gebhart/patrepeval huggingface dataset:
Studies of synthetic peptide analogs of the amphipathic helix. Structure of complexes with dimyristoyl phosphatidylcholine. (1985)

The amphipathic helix hypothesis for the lipid-associating domains of exchangeable plasma apolipoproteins has been further studied by analysis of the structure of the complexes formed between four synthetic peptide analogs of the amphipathic helix and dimyristoyl phosphatidylcholine (DMPC). Density gradient ultracentrifugation, negative stain electron microscopy, nondenaturing gradient gel electrophoresis, 1H NMR, high sensitivity differential scanning calorimetry, and circular dichroism were the techniques used in these studies. The two analogs Asp-Trp-Leu-Lys-Ala-Phe-Tyr-Asp-Lys-Val-Ala-Glu-Lys-Leu-Lys-Glu-Ala-Phe (18A) and 18A-Pro-18A whose sequences most strongly mimic native amphipathic sequences were found also most strongly to mimic apolipoprotein A-I in DMPC complex structure. The covalently linked dimer of the prototype amphipathic analog 18A, 18A-Pro-18A, appears to have greater lipid affinity than 18A. This presumably is the result of the cooperativity provided by two covalently linked lipid-associating domains in 18A-Pro-18A. The studies further suggest that the charge-reversed analog of the prototype 18A, reverse-18A, has the lowest lipid affinity of the four analogs studied and forms only marginally stable discoidal DMPC complexes. We postulate that this low lipid affinity is due predominantly, but not necessarily exclusively, to the lack of a hydrophobic contribution of lysine residues at the polar-nonpolar interface of reverse-18A versus 18A. The intermediate lipid affinity of des-Val10-18A, the fourth analog peptide, to produce a rank order of 18A-Pro-18A greater than 18A greater than des-Val10-18A greater than reverse-18A, supports this interpretation. Des-Val10-18A which has Val deleted from 18A has an amphipathic helical structure partially disrupted by the shift of 2 lysine residues away from the polar-nonpolar interface.
On making TCP more robust to packet reordering (2002)

Previous research indicates that packet reordering is not a rare event on some Internet paths. Reordering can cause performance problems for TCP's fast retransmission algorithm, which uses the arrival of duplicate acknowledgments to detect segment loss. Duplicate acknowledgments can be caused by the loss of a segment or by the reordering of segments by the network. In this paper we illustrate the impact of reordering on TCP performance. In addition, we show the performance of a conservative approach to "undo" the congestion control state changes made in conjunction with spurious retransmissions. Finally, we propose several alternatives to dynamically make the fast retransmission algorithm more tolerant of the reordering observed in the network and assess these algorithms.
Sulfonamido Derivatives of Pyrimidines (1941)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSulfonamido Derivatives of PyrimidinesJames M. Sprague, L. W. Kissinger, and Robert M. LincolnCite this: J. Am. Chem. Soc. 1941, 63, 11, 3028–3030Publication Date (Print):November 1, 1941Publication History Published online1 May 2002Published inissue 1 November 1941https://doi.org/10.1021/ja01856a046RIGHTS & PERMISSIONSArticle Views269Altmetric-Citations19LEARN 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 (336 KB) Get e-Alerts Get e-Alerts
Methionine‐enkephalin secreted by human colorectal cancer cells suppresses T lymphocytes (2009)

The role of methionine-enkephalin (MENK) as an immunomodulator in colorectal carcinomas (CRC) was examined. MENK was produced in CT26, IEC6A, Colo320, and HT29 CRC cell lines but not in IEC6 intestinal cells. MENK secretion was associated with tumorigenicity and metastasis of CRC cells in syngeneic rodent models. The MENK concentration in subcutaneous tumors of CT26 and IEC6A CRC cells exhibited an inverse correlation with the number of tumor-infiltrating T lymphocytes. MENK inhibited the growth of MOLT-4 T-lymphoblastic cells in a dose-dependent manner. Furthermore, it increased the phosphorylation level of c-Jun N-terminal kinase and induced apoptosis in MOLT-4 cells. MENK-induced apoptosis was abrogated by a c-Jun N-terminal kinase inhibitor. Immunohistochemical analysis revealed moderate to strong expression of MENK in 33 (54%) of 61 CRC. MENK expression was associated with Dukes' staging, nodal metastasis, and liver metastasis. The MENK concentration in tumor tissues was higher in Dukes' C cases than in Dukes' B cases. MENK expression was associated with tumor-infiltrating T lymphocytes, especially those belonging to the CD4(+) subset. These findings suggest that MENK secreted by CRC cells caused escape of the host from the effects of immunity.
IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2 (2011)

Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance of IL-13. We propose that Ab modulation of IL-13 interaction with IL-13Rα2 underlies this effect. Two Abs were administered to healthy subjects and mild asthmatics in separate dose-ranging studies and allergen-challenge studies. IMA-638 allows IL-13 interaction with IL-13Rα1 or IL-13Rα2 but blocks recruitment of IL-4Rα to the IL-13/IL-13Rα1 complex, whereas IMA-026 competes with IL-13 interaction with IL-13Rα1 and IL-13Rα2. We found ∼10-fold higher circulating titer of captured IL-13 in subjects treated with IMA-026 compared with those administered IMA-638. To understand how this difference could be related to epitope, we asked whether either Ab affects IL-13 internalization through cell surface IL-13Rα2. Humans inducibly express cell surface IL-13Rα2 but lack the soluble form that regulates IL-13 responses in mice. Cells with high IL-13Rα2 expression rapidly and efficiently depleted extracellular IL-13, and this activity persisted in the presence of IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway suggest that cell surface IL-13Rα2 acts as a scavenger for IL-13. These findings could have important implications for the design and characterization of IL-13 antagonists.
Reprogramming CD19-Specific T Cells with IL-21 Signaling Can Improve Adoptive Immunotherapy of B-Lineage Malignancies (2011)

Improving the therapeutic efficacy of T cells expressing a chimeric antigen receptor (CAR) represents an important goal in efforts to control B-cell malignancies. Recently an intrinsic strategy has been developed to modify the CAR itself to improve T-cell signaling. Here we report a second extrinsic approach based on altering the culture milieu to numerically expand CAR(+) T cells with a desired phenotype, for the addition of interleukin (IL)-21 to tissue culture improves CAR-dependent T-cell effector functions. We used electrotransfer of Sleeping Beauty system to introduce a CAR transposon and selectively propagate CAR(+) T cells on CD19(+) artificial antigen-presenting cells (aAPC). When IL-21 was present, there was preferential numeric expansion of CD19-specific T cells which lysed and produced IFN-γ in response to CD19. Populations of these numerically expanded CAR(+) T cells displayed an early memory surface phenotype characterized as CD62L(+)CD28(+) and a transcriptional profile of naïve T cells. In contrast, T cells propagated with only exogenous IL-2 tended to result in an overgrowth of CD19-specific CD4(+) T cells. Furthermore, adoptive transfer of CAR(+) T cells cultured with IL-21 exhibited improved control of CD19(+) B-cell malignancy in mice. To provide coordinated signaling to propagate CAR(+) T cells, we developed a novel mutein of IL-21 bound to the cell surface of aAPC that replaced the need for soluble IL-21. Our findings show that IL-21 can provide an extrinsic reprogramming signal to generate desired CAR(+) T cells for effective immunotherapy.
Serial Analysis of Gene Expression as a Tool to Assess the Human Thyroid Expression Profile and to Identify Novel Thyroidal Genes* (2000)

The assessment of the expression profile of normal human thyroid tissue using serial analysis of gene expression (SAGE) generated a collection of 10,994 sequence transcripts (tags). Each tag represented a messenger RNA transcript, and, in total, 6099 different tags could be distinguished. The presence and abundance of thyroid-specific transcripts showed the overall expression profile to be from a normal thyroid cell. The expression level of several transcripts was confirmed on Northern blot. Seventy percent of tags could not be attributed to a known human gene and, therefore, possibly correspond to novel genes putatively involved in thyroid function. The tag sequence generated by the SAGE technique can be used to further characterize these novel genes. In this way, application of the SAGE technique to thyroid tissue gives insight in the expression profile of a normal thyroid gland and provides the information to characterize novel genes involved in thyroid pathology, such as congenital hypothyroidism and thyroid neoplasia.
Expansion Microscopy: A New Approach to Microscopic Evaluation (2020)

Optical microscopy resolution is limited by the wavelengths of light and the series of microscope lenses and other optical components used to create a magnified image of cell structures in a sample. Often the cell structures are smaller or closer together than the resolution limits of a light microscope. In 2015 the Boyden group at the Massachusetts Institute of Technology (MIT) created a sample preparation technique, expansion microscopy which involves embedding biological samples in a crosslinked, swellable, hydrogel polymer that allows for uniform physical separation of cell components so that they can subsequently be resolved by light microscopy. Using the protein retention variant of expansion microscopy, these experiments evaluated the efficacy of the technique. Forty-micron thick rat hippocampal specimens were labeled GFAP and NeuN antibodies to image the neurons and astrocytes within the tissue. The expansion process produced a 4.7-fold physical expansion of the hippocampal slices. The process was also evaluated using 50 – 100 um thick samples of mouse cardiac tissue, labeled to visualize the cytoskeleton, intercalated discs, and cellular nuclei. However, due to the strong structural integrity of cardiac tissue expansion was inconsistent and incompatible with cardiac tissue samples. Variations to the procedure are required to compensate for the rigidity and anisotropic nature of cardiac tissue. One challenge faced when expanding the samples was creation of a consistent and uniform expansion gel and handling of the fragile embedded tissue. To alleviate these difficulties, we designed a new gelation chamber that allowed for more consistent sample preparation.
Quorum sensing in fungi – a review (2012)

Quorum sensing (QS) is a mechanism of microbial communication dependent on cell density that can regulate several behaviors in bacteria such as secretion of virulence factors, biofilm formation, competence and bioluminescence. The existence of fungal QS systems was revealed ten years ago after the discovery that farnesol controls filamentation in the pathogenic polymorphic fungus Candida albicans. In the past decade, farnesol has been shown to play multiple roles in C. albicans physiology as a signaling molecule and inducing detrimental effects on host cells and other microbes. In addition to farnesol, the aromatic alcohol tyrosol was also found to be a C. albicans QS molecule (QSM) controlling growth, morphogenesis and biofilm formation. In Saccharomyces cerevisiae, two other aromatic alcohols, phenylethanol and tryptophol were found to be QSMs regulating morphogenesis during nitrogen starvation conditions. Additionally, population density-dependent behaviors that resemble QS have been described in several other fungal species. Although fungal QS research is still in its infancy, its discovery has changed our views about the fungal kingdom and could eventually lead to the development of new antifungal therapeutics.
Molecular neurology of prion disease (2005)

Prions are infectious pathogens principally composed of abnormal forms of a protein encoded in the host genome. They cause lethal neurodegenerative conditions including CJD, GSS, and kuru in humans and scrapie and bovine spongiform encephalopathy in domestic animals. Remarkably, distinct strains of prions occur despite absence of an agent-specific genome: misfolded proteins themselves may encode strain diversity--with wide implications in biology. The arrival of variant CJD, and the experimental confirmation that it is caused by infection with BSE-like prions, has focussed research on early diagnosis and treatment. Recent advances lead to considerable optimism that effective human therapies may now be developed. While several drugs have been tried in small numbers of patients, there is no clear evidence of efficacy of any agent and controlled clinical trials are urgently needed. Importantly, there is increasing recognition that fundamental processes involved in prion propagation--seeded aggregation of misfolded host proteins--are of far wider significance, not least in understanding the commoner neurodegenerative diseases that pose such a major and increasing challenge for healthcare in an ageing population.
HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention (2010)

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.
Characterization and sequence analyses of antibody-selected antigenic variants of herpes simplex virus show a conformationally complex epitope on glycoprotein H (1991)

Thirteen antigenic variants of herpes simplex virus which were resistant to neutralization by monoclonal antibody 52S or LP11 were isolated and characterized. The antibodies in the absence of complement potently neutralize infectivity of wild-type virus as well as inhibit the transfer of virus from infected to uninfected cells ("plaque inhibition") and decrease virus-induced cell fusion by syncytial strains. The first variant isolated arose in vivo. Of 66 type 1 isolates analyzed from typing studies of 100 clinical isolates, one was identified as resistant to neutralization by LP11 antibody. The glycoprotein H (gH) sequence was derived and compared with those of wild-type and syncytial laboratory strains SC16, strain 17, and HFEM. The sequences were highly conserved in contrast to the diversity observed between gH sequences from herpesviruses of different subgroups. Only four coding changes were present in any of the comparisons, and only one unique coding change was observed between the laboratory strains and the clinical isolate (Asp-168 to Gly). These sequences were compared with those of antigenic variants selected by antibody in tissue culture. Twelve variants were independently selected with antibody LP11 or 52S from parent strain SC16 or HFEM. For each variant, the gH nucleotide sequence was derived and a point mutation was identified giving rise to a single amino acid substitution. The LP11-resistant viruses encoded gH sequences with amino acid substitutions at sites distributed over one-half of the gH external domain, Glu-86, Asp-168, or Arg-329, while the 52S-resistant mutant viruses had substitutions at adjacent positions Ser-536 and Ala-537. One LP11 mutant virus had a point mutation in the gH gene that was identical to that of the clinical isolate, giving rise to a substitution of Asp-168 with Gly. Both LP11 and 52S appeared to recognize distinct gH epitopes as mutant virus resistant to neutralization and immunoprecipitation with LP11 remained sensitive to 52S and the converse was shown for the 52S-resistant mutant virus. This is consistent with previous studies which showed that while the 52S epitope could be formed in the absence of other virus products, virus gene expression was required for stable presentation of the LP11 epitope, and for transport of gH to the cell surface (Gompels and Minson, J. Virol. 63:4744-4755, 1989). All mutant viruses produced numbers of infectious particles that were similar to those produced by the wild-type virus, with the exception of one variant which produced lower yields.(ABSTRACT TRUNCATED AT 400 WORDS)
Paroxysmal Cold Hemoglobinuria (P.C.H.) Following Mycoplasma Infection: Anti‐I Specificity of the Biphasic Hemolysin (1973)

A 17‐year‐old boy developed paroxysmal cold hemoglobinuria (P.C.H.) following a respiratory infection due to Mycoplasma. The Donath‐Landsteiner test was positive; the specificity of the biphasic hemolysin was anti‐I. The cold agglutinin phase of the hemolysin had specificity compatible with Marsh's concept 10 of anti‐I FetaI and anti‐I Developed as shown by reactions with group O, I+, i adult and i cord cell, and serum inhibition studies with human milk.
Reinforcement Learning with Unsupervised Auxiliary Tasks (2016)

Deep reinforcement learning agents have achieved state-of-the-art results by directly maximising cumulative reward. However, environments contain a much wider variety of possible training signals. In this paper, we introduce an agent that also maximises many other pseudo-reward functions simultaneously by reinforcement learning. All of these tasks share a common representation that, like unsupervised learning, continues to develop in the absence of extrinsic rewards. We also introduce a novel mechanism for focusing this representation upon extrinsic rewards, so that learning can rapidly adapt to the most relevant aspects of the actual task. Our agent significantly outperforms the previous state-of-the-art on Atari, averaging 880\% expert human performance, and a challenging suite of first-person, three-dimensional \emph{Labyrinth} tasks leading to a mean speedup in learning of 10$\times$ and averaging 87\% expert human performance on Labyrinth.
Determination of the energetics governing the regulatory step in growth hormone-induced receptor homodimerization (2003)

Signaling in the human growth hormone (hGH)-human GH receptor system is initiated by a controlled sequential two-step hormone-induced dimerization of two hGH receptors via their extracellular domains (ECDs). Little is currently known about the energetics governing the important regulatory step in receptor signaling (step 2) because of previously existing experimental barriers in characterizing the binding of the second receptor (ECD2). A further complication is that ECD2 binds through contacts from two spatially distinct sites: through its N-terminal domain to hGH, and to ECD1 through its C-terminal domain, which forms a pseudo-2-fold symmetrical interaction between the stems of the two receptors. We report here a detailed evaluation of the energetics of step 2 binding using a modified surface plasmon resonance method that is able to measure accurately the kinetics of the trimolecular binding process and separate the effects of the two binding sites. The binding kinetics of 23 single and 126 ECD1-ECD2 pair-wise alanine mutations was measured. Although both of the ECD2 binding interfaces were found to be important, the ECD1-ECD2 stem-stem contact is the stronger of the two. It was determined that most residues in the binding interfaces act in additive fashion, and that the six residues common in both ECDs contribute very differently to homodimerization depending on which ECD they reside in. This interface is characterized by a binding "hot-spot" consisting of a core of three residues in ECD1 and two in ECD2. There is no similar hot-spot in the N-terminal domain of ECD2 binding to Site2 of hGH. This study suggests ways to engineer ECD molecules that will bind specifically to either Site1 or Site2 of hGH, providing novel reagents for biophysical and biological studies.
Recent trends in aerosol therapy for allergic rhinitis. (1986)

By analysing patients who visited our out-patient clinic during 4 years (1980-1983), it was found that 18.1% of total patients were suffering from allergic rhinitis. We also analysed prescriptions for allergic rhinitis and it was found that sodium cromoglycate was administered to about 50% of the patients and was the main therapy not only in aerosol type therapy but also in all therapies used for allergic rhinitis. In particular, sodium cromoglycate was administered to over 50% of pediatric patients. Sodium cromoglycate was administered alone in nearly 50% of the patients who used sodium cromoglycate. Accordingly, it can be said that about 25% of all patients were controlled by sodium cromoglycate alone. Steroid aerosol therapy was given to 30-40% of all allergic rhinitis patients. This was mainly due to a rapid increase of usage of beclomethasone dipropionate after 1982 when this was launched. Beclomethasone dipropionate was mainly used for adults patients and was used about 10% of pediatric patients.