gebhart/patrepeval huggingface dataset:
On the stability and plastic properties of the interior L3 loop in R.capsulatus porin. A molecular dynamics study (1994)

Structural properties of Rhodobacter capsulatus porin are studied by molecular dynamics simulation using the GROMOS force field. Unconstrained simulations of the trimer and monomer show the trimer to be more stable than the isolated monomer. Simulations of the L3 loop inside the pore are used to assess its stability and plastic properties. Simulated annealing shows that the conformational space available to the L3 loop inside the pore is very large. Simulations at different temperatures show that the energy hypersurface around the open state is complex and flat. These studies also indicate four zones that are more flexible than the rest of the loop. Two of these are stabilized by the addition of the detergent molecule present in the X-ray structure. It is possible that the two remaining flexible zones, situated in the half of the loop facing the extracellular end of the porin molecule, residues Asp93-Gly98 and Arg110-Leu111, are involved in a mechanism for opening and closing of the pore.
Anti-CD180 (RP105) Activates B Cells To Rapidly Produce Polyclonal Ig via a T Cell and MyD88-Independent Pathway (2011)

CD180 is homologous to TLR4 and regulates TLR4 signaling, yet its function is unclear. We report that injection of anti-CD180 mAb into mice induced rapid Ig production of all classes and subclasses, with the exception of IgA and IgG2b, with up to 50-fold increases in serum IgG1 and IgG3. IgG production after anti-CD180 injection was not due to reactivation of memory B cells and was retained in T cell-deficient (TCR knockout [KO]), CD40 KO, IL-4 KO, and MyD88 KO mice. Anti-CD180 rapidly increased both transitional and mature B cells, with especially robust increases in transitional B cell number, marginal zone B cell proliferation, and CD86, but not CD80, expression. In contrast, anti-CD40 induced primarily follicular B cell and myeloid expansion, with increases in expression of CD80 and CD95 but not CD86. The expansion of splenic B cells was due, in part, to proliferation and occurred in wild-type and TCR KO mice, whereas T cell expansion occurred in wild-type, but not in B cell-deficient, mice, indicating a direct role for B cells in CD180 stimulation in vivo. Combination of anti-CD180 with various MyD88-dependent TLR ligands biased B cell fate because coinjection diminished Ig production, but purified B cells exhibited synergistic proliferation. Anti-CD180 had no effect on cytokine production from B cells, but it increased IL-6, IL-10, and TNF-α production in combination with LPS or CpG. Thus, CD180 stimulation induces intrinsic B cell proliferation and differentiation, causing rapid increases in IgG, and integrates MyD88-dependent TLR signals to regulate proliferation, cytokine production, and differentiation.
A Strategy for Adenovirus Vector Targeting with a Secreted Single Chain Antibody (2009)

This work describes a new approach to produce targeted Ad vectors using a secreted scFv molecule, thereby avoiding the problem of structural and biosynthetic incompatibility between Ad and a complex targeting ligand. This approach may facilitate Ad targeting using a wide variety of targeting ligands directed towards a variety of cellular receptors.
Accumulation of Multiple Mutations In Vivo Confers Cross-Resistance to New and Existing Integrase Inhibitors (2018)

Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions. The accumulation of multiple integrase substitutions confers high-level resistance to all 5 integrase inhibitors. There is extensive cross-resistance between DTG, BIC, and CAB (r = 0.96-0.97).
Association of the Sweetpotato Whitefly with a Silverleaf Disorder of Squash (1991)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), was associated with symptoms of a silverleaf disorder of acorn squash (Cucurbita pepo L. cvs. Table King Bush and Table Ace) in cage studies in the greenhouse. Symptoms appeared on uninfested leaves that developed after plants were infested with the whitefly. When the infested lower leaves were removed and the young leaves protected from infestation with insecticides, new growth was asymptomatic or nearly so and symptomatic leaves remained symptomatic. Symptom expression was related more to nymphal density than to adult density since the relationship between log nymph density and symptoms was linear when adult densities were equal.
Synthesis, DNA-binding and biological activity of a double intercalating analog of ethidium bromide (1978)

A bis-phenanthridinium salt has been synthesized and its DNA-binding studied. Evidence provided by UV and CD spectra, by thermal denaturation profiles and by equilibrium dialysis of the drug-DNA complex lead to the conclusion that both phenanthridine moieties intercalate in the helix. The double intercalator appears to be less potent than ethidium chloride as an inhibitor of nucleic acid synthesis in cultured L1210 cells, though it is more potent than a monomeric analog. The low potency may be due to a low cell influx rate.
Human deafness dystonia syndrome is a mitochondrial disease (1999)

The human deafness dystonia syndrome results from the mutation of a protein (DDP) of unknown function. We show now that DDP is a mitochondrial protein and similar to five small proteins (Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p) of the yeast mitochondrial intermembrane space. Tim9p, Tim10p, and Tim12p mediate the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane and interact structurally and functionally with Tim8p and Tim13p. DDP is most similar to Tim8p. Tim8p exists as a soluble 70-kDa complex with Tim13p and Tim9p, and deletion of Tim8p is synthetically lethal with a conditional mutation in Tim10p. The deafness dystonia syndrome thus is a novel type of mitochondrial disease that probably is caused by a defective mitochondrial protein-import system.
Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data (2008)

Increasing evidence indicates that malignant stem cells are important for the pathogenesis of acute myelogenous leukemia (AML) and represent a reservoir of cells that drive the development of AML and relapse. Therefore, new treatment regimens are necessary to prevent relapse and improve therapeutic outcomes. Previous studies have shown that the sesquiterpene lactone, parthenolide (PTL), ablates bulk, progenitor, and stem AML cells while causing no appreciable toxicity to normal hematopoietic cells. Thus, PTL must evoke cellular responses capable of mediating AML selective cell death. Given recent advances in chemical genomics such as gene expression-based high-throughput screening (GE-HTS) and the Connectivity Map, we hypothesized that the gene expression signature resulting from treatment of primary AML with PTL could be used to search for similar signatures in publicly available gene expression profiles deposited into the Gene Expression Omnibus (GEO). We therefore devised a broad in silico screen of the GEO database using the PTL gene expression signature as a template and discovered 2 new agents, celastrol and 4-hydroxy-2-nonenal, that effectively eradicate AML at the bulk, progenitor, and stem cell level. These findings suggest the use of multicenter collections of high-throughput data to facilitate discovery of leukemia drugs and drug targets.
THz Sommerfeld wave propagation on a single metal wire (2005)

We report an experimental and theoretical study of THz Sommerfeld wave propagation on a single copper wire. THz pulses are optoelectronically generated and launched onto 0.52-mm-diam copper wire, and the guided THz pulses are detected at the end of the wire by a standard photoconductive antenna. Very low attenuation and group velocity dispersion are observed, and the measured radial field amplitude of the Sommerfeld wave is inversely proportional to the radial distance. These results are consistent with theoretical predictions. Experimental results from curved wires show the weakly guiding property of the THz Sommerfeld wave, which will limit its applications.
Murine hepatocyte apoptosis induced in vitro and in vivo by TNF- alpha requires transcriptional arrest. (1994)

Freshly isolated mouse hepatocytes were essentially insensitive to TNF-alpha cytotoxicity. However, TNF-alpha induced a concentration-dependent cell death in hepatocytes that had been pretreated with the transcriptional inhibitors actinomycin D (ActD), D-galactosamine, or alpha-amanitin. Unlike RNA synthesis inhibition, a translational block in the presence of cycloheximide (CHX) or puromycin did not sensitive hepatocytes to TNF. On the contrary, these agents prevented hepatocytotoxicity induced by ActD/TNF. Pretreatment with peroxides or glutathione depletors had no significant influence on TNF cytotoxicity. In vivo treatment of mice with ActD/TNF caused hepatic failure, which was significantly reduced by co-treatment with CHX. These findings demonstrate that protein synthesis is required for this mechanism of cell death. To test whether TNF may trigger an endogenous suicide program in hepatocytes, we examined whether DNA fragmentation preceded cell death. In the culture system, hepatocellular DNA fragmentation in the presence of ActD/TNF was observed several hours before lactate dehydrogenase release and was inhibited by CHX. Similar results were obtained in vivo. Chromatin condensation and the formation of apoptotic bodies were observed in livers from mice treated with ActD/TNF and significant DNA fragmentation was detected as early as 4 h after challenge. At this time, organ total glutathione content and plasma transaminase levels were not significantly different from those of untreated controls. The findings of this study demonstrate that direct hepatotoxicity of TNF-alpha is associated with an apoptotic mechanism that becomes manifest under the metabolic condition of arrested transcription and functional translation.
Detection of Microsatellite Alterations in Plasma DNA of Malignant Mucosal Melanoma Using Whole Genome Amplification (2008)

Malignant mucosal melanoma (MMM) still has the poorest prognosis. There is a paucity of molecular biological studies on MMM of the head and neck. We investigated free-circulating DNA microsatellites with loss of heterozygosity (LOH) in the blood of MMM patients. Cancer-related DNA is found in plasma, with cancer patients showing a higher level of free-circulating DNA than normal subjects. However, it is difficult to obtain sufficient amounts of such DNA for PCR analysis. We have searched for ways to improve all stages of such research, and detected new microsatellite alterations by triplicated whole genome amplification (WGA) and triplicated PCR amplification. In order to achieve a better understanding of the extent of the alterations affecting chromosomes we determined the occurrence of LOH at the following gene loci: D1S243, D6S311, D9S161, and D19S246; only 4 out of the 20 microsatellite markers usually used in MMM were used in this study. We determined LOH in 17 MMM patients.It was possible to confirm LOH on at least one marker in 12 (70.6%) out of the 17 patients. Metastasis or recurrence was confirmed in 3 (17.6%) out of the 17 patients, and all of them were found to have LOH. LOH at microsatellite markers D1S243, D6S311, D9S161 and D19S246 in the plasma of these patients statistically correlated with MMM.The results of this study suggest that these loci are suitable for identifying cancerrelated DNA of MMM, and that analysis of LOH in plasma DNA released into the circulation may be useful as a screening tool.
[Strengthening the immune response to typhoid vaccine by subcutaneous RNA administration]. (1977)

The authors demonstrated the adjuvant activity of the RNA preparations injected subcutaneously. In the treatment of mice with the vaccine with a stimulant there was increase of antibody production and of their resistance to infection with typhoid causative agent in comparison with the animals which were only immunized. When the adjuvant was used the vaccine dose could be devreased 2- to 8-fold without any reduction of the immunity formed. RNA injection to the immunized animals on the 25th day after the onset of the experiment produced a revaccinating effect.
Cardiosphere-Derived Cells from Pediatric End-Stage Heart Failure Patients Have Enhanced Functional Activity Due to the Heat Shock Response Regulating the Secretome (2015)

We have demonstrated that human neonatal cardiosphere-derived cells (CDCs) derived from the young are more regenerative due to their robust secretome. However, it is unclear how the decompensated pediatric heart impacts the functional activity of their CDCs. Our aim was to characterize the potency of pediatric CDCs derived from normal functioning myocardium of control heart disease (CHD) patients to those generated from age-matched end stage heart failure (ESHF) patients and to determine the mechanisms involved. ESHF-derived CDCs contained a higher number of c-kit(+) , Islet-1(+) , and Sca-1(+) cells. When transplanted into an infarcted rodent model, ESHF-derived CDCs significantly demonstrated higher restoration of ventricular function, prevented adverse remodeling, and enhanced angiogenesis when compared with CHD patients. The superior functional recovery of the ESHF-derived CDCs was mediated in part by increased SDF-1α and VEGF-A secretion resulting in augmented recruitment of endogenous stem cells and proliferation of cardiomyocytes. We determined the mechanism is due to the secretome directed by the heat shock response (HSR), which is supported by three lines of evidence. First, gain of function studies demonstrated that increased HSR induced the lower functioning CHD-derived CDCs to significantly restore myocardial function. Second, loss-of function studies targeting the HSR impaired the ability of the ESHF-derived CDCs to functionally recover the injured myocardium. Finally, the native ESHF myocardium had an increased number of c-kit(+) cardiac stem cells. These findings suggest that the HSR enhances the functional activity of ESHF-derived CDCs by increasing their secretome activity, notably SDF-1α and VEGF-A.
Osteopontin (2000)

Osteopontin (OPN) is a highly phosphorylated sialoprotein that is a prominent component of the mineralized extracellular matrices of bones and teeth. OPN is characterized by the presence of a polyaspartic acid sequence and sites of Ser/Thr phosphorylation that mediate hydroxyapatite binding, and a highly conserved RGD motif that mediates cell attachment/signaling. Expression of OPN in a variety of tissues indicates a multiplicity of functions that involve one or more of these conserved motifs. While the lack of a clear phenotype in OPN "knockout" mice has not established a definitive role for OPN in any tissue, recent studies have provided some novel and intriguing insights into the versatility of this enigmatic protein in diverse biological events, including developmental processes, wound healing, immunological responses, tumorigenesis, bone resorption, and calcification. The ability of OPN to stimulate cell activity through multiple receptors linked to several interactive signaling pathways can account for much of the functional diversity. In this review, we discuss the structural features of OPN that relate to its function in the formation, remodeling, and maintenance of bones and teeth.
Development and application of a metric on semantic nets (1989)

Motivated by the properties of spreading activation and conceptual distance, the authors propose a metric, called distance, on the power set of nodes in a semantic net. Distance is the average minimum path length over all pairwise combinations of nodes between two subsets of nodes. Distance can be successfully used to assess the conceptual distance between sets of concepts when used on a semantic net of hierarchical relations. When other kinds of relationships, like 'cause', are used, distance must be amended but then can again be effective. The judgements of distance significantly correlate with the distance judgements that people make and help to determine whether one semantic net is better or worse than another. The authors focus on the mathematical characteristics of distance that presents novel cases and interpretations. Experiments in which distance is applied to pairs of concepts and to sets of concepts in a hierarchical knowledge base show the power of hierarchical relations in representing information about the conceptual distance between concepts.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Restricted Lateral Diffusion of PH-20, a PI-Anchored Sperm Membrane Protein (1988)

The rate of lateral diffusion of integral membrane proteins is constrained in cells, but the constraining factors for most membrane proteins have not been defined. PH-20, a sperm surface protein involved in sperm-egg adhesion, was shown to be anchored in the plasma membrane by attachment to the lipid phosphatidylinositol and to have a diffusion rate that is highly restricted on testicular sperm, being more than a thousand times slower than lipid diffusion. These results support the hypothesis that lateral mobility of a membrane protein can be regulated exclusively by interactions of its ectodomain.
Structures of two histidine ammonia‐lyase modifications and implications for the catalytic mechanism (2002)

Histidine ammonia-lyase (EC 4.3.1.3) catalyzes the nonoxidative elimination of the alpha-amino group of histidine using a 4-methylidene-imidazole-5-one (MIO), which is formed autocatalytically from the internal peptide segment 142Ala-Ser-Gly. The structure of the enzyme inhibited by a reaction with l-cysteine was established at the very high resolution of 1.0 A. Five active center mutants were produced and their catalytic activities were measured. Among them, mutant Tyr280-->Phe could be crystallized and its structure could be determined at 1.7 A resolution. It contains a planar sp2-hybridized 144-N atom of MIO, in contrast to the pyramidal sp3-hybridized 144-N of the wild-type. With the planar 144-N atom, MIO assumes the conformation of a putative intermediate aromatic state of the reaction, demonstrating that the conformational barrier between aromatic and wild-type states is very low. The data led to a new proposal for the geometry for the catalyzed reaction, which also applies to the closely related phenylalanine ammonia-lyase (EC 4.3.1.5). Moreover, it suggested an intermediate binding site for the released ammonia.
Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells (2012)

Cell migration and invasion are largely dependent on the complex organization of the various cytoskeletal components. Whereas the role of actin filaments and microtubules in cell motility is well established, the role of intermediate filaments in this process is incompletely understood. Organization and structure of the keratin cytoskeleton, which consists of heteropolymers of at least one type 1 and one type 2 intermediate filament, are in part regulated by post-translational modifications. In particular, phosphorylation events influence the properties of the keratin network. Sphingosylphosphorylcholine (SPC) is a bioactive lipid with the exceptional ability to change the organization of the keratin cytoskeleton, leading to reorganization of keratin filaments, increased elasticity, and subsequently increased migration of epithelial tumor cells. Here we investigate the signaling pathways that mediate SPC-induced keratin reorganization and the role of keratin phosphorylation in this process. We establish that the MEK-ERK signaling cascade regulates both SPC-induced keratin phosphorylation and reorganization in human pancreatic and gastric cancer cells and identify Ser431 in keratin 8 as the crucial residue whose phosphorylation is required and sufficient to induce keratin reorganization and consequently enhanced migration of human epithelial tumor cells.
Improved GaLV-TR Glycoproteins to Pseudotype Lentiviral Vectors: Impact of Viral Protease Activity in the Production of LV Pseudotypes (2019)

Lentiviral vectors (LVs) are excellent tools for gene transfer into mammalian cells. It is noteworthy that the first gene therapy treatment using LVs was approved for commercialization in 2017. The G glycoprotein from rhabdovirus vesicular stomatitis virus (VSV-G) is the glycoprotein most used to pseudotype LVs, due to its high efficiency in transducing several cell types and its resistance to viral vector purification and storage conditions. However, VSV-G expression induces cytotoxicity, which limits LV production to short periods. As alternative to VSV-G, γ-retrovirus glycoproteins (4070A derived, GaLV derived, and RD114 derived) have been used to pseudotype both γ-retroviral vectors (RVs) and LVs. These glycoproteins do not induce cytotoxicity, allowing the development of stable LV producer cells. Additionally, these LV pseudotypes present higher transduction efficiencies of hematopoietic stem cells when compared to VSV-G. Here, new 4070A-, RD114-TR-, and GaLV-TR-derived glycoproteins were developed with the aim of improving its cytoplasmic tail R-peptide cleavage and thus increase LV infectious titers. The new glycoproteins were tested in transient LV production using the wild-type or the less active T26S HIV-1 protease. The GaLV-TR-derived glycoproteins were able to overcome titer differences observed between LV production using wild-type and T26S protease. Additionally, these glycoproteins were even able to increase LV titers, evidencing its potential as an alternative glycoprotein to pseudotype LVs.
Spectrroscopic Sensing of Cancer and Cancer Therapy: Current Status of Translational Research (2004)

Various types of optical spectroscopy have been investigated as methods to effect a non-invasive, real-time in-situ assessment of tissue pathology. All of these methods have one basic principle in common: the optical spectrum of a tissue contains information about the biochemical composition and/or the structure of the tissue, and that information conveys diagnostic information. The biochemical information can be obtained by measuring absorption, fluorescence, or Raman scattering signals. Structural and morphological information may be obtained by techniques that assess the elastic-scattering properties of tissue. These basic approaches are useful for the detection of cancer as well as for other diagnostic applications such as hemoglobin saturation, intra-luminal detection of atherosclerosis, and simply the identification of different tissue types during procedures. Optical spectroscopic measurements can also be employed in the management of disease treatment. The site-specific pharmacokinetics of chemotherapy and photodynamic therapy agents can be used to customize dosage to the patient, and diagnostic spectroscopy can be used to monitor response to treatment. In recent years clinical studies have provided indications of potential efficacy, and some of these modalities are now entering a translational research stage, with an eye to approval and commercialization. A benefit of these methods is their inherent low cost and ease of implementation, generally mediated with small portable instruments, not requiring any specialized facilities, and eventually not requiring expert interpretation. This paper reviews briefly the most common methods of diagnostic optical spectroscopy, and reviews in greater depth recent clinical translational research invoking scattering spectroscopy as the enabling technology, which has been the experience of the authors.