gebhart/patrepeval huggingface dataset:
Extending Single-Molecule Microscopy Using Optical Fourier Processing (2014)

This article surveys the recent application of optical Fourier processing to the long-established but still expanding field of single-molecule imaging and microscopy. A variety of single-molecule studies can benefit from the additional image information that can be obtained by modulating the Fourier, or pupil, plane of a widefield microscope. After briefly reviewing several current applications, we present a comprehensive and computationally efficient theoretical model for simulating single-molecule fluorescence as it propagates through an imaging system. Furthermore, we describe how phase/amplitude-modulating optics inserted in the imaging pathway may be modeled, especially at the Fourier plane. Finally, we discuss selected recent applications of Fourier processing methods to measure the orientation, depth, and rotational mobility of single fluorescent molecules.
Characterization of two Epstein‐Barr virus epitopes restricted by HLA‐B7 (1995)

We have identified two epitopes for Epstein-Barr virus specific cytotoxic T lymphocytes (CTL) restricted by the common allele HLA-B7. They are EBNA 3C 881-9 (QPRAPIRPI) and EBNA 3A 379-387 (RPPIFIRRL). The epitopes conform well to the recently described motif for HLA-B7-binding peptides (Huckzo et al., J. Immunol. 1993. 151:2572). Titration of the peptides in CTL assays and detergent lysate binding assays revealed that extending the peptides at either the N or C terminus did not reduce their affinity for HLA-B7. This behavior contrasted with HLA-B51, which binds peptides with a similar motif to B7, and has identical amino acid residues at sites expected to form the "F" pocket of the peptide-binding groove. HLA-B51 also bound the peptide EBNA 3C 881-9, but was unable to bind peptides extended at the C terminus.
Mode of inhibition of acid proteases by pepstatin. (1976)

Four derivatives of pepstatin, each of which contains the unusual amino acid 4-amino-3-hydroxy-6-methylheptanoic acid (statine) have been prepared. All four are porcine pepsin inhibitors. Both N-acetylstatine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with Ki values of 1.2 X 10(-4) M and 5.65 X 10(-6) M, respectively. The Ki values for N-acetyl-valyl-statine is 4.8 X 10(-6) M. These statyl derivatives, therefore, are very strong inhibitors. The Ki value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from Rhizopus chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. It is suggested that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases.
Polymer-supported lipid shells, onions, and flowers (2008)

Phospholipid-enveloped biodegradable polymer microparticles and nanoparticles synthesized by an emulsion/solvent evaporation process were characterized by confocal and cryoelectron microscopies to show that the lipid envelope exhibits two-dimensional fluidity and can be configured into 'shell', 'onion', or 'flower' nanostructures, depending on the quantity and composition of lipids employed in the synthesis.
Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model (2015)

iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.
Brain-specific epigenetic markers of schizophrenia (2015)

Epigenetics plays a crucial role in schizophrenia susceptibility. In a previous study, we identified over 4500 differentially methylated sites in prefrontal cortex (PFC) samples from schizophrenia patients. We believe this was the first genome-wide methylation study performed on human brain tissue using the Illumina Infinium HumanMethylation450 Bead Chip. To understand the biological significance of these results, we sought to identify a smaller number of differentially methylated regions (DMRs) of more functional relevance compared with individual differentially methylated sites. Since our schizophrenia whole genome methylation study was performed, another study analysing two separate data sets of post-mortem tissue in the PFC from schizophrenia patients has been published. We analysed all three data sets using the bumphunter function found in the Bioconductor package minfi to identify regions that are consistently differentially methylated across distinct cohorts. We identified seven regions that are consistently differentially methylated in schizophrenia, despite considerable heterogeneity in the methylation profiles of patients with schizophrenia. The regions were near CERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C and a region on chromosome 10. Of particular interest is PRDM9 which encodes a histone methyltransferase that is essential for meiotic recombination and is known to tag genes for epigenetic transcriptional activation. These seven DMRs are likely to be key epigenetic factors in the aetiology of schizophrenia and normal brain neurodevelopment.
Mechanistic Studies on Human Platelet Isoprenylated Protein Methyltransferase: Farnesylcysteine Analogs Block Platelet Aggregation without Inhibiting the Methyltransferase (1994)

The kinetic mechanism of the human platelet S-adenosyl-L-methionine (AdoMet)-linked isoprenylated protein methyltransferase was studied and determined to be ordered bibi. AdoMet binds first, and S-adenosyl-L-homocysteine (AdoHcy) departs last. Simple N-acetylated farnesylated cysteine analogs, such as N-acetyl-S-farnesyl-L-cysteine (AFC), are excellent substrates for the enzyme. Although many N-acetylated farnesylated cysteine analogs are excellent substrates for the enzyme, analogs with bulky moieties adjacent to the farnesylcysteine are neither substrates nor inhibitors of the enzyme. Two molecules of this class, N-benzoyl-S-farnesyl-L-cysteine (BzFC) and N-pivaloyl-S-farnesyl-L-cysteine (PFC) are useful in sorting out the putative physiological role of the methyltransferase in mediating human platelet aggregation because their pharmacological activities are unlinked to methyltransferase inhibition. When studied as inhibitors of platelet aggregation, the analogs are as active, or more active, than bona fide methyltransferase inhibitors of similar structure. Therefore, although it is possible that methyltransferase inhibitors, such as AFC, inhibit the enzyme when applied to cells, the observed pharmacological effects appear to be unrelated to this blockade. The new FC analogs described here have revealed a new signal transduction target which will be of some interest to explore.
Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18 (2009)

The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 A resolution; the 125-2H Fab (2.3 A); and the ABT-325 Fab (1.5 A). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (> 10 A) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966-971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody binding may in some cases be water-mediated.
Automatic manipulation of microlitre volumes of liquid reagents (1987)

An automatic reagent manipulating system (ARMS) for measuring, dispensing and mixing microlitre volumes of liquid reagents to react at ambient temperatures is described, for use mainly in the life science laboratory. The necessary attributes of such a system are outlined and an account is provided of the ARMS components-a reagent handling device, a liquid dispenser and a control module. The operation of the system is described and reference is made to its use in automating the Sanger DNA sequencing reactions. In conclusion, the potential of the ARMS for use in other molecular biology and biotechnology laboratory protocols is mentioned.
s-Triazines as nitrogen sources for bacteria (1981)

Isolation of bacteria able to utilize s-triazines as the sole and limiting nitrogen sources for growth is described. Three strains of Pseudomonas (A, D, and F) and two strains of Klebsiella pneumoniae (90 and 99) were examined. Strains D and F utilized N-ethylammelide, N-isopropylammelide, ammeline, ammelide, cyanuric acid, and ammonium ion as nitrogen sources. Strain A utilized melamine, ammeline, ammelide, cyanuric acid, ammonium ion, and deaminated N-ethylammeline and N-isopropylammeline. Strains 90 and 99 utilized ammelide, cyanuric acid, and ammonium ion. Growth yields of strains were independent of the nitrogen source, and specific growth rates with s-triazines were similar to those with ammonium ion as the nitrogen source (~0.3-0.6 h-l). Suspensions of nongrowing cells generally gave quantitative yields of ammonium ion from s-triazines, and ring carbon atoms were released as carbon dioxide. N-Alkylammelines in mixtures of strains A and D were quantitatively degraded to ammonium ion.
Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo (2008)

Angiogenesis is critical to tumor growth and is stimulated by tissue hypoxia due to poor oxygen delivery. In turn, cellular hypoxia leads to angiogenesis via the induction of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at a cellular level. Pomegranate juice and extracts, which are rich sources of ellagitannins, have been shown to have chemopreventive potential against prostate cancer, but there have been no studies on the effects of an ellagitannin-rich pomegranate extract on angiogenesis. Human prostate cancer cells (LNCaP) and human umbilical vein endothelial cells (HUVEC) were incubated with a pomegranate extract standardized to ellagitannin content (POMx), under normoxic and hypoxic conditions in vitro. Human prostate cancer cells (LAPC4) were injected subcutaneously into severe combined immunodeficient (SCID) mice and the effects of oral administration of POMx on tumor growth, microvessel density, and HIF-1alpha and VEGF expression were determined after 4 weeks of treatment. POMx inhibited the proliferation of LNCaP and HUVEC cells significantly under both normoxic and hypoxic conditions. HIF-1alpha and VEGF protein levels were also reduced by POMx under hypoxic conditions. POMx decreased prostate cancer xenograft size, tumor vessel density, VEGF peptide levels and HIF-1alpha expression after 4 weeks of treatment in SCID mice. These results demonstrate that an ellagitannin-rich pomegranate extract can inhibit tumor-associated angiogenesis as one of several potential mechanisms for slowing the growth of prostate cancer in chemopreventive applications. Further studies in humans are needed to confirm that angiogenesis can be inhibited by an ellagitannin-rich pomegranate extract administered orally as a dietary supplement.
Catalytic, Asymmetric Mannich-Type Reactions of N-Acylimino Esters for Direct Formation of N-Acylated Amino Acid Derivatives. Efficient Synthesis of a Novel Inhibitor of Ceramide Trafficking, HPA-12 (2001)

[reaction: see text] Catalytic, enantioselective Mannich-type reactions of N-acylimino esters for direct formation of N-acylated amino acid derivatives are described. A chiral copper catalyst prepared from Cu(OTf)(2) and a chiral diamine ligand is used. A novel inhibitor of ceramide trafficking, HPA-12, is efficiently synthesized using this reaction.
Is BCG an “Orphan” Drug Suffering from Chemotherapists’ Overkill? (1986)

Modern interest in cancer immunotherapy emerged in 1969 following the pioneer reports of George Mathe on the effect of Bacillus Calmette-Guerin (BCG) in suppressing murine cancer and apparently increasing survival of children with acute lymphatic leukemia (1). Mathe employed intensive repeated weekly multisite scarifications with BCG during both the induction and maintenance phases of the steadily improving chemotherapy in vogue in the late 1960s. His favorable but uncontrolled studies stimulated a number of “historically controlled” trials of intensive heavy weekly BCG treatment. In the last eight years, at least 60 randomized controlled trials and many other nonrandomized studies have been completed. These employ diverse immunomodulators including various formulations of BCG (2) and BCG derivatives [BCG-MER, BCG cell wall skeletons (CWS)], as well as Corynebacterium parvumlevamisole, thymosin, poly A-poly U, and other agents. A vast array of confusing fragmentary observations and generally nonsignificant borderline findings have been summarized in several published international symposia.
Strong and regulated promoters in the cyanobacteriumAnabaenaPCC 7120 (1993)

The strengths of several promoters were assessed in the cyanobacterium Anabaena PCC 7120 by fusing them to luxAB, encoding bacterial luciferase. Two promoters, Ptac and PpsbA, with sequences nearly identical to consensus Escherichia coli sigma 70 promoters, gave as high or higher expression than the strong Anabaena promoter, Prbc. Pnpt, the natural promoter driving expression of the kanamycin-resistance determinant from Tn5, was poorly expressed in Anabaena. The Lac repressor partially repressed expression from Ptac, permitting regulated expression in Anabaena after induction with isopropyl thiogalactoside to a level 4-5-fold higher than without inducer.
Isolation of porcine adenovirus from the respiratory tract of pigs in Japan. (1990)

[in Japanese]
Oxyradicals and DNA damage (2000)

A major development of carcinogenesis research in the past 20 years has been the discovery of significant levels of DNA damage arising from endogenous cellular sources. Dramatic improvements in analytical chemistry have provided sensitive and specific methodology for identification and quantitation of DNA adducts. Application of these techniques to the analysis of nuclear DNA from human tissues has debunked the notion that the human genome is pristine in the absence of exposure to environmental carcinogens. Much endogenous DNA damage arises from intermediates of oxygen reduction that either attack the bases or the deoxyribosyl backbone of DNA. Alternatively, oxygen radicals can attack other cellular components such as lipids to generate reactive intermediates that couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations that are commonly observed in mutated oncogenes and tumor suppressor genes. Their mutagenicity is mitigated by repair via base excision and nucleotide excision pathways. The levels of oxidative DNA damage reported in many human tissues or in animal models of carcinogenesis exceed the levels of lesions induced by exposure to exogenous carcinogenic compounds. Thus, it seems likely that oxidative DNA damage is important in the etiology of many human cancers. This review highlights some of the major accomplishments in the study of oxidative DNA damage and its role in carcinogenesis. It also identifies controversies that need to be resolved. Unraveling the contributions to tumorigenesis of DNA damage from endogenous and exogenous sources represents a major challenge for the future.
International Consensus on Use of Continuous Glucose Monitoring (2017)

Measurement of glycated hemoglobin (HbA<sub>1c</sub>) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA<sub>1c</sub> testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA<sub>1c</sub> measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.
Improved Mechanoenergetics and Cardiac Rest and Reserve Function of In Vivo Failing Heart by Calcium Sensitizer EMD-57033 (2000)

Selective Ca(2+) sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist.
Characterizing and preventing chargebacks in next generation web payments services (2012)

The volume of electronic transactions has raised a lot in last years, mainly due to the popularization of ecommerce, such as online retailers. We also observe a significant increase in the number of fraud cases, resulting in billions of dollars losses each year worldwide. Therefore it is important and necessary to developed and apply techniques that can assist in fraud detection, which motivates our research. This work aims to apply and evaluate some computational intelligence techniques to identify fraud in electronic transactions, more specifically in credit card operations. In order to evaluate the techniques, we define a concept of economic efficiency and apply them in an actual dataset of the most popular Brazilian electronic payment service. Our results show good performance in fraud detection, presenting significant gains in comparison to the actual scenario of the company.
BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells (2013)

Amyloids are often associated with pathologic processes such as in Alzheimer's disease (AD), but can also underlie physiological processes such as pigmentation. Formation of pathological and functional amyloidogenic substrates can require precursor processing by proteases, as exemplified by the generation of Aβ peptide from amyloid precursor protein (APP) by beta-site APP cleaving enzyme (BACE)1 and γ-secretase. Proteolytic processing of the pigment cell-specific Melanocyte Protein (PMEL) is also required to form functional amyloid fibrils during melanogenesis, but the enzymes involved are incompletely characterized. Here we show that the BACE1 homologue BACE2 processes PMEL to generate functional amyloids. BACE2 is highly expressed in pigment cells and Bace2(-/-) but not Bace1(-/-) mice display coat color defects, implying a specific role for BACE2 during melanogenesis. By using biochemical and morphological analyses, combined with RNA silencing, pharmacologic inhibition, and BACE2 overexpression in a human melanocytic cell line, we show that BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis. These studies identify an amyloidogenic substrate of BACE2, reveal an important physiological role for BACE2 in pigmentation, and highlight analogies in the generation of PMEL-derived functional amyloids and APP-derived pathological amyloids.
Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma (2012)

Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B-cell malignancies, although many still relapse and little progress has been made with T-cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhance antitumor immune responses using novel immunomodulatory agents in combination with standard of care treatments. Here we report that intravenous administration of the Toll-like receptor 7 (TLR7) agonist, R848 in combination with radiation therapy (RT), leads to the longstanding clearance of tumor in T- and B-cell lymphoma bearing mice. In combination, TLR7/RT therapy leads to the expansion of tumor antigen-specific CD8(+) T cells and improved survival. Furthermore, those mice that achieve long-term clearance of tumor after TLR7/RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response. Our findings demonstrate the potential for enhancing the efficacy of conventional cytotoxic anticancer therapy through combination with a systemically administered TLR7 agonist to improve antitumor immune responses and provide durable remissions.
A computer-assisted analysis of conserved residues in the three-dimensional structures of the polymerase domains of Escherichia coli DNA polymerase I and HIV-1 reverse transcriptase. (1994)

Using a computer-assisted molecular modeling protocol, we have completed the three-dimensional structures of HIV-1 reverse transcriptase and the Klenow fragment of DNA polymerase I based on the C alpha crystal coordinates of the individual enzymes. The two model-built structures were then used to compare the electrostatic potential contours and analyze the spatial positions of residues conserved in the catalytic domains of the two enzymes. In spite of rather weak sequence similarity and different folding patterns between the DNA-dependent DNA polymerase (pol I) and the RNA-dependent DNA polymerases (RT), we have noted the occurrence of identical or similar residues at common spatial positions in pol I and RT in a three-dimensional context. The homologous residues present at equivalent spatial position in the Klenow fragment and the p66 subunit of HIV-1 RT may therefore imply their functional similarity. Furthermore, these conserved residues may represent a similar structure-function feature in all polymerases.