gebhart/patrepeval huggingface dataset:
Structure-Based Approach for the Discovery of Bis-benzamidines as Novel Inhibitors of Matriptase (2001)

Matriptase, a trypsin-like serine protease, which may be involved in tissue remodeling, cancer invasion, and metastasis. Potent and selective matriptase inhibitors not only would be useful pharmacological tools for further elucidation of the role of matriptase in these processes but also could have therapeutic potential for the treatment and/or prevention of cancers. We report herein the structure-based approach for the discovery of bis-benzamidines as a novel class of potent matriptase inhibitors. The lead compound, hexamidine (1), inhibits not only the proteolytic activity of matriptase, (K(i) = 924 nM) but also of thrombin K(i) = 224 nM). By testing several available analogues, we identified a new analogue (7) that has a K(i) = 208 nM against matriptase and has only weak inhibitory activity against thrombin (K(i) = 2670 nM), thus displaying a 13-fold selectivity toward matriptase. Our results demonstrated that structure-based database screening is effective in the discovery of matriptase inhibitors and that bis-benzamidines represent a class of promising matriptase inhibitors that can be used for further drug design studies. Finally, our study suggested that there is sufficient structural differences between matriptase and its closely related serine proteases, such as thrombin, for the design of potent and selective matriptase inhibitors.
Alphaviruses and their Derived Vectors as Anti-Tumor Agents (2004)

The alphaviruses Semliki Forest virus (SFV) and Sindbis virus have recently been developed as prototype anti-cancer agents. These are RNA-containing enveloped viruses that code for only 9 proteins of unique sequence. The standard recombinant SFV vector system consists of suicide particles containing recombinant RNA. In addition, alphavirus vectors capable of limited multiplication in the host are also being developed. Several strategies are being adopted to construct prototype SFV vectors for cancer treatment. These include: 1) construction of both prophylactic and therapeutic vaccines to stimulate immunity to tumor-associated antigens, 2) use of apoptosis induction to destroy tumor cells, which includes both the use of the inherent apoptosis-inducing ability of the vector and the action of pro-apoptotic genes cloned into the vector, and 3) expression of cytokines and other immunoregulatory proteins by the vector that enhance anti-tumor immune responses and/or inhibit tumor cell growth. This includes the use of cytokines such as IL-12 that target angiogenesis. Sindbis virus appears to have a natural tropism for tumor cells that may allow targeting both of the wild-type virus and the vector. This approach may also be useful for targeting metastases. For SFV, neurovirulence and/or neurotropism, as well as other tissue damage, may preclude the use of unmodified replication competent wild-type virus in tumor treatment. However, it may be possible to use such a virus in animals that have been vaccinated, using a vector-derived vaccine.
Biodegradable Electrospun Poly(lactic acid) Nanofibers for Effective PM 2.5 Removal (2019)

Abstract In addition to the rapid urbanization and industrialization around the world, air pollution due to particulate matter is a substantial threat to human health. A considerable research effort has been devoted to the development of electrospun polymer nanofibers for air filter applications. Among these new technologies, electrostatic charge‐assisted air filtration is a promising technology for removing small particulate matter (PM). In this investigation, biodegradable electrospun poly( l ‐lactic acid) (PLLA) polymer nanofibers are employed for air filter applications. Electrostatic charges generated from the PLLA nanofiber can significantly enhance air filter applications. Compared with a 3M commercial respirator filter, electrospun PLLA fibrous filters exhibit a high efficiency of 99.3%. Even after 6 h of filtration time, the PLLA filtration membrane still exhibits a 15% improvement in quality factor for PM 2.5 particles than the 3M respirator. This is mainly attributed to the electrostatic force generated from the electrospun PLLA nanofibers, which significantly benefit submicron particle absorption. Due to their biodegradability, ease of fabrication, and relatively high efficiency, electrospun PLLA nanofibers show great promise in applications such as air cleaning systems and personal air purifier applications.
Characterization of the 1,4-dihydropyridine receptor using subunit-specific polyclonal antibodies (1989)

The purified receptor for the 1,4-dihydropyridine Ca2+ channel blockers from rabbit skeletal muscle contains protein components of 170,000 Da (alpha 1), 175,000 Da (alpha 2), 52,000 Da (beta), and 32,000 Da (gamma) when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. Subunit-specific polyclonal antibodies have now been prepared and used to characterize the association of the 32,000-Da polypeptide (gamma subunit) with other subunits of the dihydropyridine receptor. Immunoblot analysis of fractions collected during purification of the dihydropyridine receptor shows that the 32,000-Da polypeptide copurified with alpha 1 and alpha 2 subunits at each step of the purification. In addition, monoclonal antibodies against the alpha 1 and beta subunits immunoprecipitate the digitonin-solubilized dihydropyridine receptor as a multisubunit complex which includes the 32,000-Da polypeptide. Polyclonal antibodies generated against both the nonreduced and reduced forms of the alpha 2 subunit and the gamma subunit have been used to show that the 32,000-Da polypeptide is not a proteolytic fragment of a larger component of the dihydropyridine receptor and not disulfide linked to the alpha 2 subunit. In addition, polyclonal antibodies against the rabbit skeletal muscle 32,000-Da polypeptide specifically react with similar proteins in skeletal muscle of other species including avian and amphibian species. Thus, our results demonstrate that the 32,000-Da polypeptide (gamma subunit) is an integral and distinct component of the dihydropyridine receptor.
Purification and carbohydrate structure of natural murine interferon‐β (1988)

Mouse interferon-beta (Mu-INF-beta) induced in C-243 cells with Newcastle disease virus was purified in four steps including ammonium sulfate fractionation. DEAE-cellulose, monoclonal Mu-IFN-beta antibody affinity and Mono-S cation-exchange chromatographies. Specific activity of the purified Mu-IFN-beta ranged over 1.1-1.4 X 10(9) NIH units/mg protein. This preparation was submitted to pronase digestion and gel on Fractogel TSK HW-40. The permethylated and acetylated glycopeptide fraction was analyzed by chemical-ionization (ammonia) mass spectrometry. The major glycopeptide is composed of Gal, Man, GlcNAc and NeuAc with a molar ratio of 2.0:3.6:3.4:0.5. The GLC pattern of methyl derivatives obtained by methanolysis and acetylation of fully methylated glycopeptide identified 2,3,4,6-tetra-O-methylgalactose; 3,4,6-tri-O-methyl-mannose; 2,3,4- and 2,4,6-tri-O-methylgalactose; 2,4,di-O-methyl mannose and 3,6-di-O-methylglucosamine. These results when compared with data on N-glycans suggest the following structure for the carbohydrate moiety of Mu-INF-beta: (formula; see text).
Adjuvant multipeptide vaccination in high-risk early melanoma patients (2008)

3014 Background: The optimal use of antitumor vaccines is to prevent recurrence after surgery for early disease, when disease burden is still limited and immune functions mostly conserved. Methods: We designed a phase II randomized trial of multipeptide vaccination in stage IIB-C/III melanoma patients. The vaccine includes HLA-A*0201-restricted peptides derived from 4 melanoma antigens (MelanA/MART-1[26–35L], gp100[209–217/210M], NY-ESO-1[157–165V], Survivin-1[96–104]) emulsified in Montanide. The administration is preceded by treatment with low-dose cyclophosphamide (CTX; 300mg/m2), aimed at reducing frequency and activity of regulatory T cells (Treg), and followed by administration of low-dose IL-2 (3x106 IU) to promote specific T cell expansion. The study will enroll 160 patients (80/arm), randomized to observation vs vaccination, consisting in 13 vaccinations given over a period of 3 years. Stage III patients begin vaccination one months prior to nodal dissection, so that tumor and vaccine-draining lymph nodes (LN) are also studied for immune responses. Results: As yet, 37 melanoma patients (18 vaccine vs 19 observation arm) have been enrolled. Peptide-specific CD8+ T cells are significantly enhanced after vaccination in peripheral blood (mean fold increase: 3.5, range 1.3–11.2) of treated but not control patients, as evaluated by IFNγ Elispot. These increases are confirmed by HLA-multimer staining, CD107a mobilization assay and short-term in vitro culture. Resected LN of vaccinated vs control patients show also improved peptide recognition by IFNγ Elispot (mean fold increase: 4, range 1.1–8) and HLA-multimer staining. LN immunohistochemical analysis further demonstrates a significant increment in the percentage of CD8+/GranzymeB+ T cells in treated patients. In contrast, CTX does not seem to significantly affect the frequency of Treg (CD4+CD25+Foxp3+) cells, nor their ability to secrete IL-10 or TGFβ. Conclusions: Multipeptide-based vaccination increases the frequency and the activation state of melanoma-specific T cells in lymphoid organs and peripheral blood of melanoma patients. Clinical data concerning disease-free and overall survival will early define whether this level of anti-melanoma T cell immunity could reduce recurrence risk in cancer patients. No significant financial relationships to disclose.
Functional selectivity of adenosine receptor ligands (2011)

Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies very much on the experimental setup that was used. Upon activation of the receptors by the ubiquitous endogenous ligand adenosine they engage classical G protein-mediated pathways, resulting in production of second messengers and activation of kinases. Besides this well-described G protein-mediated signaling pathway, adenosine receptors activate scaffold proteins such as β-arrestins. Using innovative and sensitive experimental tools, it has been possible to detect ligands that preferentially stimulate the β-arrestin pathway over the G protein-mediated signal transduction route, or vice versa. This phenomenon is referred to as functional selectivity or biased signaling and implies that an antagonist for one pathway may be a full agonist for the other signaling route. Functional selectivity makes it necessary to redefine the functional properties of currently used adenosine receptor ligands and opens possibilities for new and more selective ligands. This review focuses on the current knowledge of functionally selective adenosine receptor ligands and on G protein-independent signaling of adenosine receptors through scaffold proteins.
Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver (2011)

Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase (AMPK) may modulate inflammatory gene expression in liver. Microarray analysis revealed that PGC-1α up-regulated expression of several cytokines and cytokine receptors, including interleukin 15 receptor α (IL15Rα) and, even more importantly, anti-inflammatory interleukin 1 receptor antagonist (IL1Rn). Overexpression of PGC-1α and induction of PGC-1α by fasting, physical exercise, glucagon, or cAMP was associated with increased IL1Rn mRNA and protein expression in hepatocytes. Knockdown of PGC-1α by siRNA down-regulated cAMP-induced expression of IL1Rn in mouse hepatocytes. Furthermore, knockdown of peroxisome proliferator-activated receptor α (PPARα) attenuated IL1Rn induction by PGC-1α. Overexpression of PGC-1α, at least partially through IL1Rn, suppressed interleukin 1β-induced expression of acute phase proteins, C-reactive protein, and haptoglobin. Fasting and exercise also induced IL15Rα expression, whereas glucagon and cAMP resulted in reduction in IL15Rα mRNA levels. Finally, AMPK activator metformin and adenoviral overexpression of AMPK up-regulated IL1Rn and down-regulated IL15Rα in primary hepatocytes. We conclude that PGC-1α and AMPK alter inflammatory gene expression in liver and thus integrate energy homeostasis and inflammation. Induction of IL1Rn by PGC-1α and AMPK may be involved in the beneficial effects of exercise and caloric restriction and putative anti-inflammatory effects of metformin.
Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis (1992)

These findings suggest that RA patients have an abnormality of the HPA axis response to immune/inflammatory stimuli which may reside in the hypothalamus. This hypothalamic abnormality may be an additional, and hitherto unrecognized, factor in the pathogenesis of RA.
Effects of transmission on Gaussian optical states (2015)

The noise properties of phase-insensitive and phase-sensitive optical transmission links are described in detail, for Gaussian input signals. Formulas are derived for the quadrature covariance matrices of the output signals, which allow one to quantify the noise figures of the links and the fidelities of transmission. Another formula is derived, which relates the density operator of an output signal, in the number-state representation, to its covariance matrix. This density matrix allows one to quantify the decrease in coherence and changes in photon-number probabilities associated with transmission. Based on the aforementioned performance metrics, links with distributed phase-sensitive amplification perform significantly better than other links.
In Situ Generation and Screening of a Dynamic Combinatorial Carbohydrate Library against Concanavalin A (2000)

Dynamic combinatorial chemistry (DCC) is a recently introduced approach that is based on the generation of combinatorial libraries by reversible interconversion of the library constituents. In this study, the implementation of such libraries on carbohydrate-lectin interactions was examined. The dynamic carbohydrate libraries were generated from a small set (four or six compounds) of initial carbohydrate dimers through mild disulfide interchange, and selection was performed under two conditions defining either adaptive or pre-equilibrated libraries. Upon initiation, libraries were formed that contained comparable amounts of 10 or 21 individual dimeric species, dynamically interchanging during the scrambling process. They were probed with respect to binding to the plant lectin concanavalin A, either present during library generation or added after equilibration. The libraries could be generated easily both in the presence and absence of the receptor, and a bis-mannose structure was preferentially bound and selected from the mixture. Scrambling of the library in the presence of the receptor resulted in slightly higher yields than when the receptor was added after scrambling, indicating that the receptor to some extent acts as a thermodynamic trap during library generation. The present results illustrate the extention of the DCC approach to carbohydrate recognition groups, the generation of isoenergetic dynamic libraries, and the implementation of either adaptive or pre-equilibrated procedures.
Apparent break in earthquake scaling due to path and site effects on deep borehole recordings (2003)

We reexamine the scaling of stress drop and apparent stress, rigidity times the ratio between seismically radiated energy to seismic moment, with earthquake size for a set of microearthquakes recorded in a deep borehole in Long Valley, California. In the first set of calculations, we assume a constant Q and solve for the corner frequency and seismic moment. In the second set of calculations, we model the spectral ratio of nearby events to determine the same quantities. We find that the spectral ratio technique, which can account for path and site effects or nonconstant Q , yields higher stress drops, particularly for the smaller events in the data set. The measurements determined from spectral ratios indicate no departure from constant stress drop scaling down to the smallest events in our data set ( M w 0.8). Our results indicate that propagation effects can contaminate measurements of source parameters even in the relatively clean recording environment of a deep borehole, just as they do at the Earth's surface. The scaling of source properties of microearthquakes made from deep borehole recordings may need to be reevaluated.
Expedient Synthesis of Triazole-Linked Glycosyl Amino Acids and Peptides (2004)

[structure: see text] An expedient, high-yielding synthesis of two types of triazole-linked glycopeptides is described. These novel and stable glycopeptide mimics were prepared via Cu(I)-catalyzed [3 + 2] cycloaddition of either azide-functionalized glycosides and acetylenic amino acids or acetylenic glycosides and azide-containing amino acids.
Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure (2017)

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.
Two-Step in Vitro Antibody Affinity Maturation Enables Estradiol-17β Assays with More than 10-Fold Higher Sensitivity (2010)

Immunoassays for haptens depend on competitive hapten-anti-hapten reactions, and consequently their sensitivities are significantly influenced by the affinities of anti-hapten antibodies. Thus, genetically engineered antibodies, which have much higher affinities than native antibodies, should increase assay sensitivities. Here, we created a mutated single-chain Fv fragment (scFv) against estradiol-17beta (E(2)) that allowed immunoassays with a much improved sensitivity. Two steps of affinity maturation were performed on a "wild-type" scFv (scFv#E4-4) composed of V(H) and V(L) domains from a mouse anti-E(2) antibody (Ab#E4-4). First, we conducted complementarity-determining region (CDR)-targeted mutagenesis by "CDR-shuffling". Gene fragments encoding CDRs H2, H3, L1, and L3, each of which contained random point mutations, were combined by "shuffling" into the gene encoding the scFv#E4-4 scaffold. After phage display and repeated panning, we isolated a mutated scFv clone [scFv#m1-e7; Ile(L29)Val] that had 5-fold higher affinity (K(a) = 2.6 x 10(8) M(-1)) compared to the Ab#E4-4 Fab fragment (Fab#E4-4). Next, the entire V(H) and V(L) of this clone were randomly mutated by error-prone polymerase chain reaction (PCR). From this library, we found an improved clone, scFv#m2-c4 (K(a) = 6.3 x 10(8) M(-1); Lys(H19)Arg, Tyr(H56)Phe, Ser(H84)Pro, Glu(H85)Gly, Gln(L27)Arg, Leu(L36)Met, Ser(L63)Gly, and Ser(L77)Gly). ScFv#m2-c4 had more than 10-fold higher sensitivity (the midpoint of its dose-response curve was 0.56 ng) than Fab#E4-4 (midpoint 9.0 ng/assay) in a competitive E(2) radioimmunoassay, and even higher sensitivity [midpoint 21 pg/assay, and a limit of detection of 0.47 pg (1.7 fmol)/assay] in a competitive enzyme-linked immunosorbent assay. Cross-reactivity with selected E(2)-related endogenous steroids strongly suggested that scFv#m2-c4 has improved specificity compared to conventional antibodies.
Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension (2008)

Magnesium, an essential intracellular cation, is critically involved in many biochemical reactions involved in the regulation of vascular tone and integrity. Decreased magnesium concentration has been implicated in altered vascular reactivity, endothelial dysfunction, vascular inflammation, and structural remodeling, processes important in vascular changes and target organ damage associated with hypertension. Until recently, very little was known about mechanisms regulating cellular magnesium homeostasis, and processes controlling transmembrane magnesium transport had been demonstrated only at the functional level. Two cation channels of the transient receptor potential melastatin (TRPM) cation channel family have now been identified as magnesium transporters, TRPM6 and TRPM7. These unique proteins, termed chanzymes because they possess a channel and a kinase domain, are differentially expressed, with TRPM6 being found primarily in epithelial cells and TRPM7 occurring ubiquitously. Vascular TRPM7 is modulated by vasoactive agents, pressure, stretch, and osmotic changes and may be a novel mechanotransducer. In addition to its magnesium transporter function, TRPM7 has been implicated as a signaling kinase involved in vascular smooth muscle cell growth, apoptosis, adhesion, contraction, cytoskeletal organization, and migration, important processes involved in vascular remodeling associated with hypertension and other vascular diseases. Emerging evidence suggests that vascular TRPM7 function may be altered in hypertension. This review discusses the importance of magnesium in vascular biology and implications in hypertension and highlights the transport systems, particularly TRPM6 and TRPM7, which may play a role in the control of vascular magnesium homeostasis. Since the recent identification and characterization of Mg2+-selective transporters, there has been enormous interest in the field. However, there is still a paucity of information, and much research is needed to clarify the exact mechanisms of magnesium regulation in the cardiovascular system and the implications of aberrant transmembrane magnesium transport in the pathogenesis of hypertension and other vascular diseases.
Self‐Assembly of 1‐D Coordination Polymers Using Organometallic Linkers and Exhibiting Argentophilic Interactions AgI···AgI (2005)

Abstract Treatment of the organometallic linkers [Cp*M(η 4 ‐benzoquinone)] [M = Rh, L Rh , ( 1a ); M = Ir, L Ir ( 1b )] with excess AgOTf provided the novel 1‐D coordination polymers of the formula {[Ag 3 (L M ) 2 (CH 3 CN) 2 (OTf)][L M ](OTf) 2 } n ( 2a , b ). Single‐crystal X‐ray diffraction studies carried out on 2a and 2b showed that these polymers exhibit, as an outstanding feature, the presence of d 10 ··· d 10 argentophilic interactions between the silver atoms. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)
Oligodeoxynucleotides Expressing Polyguanosine Motifs Promote Antitumor Activity through the Upregulation of IL-2 (2013)

The primary goal of cancer immunotherapy is to elicit an immune response capable of eliminating the tumor. One approach toward accomplishing that goal uses general (rather than tumor-specific) immunomodulatory agents to boost the number and activity of pre-existing CTLs. We find that the intratumoral injection of polyguanosine (poly-G) oligonucleotides (ODN) has such an effect, boosting antitumor immunity and promoting tumor regression. The antitumor activity of poly-G ODN was mediated through CD8 T cells in a TLR9-independent manner. Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell-signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation. These findings establish poly-G ODN as a novel type of cancer immunotherapy.