gebhart/patrepeval huggingface dataset:
Bispecific Designed Ankyrin Repeat Proteins (DARPins) Targeting Epidermal Growth Factor Receptor Inhibit A431 Cell Proliferation and Receptor Recycling (2011)

The EGF receptor (EGFR) has been implicated in the development and progression of many tumors. Although monoclonal antibodies directed against EGFR have been approved for the treatment of cancer in combination with chemotherapy, there are limitations in their clinical efficacy, necessitating the search for robust targeting molecules that can be equipped with new effector functions or show a new mechanism of action. Designed ankyrin repeat proteins (DARPins) may provide the targeting component for such novel reagents. Previously, four DARPins were selected against EGFR with (sub)nanomolar affinity. As any targeting module should preferably be able to inhibit EGFR-mediated signaling, their effect on A431 cells overexpressing EGFR was examined: three of them were shown to inhibit proliferation by inducing G(1) arrest, as seen for the Food and Drug Administration-approved antibody cetuximab. To understand this inhibitory mechanism, we mapped the epitopes of the DARPins using yeast surface display. The epitopes for the biologically active DARPins overlapped with the EGF-binding site, whereas the fourth DARPin bound to a different domain, explaining the lack of a biological effect. To optimize the biological activity of the DARPins, we combined two DARPins binding to different epitopes with a flexible linker or with a leucine zipper, leading to a homodimer. The latter DARPin was able to reduce surface EGFR by inhibiting receptor recycling, leading to a dramatic decrease in cell viability. These results indicate that multispecific EGFR-specific DARPins are superior to cetuximab and may form the basis of new opportunities in tumor targeting and tumor therapy.
Lensless Ultra-Miniature Imagers Using Odd-Symmetry Spiral Phase Gratings (2013)

We introduce a new type of diffractive element based on odd-symmetry phase gratings. Spiral arrangements of these gratings over photosensors constitute a new class of unprecedentedly-small computational camera.
Extracellular Acidity Potentiates AMPA Receptor-Mediated Cortical Neuronal Death (1998)

The extracellular acidity that accompanies brain hypoxia-ischemia is known to reduce both NMDA and AMPA-kainate receptor-mediated currents and NMDA receptor-mediated neurotoxicity. Although a protective effect of acidic pH on AMPA-kainate receptor-mediated excitotoxicity has been assumed, such has not been demonstrated. Paradoxically, we found that lowering extracellular pH selectively increased AMPA-kainate receptor-mediated neurotoxicity in neocortical cell cultures, despite reducing peak elevations in intracellular free Ca2+. This injury potentiation may, at least in part, be related to a slowed recovery of intracellular Ca2+ homeostasis, observed after AMPA-kainate receptor activation, but not after NMDA receptor activation or exposure to high K+. The ability of acidic pH to selectively augment AMPA-kainate receptor-mediated excitotoxicity may contribute to the prominent role that these receptors play in selective neuronal death after transient global ischemia.
The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro (1997)

Regulators of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Gi but not by Gs class alpha-subunits. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. We have demonstrated that the RGS domains of RGS4, RGS10, and GAIP retain GTPase accelerating activity with the Gi class substrates Gialpha1, Goalpha, and Gzalpha in vitro. No regulatory activity of the RGS domains was detected for Gsalpha. Short deletions within the RGS domain of RGS4 destroyed GTPase activating protein activity and Gialpha1 substrate binding. Comparable protein-protein interactions between Gialpha1-GDP-AlF4- and the RGS domain or full-length RGS4 were detected using surface plasmon resonance.
Deep multi-task learning with low level tasks supervised at lower layers (2016)

In all previous work on deep multi-task learning we are aware of, all task supervisions are on the same (outermost) layer. We present a multi-task learning architecture with deep bi-directional RNNs, where different tasks supervision can happen at different layers. We present experiments in syntactic chunking and CCG supertagging, coupled with the additional task of POS-tagging. We show that it is consistently better to have POS supervision at the innermost rather than the outermost layer. We argue that this is because “lowlevel” tasks are better kept at the lower layers, enabling the higher-level tasks to make use of the shared representation of the lower-level tasks. Finally, we also show how this architecture can be used for domain adaptation.
"Diabodies": small bivalent and bispecific antibody fragments. (1993)

Bivalent and bispecific antibodies and their fragments have immense potential for practical application. Here we describe the design of small antibody fragments with two antigen-binding sites. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) on the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. As indicated by a computer graphic model of the dimers, the two pairs of domains can pack together with the antigen-binding sites pointing in opposite directions. The dimeric antibody fragments, or "diabodies," can be designed for bivalent or bispecific interactions. Starting from the monoclonal antibodies NQ11.7.22 (NQ11) and D1.3 directed against the hapten phenyloxazolone and hen egg lysozyme, respectively, we built bivalent fragments (VHNQ11-VLNQ11)2 and (VHD1.3-VLD1.3)2 and bispecific fragments VHNQ11-VLD1.3 and VHD1.3-VLNQ11. The fragments were expressed by secretion from bacteria and shown to bind specifically to the hapten and/or antigen. Those with 5- and 15-residue linkers had similar binding affinities to the parent antibodies, but a fragment with the VH domain joined directly to the VL domain was found to have slower dissociation kinetics and an improved affinity for hapten. Diabodies offer a ready means of constructing small bivalent and bispecific antibody fragments in bacteria.
Vapor phase anti-stiction coatings for MEMS (2003)

Due to their large surface-area-to-volume ratio, most micromechanical devices are susceptible to adhesion, friction, and wear. Conventional approaches to abate the deleterious effects of adhesion and friction rely on the deposition of organically based anti-stiction monolayers produced from liquid phase processes. It has become widely accepted that liquid phase monolayer processes are less desirable than vapor phase processes, especially for manufacturing purposes. Thus, current research is aimed at the development of vapor phase anti-stiction processes that yield comparable or better films than their corresponding liquid phase processes. To date, a variety of monolayer systems that have been well established via liquid phase deposition processes have been adapted to vapor processes. In this paper, current trends in anti-stiction technology and a discussion of available vapor phase anti-stiction methods are presented.
t(6;11) Renal Cell Carcinoma (RCC) (2014)

Renal cell carcinomas (RCCs) harboring the t(6;11)(p21;q12) translocation were first described in 2001 and recently recognized by the 2013 International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. Although these RCCs are known to label for melanocytic markers HMB45 and Melan A and the cysteine protease cathepsin K by immunohistochemistry (IHC), a comprehensive IHC profile has not been reported. We report 10 new t(6;11) RCCs, all confirmed by break-apart TFEB fluorescence in situ hybridization. A tissue microarray containing 6 of these cases and 7 other previously reported t(6;11) RCCs was constructed and immunolabeled for 21 different antigens. Additional whole sections of t(6;11) RCC were labeled with selected IHC markers. t(6;11) RCC labeled diffusely and consistently for cathepsin K and Melan A (13 of 13 cases) and almost always at least focally for HMB45 (12 of 13 cases). They labeled frequently for PAX8 (14 of 23 cases), CD117 (10 of 14 cases), and vimentin (9 of 13 cases). A majority of cases labeled at least focally for cytokeratin Cam5.2 (8 of 13 cases) and CD10 and RCC marker antigen (10 of 14 cases each). In contrast to a prior study's findings, only a minority of cases labeled for Ksp-cadherin (3 of 19 cases). The median H score (product of intensity score and percentage labeling) for phosphorylated S6, a marker of mTOR pathway activation, was 101, which is high relative to most other RCC subtypes. In summary, IHC labeling for PAX8, Cam5.2, CD10, and RCC marker antigen supports classification of the t(6;11) RCC as carcinomas despite frequent negativity for broad-spectrum cytokeratins and EMA. Labeling for PAX8 distinguishes the t(6;11) RCC from epithelioid angiomyolipoma, which otherwise shares a similar immunoprofile. CD117 labeling is more frequent in the t(6;11) RCC compared with the related Xp11 translocation RCC. Increased pS6 expression suggests a possible molecular target for the uncommon t(6;11) RCCs that metastasize.
Electron microscopic evidence for the mechanism of blood-retinal barrier breakdown in diabetic rabbits: Comparison with magnetic resonance imaging (1998)

Diabetes leads to a breakdown of the blood-retinal barrier (BRB), which can be demonstrated in experimental models by immunocytochemistry and magnetic resonance imaging (MRI). The present study utilizes these methods to investigate the mechanism of BRB breakdown in diabetic rabbits, a model ideally suited to both procedures. Rabbits were treated with alloxan and examined 2 months, 1 year, and 1.5 years after the development of diabetes to assess BRB breakdown using MRI and immunocytochemical staining for endogenous albumin. Using MRI, an increased incidence of retinal vascular leakage is first evident at 1 year of diabetes. Electron microscopic immunolocalization of albumin suggests that BRB compromise is principally mediated by transendothelial transport of serum proteins in endocytic vesicle-like structures of approximately 0.4-1 micron diameter. Some additional retinal vascular leakage is occasionally demonstrated through the interendothelial cell tight junctions, but only when adjacent vascular endothelial cells show degenerative changes. The similarity of these findings to those previously reported for diabetic humans and rats supports the use of the diabetic rabbit as a model for studying BRB dysfunction. MRI and electron microscopic (EM) immunocytochemistry are complementary methods for evaluating BRB dysfunction. MRI can provide an overall picture of the entire eye without sacrificing the animal. EM immunocytochemistry can provide a more detailed picture of a limited area of interest to gain insight into the mechanisms of extravasation. Together, both methods provide a more complete understanding of BRB breakdown in diabetic rabbits.
Very long optical paths in air (1976)

Two different multiple traversal optical systems are described; one gives the longest paths, the other the best compensation for vibration and misalignment problems. In the first, seven mirrors in a near confocal arrangement permit a large aperture beam of light to pass through a restricted volume for a discrete and very large number of times. A rectangular array of images corresponding to different numbers of passes appears on four mirrors at one end of the system. At the other end, three mirrors form the array and illuminate each image in it from one or more different directions. The possible numbers of passes are (4mn − 2)k + 2, where m and n are any integers representing, respectively, the number of columns and half the number of rows in the array. k is the number of different directions from which the array is illuminated. Geometrically, the beam may be isolated after thousands of passes; practically, the number is limited by reflection losses. In the second system the addition of four diagonal mirrors to a White cell converts the two lines of images on the single mirror to a rectangular array of images, almost squaring the maximum possible number of passes. With multiples of four rows of images in the array, the position of the output image is invariant to small errors in alignment of the mirrors.
Altropane, a SPECT or PET imaging probe for dopamine neurons: II. distribution to dopamine-rich regions of primate brain (1998)

The dopamine transporter in brain, localized almost exclusively on dopamine neurons, is an effective window on dopamine neurons. SPECT or PET imaging of the transporter in brain requires selective imaging agents that display appropriate pharmacokinetic properties. We previously reported that [125I]altropane ([125I]IACFT,2beta-carbomethoxy-3beta-(4-fluorophenyl)-n-(1- iodoprop-1-en-3-yl)nortropane) bound with high affinity (Kd: 5.33 nM) to a single site on the dopamine transporter and was selective for dopamine over the serotonin transporter in homogenates of monkey striatum. To determine whether the selective binding of [125I]altropane is reflected in its brain distribution, the in vitro and ex vivo distribution of [125I]altropane in squirrel monkey (Saimiri sciureus) brain was determined by quantitative autoradiography of coronal brain sections. In vitro, [125I]altropane (2 nM) distribution was discrete and was detectable primarily in the dopamine-rich putamen, caudate nucleus, and nucleus accumbens. The resulting putamen:cerebellum ratio exceeded 120:1 (n = 3). The selective in vitro binding of [125I]altropane to the dopamine transporter, at concentrations approaching its Kd value (Kd: 5.33 nM, a single high affinity site), highlight its suitability for investigating the density of the dopamine transporter in various brain regions in vitro. Ex vivo autoradiography was conducted in monkeys to determine whether the brain distribution of [125I]altropane in vitro was predictive of its brain distribution pattern after intravenous administration. Thirty minutes after intravenous injection, highest levels of [125I]altropane (0.3 nmol/kg) were detected in the caudate-putamen and nucleus accumbens and lowest levels in the cerebellum and cortex. The putamen or caudate:cerebellum ratio was 7. SPECT imaging of the brain within 30 min of i.v. injection confirmed the rapid and selective accumulation of [123I]altropane to the striatum. The selective binding of altropane to the dopamine-rich striatum within 30 min of i.v. administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated dopamine neurons.
Regulatory T cells and autoimmune disease (2005)

Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4(+)CD25(+) T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T-effector cells as a target molecule for Treg-dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T-cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa-1 on effector T cells is not addressed in this review.
Advances in understanding the biology and function of the G-CSF receptor (1996)

G-CSF is the major growth factor involved in the production of neutrophilic granulocytes. G-CSF exerts its function via the activation of a membrane receptor that belongs to the super-family of hematopoietin receptors, also referred to as class I cytokine receptors. In this review we summarize the current knowledge of the function of the G-CSF receptor in normal granulopoiesis, as well as in some patients with severe congenital neutropenia and acute myeloblastic leukemia, diseases characterized by disturbed myeloid maturation.
Synthesis of the indolo[2,3-a]carbazole natural products staurosporinone and arcyriaflavin B (1990)

Flexible synthetic routes involving double nitrene insertions are described leading to the indolo[2,3-a]carbazole systems present in a growing group of natural products. The methods are exemplified by the total synthesis of two members of this group staurosporinone (9; R = H) and arcyriaflavin B (2).
Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of LGMD-2D (2007)

Limb girdle muscular dystrophy (LGMD) describes a group of inherited diseases resulting from mutations in genes encoding proteins involved in maintaining skeletal muscle membrane stability. LGMD type-2D is caused by mutations in alpha-sarcoglycan (sgca). Here we describe muscle-specific gene delivery of the human sgca gene into dystrophic muscle using an adeno-associated virus 1 (AAV1) capsid and creatine kinase promoter. Delivery of this construct to adult sgca(-/-) mice resulted in localization of the sarcoglycan complex to the sarcolemma and a reduction in muscle fiber damage. Sgca expression prevented disease progression as observed in vivo by T(2)-weighted magnetic resonance imaging (MRI) and confirmed in vitro by decreased Evan's blue dye accumulation. The ability of recombinant AAV-mediated gene delivery to restore normal muscle mechanical properties in sgca(-/-) mice was verified by in vitro force mechanics on isolated extensor digitorum longus (EDL) muscles, with a decrease in passive resistance to stretch as compared with untreated controls. In summary, AAV/AAV-sgca gene transfer provides long-term muscle protection from LGMD and can be non-invasively evaluated using magnetic resonance imaging.
Solution Structure and Antibody Binding Studies of the Envelope Protein Domain III from the New York Strain of West Nile Virus (2004)

The solution structure of domain III from the New York West Nile virus strain 385-99 (WN-rED3) has been determined by NMR methods. The West Nile domain III structure is a beta-barrel structure formed from seven anti-parallel beta-strands in two beta-sheets. One anti-parallel beta-sheet consists of beta-strands beta1 (Phe(299)-Asp(307)), beta2 (Val(313)-Tyr(319)), beta4 (Arg(354)-Leu(355)), and beta5 (Lys(370)-Glu(376)) arranged so that beta2 is flanked on either side by beta1 and beta5. The short beta4 flanks the end of the remaining side of beta5. The remaining anti-parallel beta-sheet is formed from strands beta3 (Ile(340)-Val(343)), beta6 (Gly(380)-Arg(388)), and beta7 (Gln(391)-Lys(399)) arranged with beta6 at the center. Residues implicated in antigenic differences between different West Nile virus strains (and other flaviviruses) and neutralization are located on the outer surface of the protein. Characterization of the binding of monoclonal antibodies to WN-rED3 mutants, which were identified through neutralization escape experiments, indicate that antibody neutralization directly correlates with binding affinities. These studies provide an insight into theoretical virus-receptor interaction points, structure of immunogenic determinants, and potential targets for antiviral agents against West Nile virus and highlight differences between West Nile virus and other flavivirus structures that may represent critical determinants of virulence.
Enzyme-Activated Antagonists of the Strychnine-Insensitive Glycine/NMDA Receptor (1994)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnzyme-Activated Antagonists of the Strychnine-Insensitive Glycine/NMDA ReceptorFrancesco G. Salituro, Ronald C. Tomlinson, Bruce M. Baron, Michael G. Palfreyman, Ian A. McDonald, Werner Schmidt, Hui Qiu Wu, Paolo Guidetti, and Robert SchwarczCite this: J. Med. Chem. 1994, 37, 3, 334–336Publication Date (Print):February 1, 1994Publication History Published online1 May 2002Published inissue 1 February 1994https://doi.org/10.1021/jm00029a003RIGHTS & PERMISSIONSArticle Views356Altmetric-Citations35LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (386 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Beta-galactosidase histochemistry and telomere loss in senescent retinal pigment epithelial cells. (1999)

Senescence-related beta-galactosidase activity and mean TRF length may prove useful in studying the senescence of RPE cells in vitro. These techniques may be valuable in determining senescence of the retinal pigment epithelium in vivo, where senescent RPE cells could be involved in the development of age-related maculopathy and age-related macular degeneration.
Impact of Maternal Diabetes on Epigenetic Modifications Leading to Diseases in the Offspring (2012)

Gestational diabetes, occurring during the hyperglycemic period of pregnancy in maternal life, is a pathologic state that increases the incidence of complications in both mother and fetus. Offspring thus exposed to an adverse fetal and early postnatal environment may manifest increased susceptibility to a number of chronic diseases later in life. Compelling evidence for the role of epigenetic transmission in these complications has come from comparison of siblings born before and after the development of maternal diabetes, exposure to this intrauterine diabetic environment being shown to cause alterations in fetal growth patterns which predispose these infants to developing overweight and obesity later in life. Diabetes of the offspring is also mainly the consequence of exposure to the diabetic intrauterine environment, in addition to genetic susceptibility. Since obesity and diabetes are known to increase the risk of cardiovascular disease, cardiovascular sequelae in the offspring of diabetic mothers are virtually inevitable. Research data also suggest that exposure to a diabetic intrauterine environment during pregnancy is associated with an increase in dyslipidemia, subclinical vascular inflammation, and endothelial dysfunction processes in the offspring, all of which are linked with development of cardiovascular disease later in life. The main underlying mechanisms involve persistent hyperglycemia hyperinsulinemia and leptin resistance.