas flow rate, undoped silicon glass (USG) and phosphorus‐doped silicon glass (PSG) films exhibited a lower fixed charge, increased Si‒O bonding sites, higher compressive film stresses, and higher refractive indexes. The USG and PSG deposition parameters were optimized to achieve a film nonuniformity of <2.7% (1σ) and deposition rates of 1500 and 3100 Å/min, respectively.
Physicochemical analysis of the hepatitis B virus core antigen produced by a baculovirus expression vector (1990)

The hepatitis B virus particle consists of an envelope carrying the surface antigen of the virus and an internal capsid consisting of the core antigen (HBcAg). The internal capsid contains the circular, partially dsDNA genome and the viral polymerase. Empty core particles have been produced in Spodoptera frugiperda cells using a recombinant baculovirus vector, YM1KTc, that expresses a 21.4K derivative of the HBcAg gene. The particles have been purified to homogeneity by caesium chloride density gradient centrifugation followed by glycerol gradient centrifugation. Physicochemical analysis of the core particles showed that they exhibited a sedimentation coefficient (s20,(0)w) of 82.5S and a diffusion coefficient (D) of 1.28 x 10(-7) cm2/s. The Mr obtained by substitution of these values in the Svedberg equation was 5.8 x 10(6), using a partial specific volume of 0.73 ml/g for the viral protein as estimated from the amino acid composition. The Mr determined from sedimentation equilibrium analyses was 6.3 x 10(6). Spectrophotometric and metabolic labelling analyses failed to detect nucleic acids in the core preparations. The data are at variance with the prediction that cores exhibit a T = 3 symmetry and contain some 180 subunits. The results suggest that the baculovirus-expressed cores may contain up to 300 subunits of HBcAg protein.
TTP4000, a soluble fusion protein inhibitor of Receptor for Advanced Glycation End Products (RAGE) is an effective therapy in animal models of Alzheimer's disease (2013)

RAGE is a member of the Ig supergene family that binds with nanomolar affinity to amyloid beta (Aβ) peptides which are implicated in the pathology of neurodegenerative Alzheimer's disease. RAGE expression is upregulated in Alzheimer's brains and involved in the retention of Aβ in the brain and inflammation in the neurovascular unit. Double transgenic mice that over‐express human RAGE and human amyloid precursor protein (APP) with the Swedish and London mutations in neurons develop learning defects and neuropathological abnormalities earlier than their mutant hAPP transgenic counterparts. Double transgenic mice expressing a dominant negative form of RAGE on the same mutant hAPP background, show a delayed onset of neuropathological and learning abnormalities compared to the APP transgenic background counterpart. This data suggests that interfering with RAGE signaling may have benefit in Alzheimer's disease. To test the therapeutic benefits of inhibition RAGE signaling. We have developed a novel fusion protein, TTP4000, using the binding domains of sRAGE linked to a human Ig Fc domain. TTP4000 has similar binding characteristics to ligand as sRAGE but a superior pharmacokinetic profile. We have tested TTP4000 in a mouse model of Alzheimer's disease and show that the protein is well tolerated and efficacious. TTP4000 was shown to significantly reduce soluble Aβ levels in brains of mice. The reduction of soluble brain Aβ levels correlated with a decrease in plaque load, a reduction in inflammatory cytokine levels and improved measures of behavior in the Morris Water Maze test. These data confirm and extend previous reports implicating RAGE in the pathogenesis of Alzheimer's disease and indicate that TTP4000, an injectable RAGE antagonist, is a viable treatment for Alzheimer's disease.