gebhart/patrepeval huggingface dataset:
Conformationally Constrained Analogues of Diacylglycerol. 11. Ultrapotent Protein Kinase C Ligands Based on a Chiral 5-Disubstituted Tetrahydro-2-furanone Template (1996)

Conformationally constrained analogues of diacylglycerol (DAG) built on a racemic 5(-)[(acyloxy)-methyl]-5-(hydroxymethyl)tetrahydro-2-furanone template were shown previously to have excellent binding affinities for protein kinase C (PK-C). Since the interaction of PK-C with DAG is stereospecific, it was anticipated that PK-C would bind tightly to only one enantiomeric form of the compounds constructed with this new lactone template. Separation of enantiomers by chiral HPLC was discarded due to the ease with which acyl migration occurs in these class of compounds, and a total chiral synthesis was undertaken. Prior to chemical synthesis, the selection of the "correct" enantiomeric template was predicted by a molecular conformational analysis that compared the two enantiomers of DAG in their presumed "active" conformation with the two enantiomeric lactone templates. This presumed "active" conformation for DAG was derived from a previously developed pharmacophore model that uses the molecule of a potent phorbol diester as the ideal rigid template. The results from this analysis indicated that the "correct" lactone template corresponded to the inactive (R)-isomer of DAG. This analysis also predicted that the lactone template corresponding to the active (S)-DAG enantiomer would not fit adequately into the pharmacophore. The chiral syntheses of target compounds 2, 4, and 6, constructed on the selected, and presumably "correct" lactone template, were achieved from a common bicyclic intermediate (5R,8R,9R)-8,9-O-isopropylidene-2-keto-1,7-dioxaspiro[4.4]nonane (10) that was synthesized from commercially available 1,2:3,5-di-O-isopropylidene-alpha-D-threo-apiofuranose (7) by a very effective spirolactonization approach. On the basis of their ability to inhibit the binding of [3H-20]phorbol 12,13-dibutyrate (PDBU) to PK-C alpha, the enantiomeric ligands 2, 4, and 6 were twice as potent as the corresponding racemates. These results confirm that binding of these lactones is stereospecific and consistent with a binding mechanism similar to that of DAG.
High-Throughput Thermal Scanning: A General, Rapid Dye-Binding Thermal Shift Screen for Protein Engineering (2009)

The low stability of natural proteins often limits their use in therapeutic, industrial, and research applications. The scale and throughput of methods such as circular dichroism, fluorescence spectroscopy, and calorimetry severely limit the number of variants that can be examined. Here we demonstrate a high-throughput thermal scanning (HTTS) method for determining the approximate stabilities of protein variants at high throughput and low cost. The method is based on binding to a hydrophobic dye akin to ANS, which fluoresces upon binding to molten globules and thermal denaturation intermediates. No inherent properties of the protein, such as enzymatic activity or presence of an intrinsic fluorophore, are required. Very small sample sizes are analyzed using a real-time PCR machine, enabling the use of high-throughput purification. We show that the apparent T(M) values obtained from HTTS are approximately linearly related to those from CD thermal denaturation for a series of four-helix bundle hydrophobic core variants. We demonstrate similar results for a small set of TIM barrel variants. This inexpensive, general, and scaleable approach enables the search for conservative, stable mutants of biotechnologically important proteins and provides a method for statistical correlation of sequence-stability relationships.
Strike a Pose: Tracking People by Finding Stylized Poses (2005)

We develop an algorithm for finding and kinematically tracking multiple people in long sequences. Our basic assumption is that people tend to take on certain canonical poses, even when performing unusual activities like throwing a baseball or figure skating. We build a person detector that quite accurately detects and localizes limbs of people in lateral walking poses. We use the estimated limbs from a detection to build a discriminative appearance model; we assume the features that discriminate a figure in one frame will discriminate the figure in other frames. We then use the models as limb detectors in a pictorial structure framework, detecting figures in unrestricted poses in both previous and successive frames. We have run our tracker on hundreds of thousands of frames, and present and apply a methodology for evaluating tracking on such a large scale. We test our tracker on real sequences including a feature-length film, an hour of footage from a public park, and various sports sequences. We find that we can quite accurately automatically find and track multiple people interacting with each other while performing fast and unusual motions.
The unfolded protein response in multiple sclerosis (2015)

The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is comprised of three signaling pathways that promote cytoprotective functions to correct ER stress; however, if ER stress cannot be resolved the UPR results in apoptosis of affected cells. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS. In this review we will cover current literature on the UPR and the evidence for its role in the development of MS.
Inhibition of vaccinia virus growth by zinc ions: effects on early RNA and thymidine kinase synthesis (1979)

Accumulation of thymidine kinase activity in vaccinia virus-infected cells was severely inhibited by zinc ions if the drug was added within 1 h postinfection. If added later, zinc ions had no effect on the enzyme synthesis. A fraction of RNA which is normally synthesized in infected cells, was missing from a proper part of the gradient if the cells were treated with zinc ions within 1 h postinfection (as has been shown by cosedimentation of pulse-labeled RNAs in isokinetic gradients). It is suggested that a transcriptional (or posttranscriptional) step is involved in zinc-caused inhibition of vaccinia virus growth.
The World Series (2009)

The World Series Hara Person (bio) To my father, 1934–2003 While machines flashed red numeralshope, despair, hopeyour long graceful fingersreached up from your ICU-induced sleep stateto trace figures in airborne columns of debits and credits. Yiddish was your first languagebut numbers were your native tongue.Balance sheets spoke to you of nuance,challenges mastered and tamed,the stories and dramas of the universe. Numbers talked,and you answered.You wrote your life story in their epic languageof plusses and minuses. [End Page 16] Ebbetts Field was your princely realm,a boyhood kingdom in whichthe beauty and order of statskept the chaos away. "Peppy" they called you in high schoolbecause Pepsi's kept you sharp.The reliable math of poker andthe clean geometry of pool sharkingprovided cool cashstored always in serial number order. Becoming an accountantprovided an arithmetic solutionto the sum of your first-generation yearnings.Controlling the figures in ledgers and spreadsheetssupplied the way to amountto a man of substance. You would have loved tonight's gamea four-of-four sweep for my son's team.As we watched, his eyes on the screen and my eyes on him,he held forth in that language ofstats and averages, innings and outs,that I haven't heard since your numbers went still. [End Page 17] Hara Person Hara E. Person is Publisher and Director of the CCAR Press. She received rabbinic ordination from HUC-JIR, an MA in Fine Arts from NYU/ICP, and a BA from Amherst College. She is the co-author of Stories of Heaven and Earth: Bible Heroes in Contemporary Children's Literature and was the Managing Editor of the The Torah: A Women's Commentary. She is the Adjunct Rabbi at the Brooklyn Heights Synagogue and is also the High Holy Day Rabbi in Fire Island Pines. She lives with her family in Brooklyn, New York. Copyright © 2009 Bridges Association
Macromol. Chem. Phys. 18/2010 (2010)

Front Cover: Novel melt-processible layer-structured metallopolymers composed of a zinc carboxylate backbone bearing n-alkyl groups are prepared by a solid-to-solid transformation using solvothermal methods. The reaction time and alkyl substituents on the backbone have a marked effect on the structure and thermal behavior. Further details can be found in the article by E.-Y. Choi, H.-J. Lee, C. Gao, O.-P. Kwon,* and S.-H. Lee* on page 1955.
The link between child abuse and psychopathology: A review of neurobiological and genetic research (2012)

Childhood abuse is associated with later psychopathology, including conduct disorder, antisocial personality disorder, anxiety and depression as well as a heightened risk of health and social problems. However, the neurobiological mechanisms by which childhood adversity increases vulnerability to psychopathology remain poorly understood. There is likely to be a complex interaction between environmental experiences (such as abuse) and individual differences in risk versus protective genes, which influences the neurobiological circuitry underpinning psychological and emotional development. Neuroendocrine studies indicate an association between early adversity and atypical development of the hypothalamic-pituitary-adrenal (HPA) axis stress response, which may predispose to psychiatric vulnerability in adulthood. Brain imaging research in children and adults is providing evidence of several structural and functional brain differences associated with early adversity. Structural differences have been reported in the corpus callosum, cerebellum and prefrontal cortex. Functional differences have been reported in regions implicated in emotional and behavioural regulation, including the amygdala and anterior cingulate cortex. These differences at the neurobiological level may represent adaptations to early experiences of heightened stress that lead to an increased risk of psychopathology. We also consider the clinical implications of future neurobiological and genetic research.
Autoradiographic visualization of the mouse egg's sperm receptor bound to sperm. (1986)

The extracellular coat, or zona pellucida, of mammalian eggs contains species-specific receptors to which sperm bind as a prelude to fertilization. In mice, ZP3, one of only three zona pellucida glycoproteins, serves as sperm receptor. Acrosome-intact, but not acrosome-reacted, mouse sperm recognize and interact with specific O-linked oligosaccharides of ZP3 resulting in sperm-egg binding. Binding, in turn, causes sperm to undergo the acrosome reaction; a membrane fusion event that results in loss of plasma membrane at the anterior region of the head and exposure of inner acrosomal membrane with its associated acrosomal contents. Bound, acrosome-reacted sperm are able to penetrate the zona pellucida and fuse with the egg's plasma membrane (fertilization). In the present report, we examined binding of radioiodinated, purified, egg ZP3 to both acrosome intact and acrosome reacted sperm by whole-mount autoradiography. Silver grains due to bound 125I-ZP3 were found localized to the acrosomal cap region of heads of acrosome-reacted sperm. Under the same conditions, 125I-fetuin bound at only bacKground levels to heads of both acrosome-intact and -reacted sperm, and 125I-ZP2, another zona pellucida glycoprotein, bound preferentially to acrosome-reacted sperm. These results provide visual evidence that ZP3 binds preferentially and specifically to heads of acrosome intact sperm; properties expected of the mouse egg's sperm receptor.
Anti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2 (2016)

Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer.
Transcutaneous Immunization with Cytotoxic T-Cell Peptide Epitopes Provides Effective Antitumor Immunity in Mice (2005)

Much attention has been focused on transcutaneous immunization strategies to stimulate systemic cytotoxic T lymphocyte responses leading to anti-tumor or anti-microbial immunity. Here we report that topical application of vaccines consisting of synthetic peptides formulated with imiquimod, a Toll-like receptor agonist that functions as a potent adjuvant generates strong T cell responses that exhibit effective anti-tumor effects in a murine melanoma model system. These results support the use of peptide-based transcutaneous vaccines as a noninvasive and effective strategy for anti-tumor immunotherapy.
Mesothelin Expression Is a Prognostic Factor in Cholangiocellular Carcinoma (2013)

Although mesothelin is highly expressed in epithelial mesotheliomas, and also in adenocarcinomas of the ovary and pancreas, the clinical significance of mesothelin in cholangiocellular carcinoma (CC) has not been reported, and its biologic features are largely unknown. In the present study, mesothelin expression was evaluated in 25 patients with CC using a well-characterized mesothelin monoclonal antibody (5B2). A total of 8 of the 25 patients with CC (32%) showed mesothelin immunoreactivity. The 25 patients were divided into 2 groups according to the percentage of tumor cells that were positive for mesothelin expression: negative (n = 17) or focally positive (mesothelin expression evident in less than 50%, n = 4; total, n = 21 for both groups), and positive (mesothelin expression evident in 50% or more, n = 4). The survival periods in both groups were statistically analyzed. The negative/focally positive group showed significantly longer postoperative survival than the positive group (P = 0.006). Also, mesothelin positivity was identified as an independent predictor of short postoperative survival. The present results suggest that mesothelin expression is a prognostic indicator in patients with CC.
Human B-lymphoid cell lines. (1992)

The collective efforts during almost three decades by hematologists, tumor biologists and immunologists have provided a collection of established human hematopoietic cell lines, representing most of the hematopoietic cell lineages. The representativity of cell lines derived from the B cell differentiation lineage, however, is the most impressive. Human B-lymphoid cell lines are extensively used world wide as models in studies of various aspects of B cell biology and as tools in research on the etiology, pathogenesis and the biology of leukemia and lymphoma. Lymphoblastoid cell lines (LCL) carrying the Epstein-Barr Virus (EBV) are of particular importance. These lines can be established spontaneously from blood and lymphoid tissue from any EBV positive individual by special techniques, and from all individuals by EBV infection of peripheral blood B cells by EBV infection in vitro. At spontaneous establishment B cells, latently infected by EBV in vivo, will release EBV which subsequently infects normal EBV-negative B cells and immortalizes them into LCL cells, but direct outgrowth of the latently infected B cells as LCLs has also been documented. The target B cells for the EBV infection in vitro are not fully defined-most are mature B cells but also pro-B and pre-B and some B-blasts can be infected. Apart from their capacity for infinite growth, LCL cells have non-malignant properties, e. g. they are diploid, do not grow in agarose and do not form tumors upon inoculation subcutaneously in nude mice. LCLs have a phenotype corresponding to activated B cells (B-blasts) and have been used as "the E. Coli" of eukaryotic cells for about two decades. LCLs are derived at a high frequency also from tumor biopsies of EBV positive patients with leukemia and lymphoma. However, tumor cell lines are available from most of the B cell lineage-derived leukemias, B-lymphomas and myeloma. The frequency of successful establishment has been particularly high from EBV positive Burkitt's lymphoma (BL). From EBV genome negative BL and other B-lymphoma and B-leukemia biopsies the frequency of successful, spontaneous establishment is low (5-10%), and such lines have, with rare exceptions, been derived from pleural effusions and ascitis of patients with advanced, chemotherapy resistant, disease. Many of the cell lines therefore do not represent the clinically most common types of leukemia and lymphoma. No authentic malignant cell lines have been established from chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and Waldenström's disease.(ABSTRACT TRUNCATED AT 400 WORDS)
Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms (2017)

Zebrafish morphants of osm-3/kif17, a kinesin-2 family member and intraflagellar transport motor, have photoreceptor outer segments that are dramatically reduced in number and size. However, two genetic mutant lines, osm-3/kif17<sup>sa0119</sup> and osm-3/kif17<sup>sa18340</sup>, reportedly lack any observable morphological outer segment defects. In this work, we use TALENs to generate an independent allele, osm-3/kif17<sup>mw405</sup>, and show that both osm-3/kif17<sup>sa0119</sup> and osm-3/kif17<sup>mw405</sup> have an outer segment developmental delay in both size and density that is fully recovered by 6 days post-fertilization. Additionally, we use CRISPRs to generate cos2/kif7<sup>mw406</sup>, a mutation in the kinesin-4 family member cos2/kif7 that has been implicated in controlling ciliary architecture and Hedgehog signaling to test whether it may be functioning redundantly with osm-3/kif17. We show that cos2/kif7<sup>mw406</sup> has an outer segment developmental delay similar to the osm-3/kif17 mutants. Using a three-dimensional mathematical model of outer segments, we show that while cos2/kif7<sup>mw406</sup> and osm-3/kif17<sup>mw405</sup> outer segments are smaller throughout the first 6 days of development, the volumetric rates of outer segment morphogenesis are not different among wild-type, cos2/kif7<sup>mw406</sup>, and osm-3/kif17<sup>mw405</sup> after 60hpf. Instead, our model suggests that cos2/kif7<sup>mw406</sup> and osm-3/kif17<sup>mw405</sup> impact outer segment morphogenesis through upstream events that that are different for each motor. In the case of cos2/kif7<sup>mw406</sup> mutants, we show that early defects in Hedgehog signaling lead to a general, non-photoreceptor-specific delay of retinal neurogenesis, which in turn causes the secondary phenotype of delayed outer segment morphogenesis. In contrast, the osm-3/kif17<sup>mw405</sup> outer segment morphogenesis delays are linked specifically to initial disc morphogenesis of photoreceptors rather than an upstream event. Further, we show that osm-3/kif17 mutant mice also exhibit a similarly delayed outer segment development, suggesting a role for osm-3/kif17 in early outer segment development that is conserved across species. In conclusion, we show that both osm-3/kif17 and cos2/kif7 have comparable outer segment developmental delays, although through independent mechanisms.
Trophic Effects of Gastrin on Colorectal Neoplasms in the Rat (1982)

This study was designed to determine the effect of gastrin on colorectal neoplasms in the rat. Multiple colon and rectal cancers were induced in each of 57 rats with methylazoxymethanol. Animals were randomly assigned to groups: (1) antral exclusion, (2) antrectomy, (3) sham, or (4) sham with subsequent pentagastrin injections. Resulting tumors were analyzed for concentration and synthesis of DNA, RNA, and protein. The number of tumors per rat and distribution of tumors within the colons did not vary among groups. Antrectomy did not alter the gastrin level, and tumors developing in these animals did not differ from those of sham controls. Antral exclusion markedly raised serum gastrin levels. Both chronic endogenous hypergastrinemia and administration of exogenous pentagastrin significantly increased tumor synthesis and concentration of DNA, RNA, and protein. We conclude that gastrin exerts a trophic effect on colorectal neoplasms in rats. This biological phenomenon suggests a tumor regulatory role for the hormone.
Pharmacokinetic model of iodine-131-G250 antibody in renal cell carcinoma patients. (1998)

A linear two-compartment model was adequate in describing the serum and whole-body kinetics of G250 antibody distribution. The median initial distribution volume predicted by the model was consistent with the nominal value of 3.81. A wide variability in fitted parameters was observed among patients, reflecting the differences in individual patient clearance and exchange kinetics of G250 antibody. By selecting median parameter values, such a model may be used to evaluate and design prolonged multiple administration radioimmunotherapy protocols.
Micromachined polysilicon microscanners for barcode readers (1996)

We describe the design and fabrication of micromachined resonant scanners that have large scan angles at fast scan speeds. Driven by an electrostatic combdrive actuator, these 200 μm×250 μm micromirrors have a maximum scan angle of 28/spl deg/ (optical) at a resonant frequency of 3 kHz when driven by a sinusoidal voltage of 9.5 V (amplitude) superimposed on a 30-V dc bias. Fabricated with a four-layer polysilicon-surface-micromachining process, these resonant scanners are compact, extremely light in weight, potentially very low in cost, and operate at very low power levels. Using the scanner as a laser-beam deflector, we have demonstrated a barcode reader system.
Silicon nanowire solar cells (2007)

Silicon nanowire-based solar cells on metal foil are described. The key benefits of such devices are discussed, followed by optical reflectance, current-voltage, and external quantum efficiency data for a cell design employing a thin amorphous silicon layer deposited on the nanowire array to form the p-n junction. A promising current density of ∼1.6mA∕cm2 for 1.8cm2 cells was obtained, and a broad external quantum efficiency was measured with a maximum value of ∼12% at 690nm. The optical reflectance of the silicon nanowire solar cells is reduced by one to two orders of magnitude compared to planar cells.