gebhart/patrepeval huggingface dataset:
Cyclische Sulfoximide, VI: Transannulare Acylwanderungen in cyclischen Sulfoximiden (1978)

Abstract 10‐Acylphenothiazin‐5‐imid‐5‐oxide ( 3 ) unterliegen einer baseninduzierten, transannularen Acylwanderung zu den isomeren Phenothiazin‐5‐acylimid‐5‐oxiden ( 4 ), weiche auch aus dem Grundkörper 5 durch unmittelbare Acylierung herstellbar sind. Bei den homologen 10‐Acyl‐10,11‐dihydrodibenzo[ b , f ][1,4]thiazepin‐5‐imid‐5‐oxiden ( 12 ) wird die Wanderung der Acylgruppe an die 5‐Imidgruppe ( 13 ) sowohl durch Basen als auch thermisch ausgelost.
The major glycoprotein of Sendai virus is dispensable for efficient virus particle budding (1991)

A temperature-sensitive mutant of Sendai virus, ts271, when grown at restrictive temperature is known to produce virions lacking integral haemagglutinin-neuraminidase (HN). In this study, it is shown that the transmembrane-cytoplasmic tail of HN is not detected either. This apparent complete lack of HN does not affect budding efficiency.
Sorafenib: Where Do We Go from Here? (2010)

The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.
Layers of mutualism with commensal bacteria protect us from intestinal inflammation (2006)

Mammals are highly adapted to their very high densities of non-pathogenic bacteria which inhabit the lower small intestine and colon. This is achieved by a series of functional and cellular layers that normally avoid the inflammatory consequences of immune activation by bacterial molecules. In this review we set out the layers of mucosal immune defence to show the many ways in which mutualism with the commensal flora can break down to trigger chronic intestinal inflammation in animal models and inflammatory bowel disease (IBD) in humans.

The immune system of the intestine is phylogenetically ancient, and its development appears to have preceded most other lymphoid structures, including the thymus.1 The intestinal mucosal immune system is also of immense size. Approximately 70% of all lymphocytes in the body are within the mucosal immune system and most of the antibody produced in healthy individuals is IgA, which is secreted across mucous membranes. Intestinal immunity must be finally balanced between the capacity for mounting protective immune responses to infectious agents and yet tolerate the enormous load of antigens and immunostimulatory molecules that constitute the commensal intestinal bacteria.

Commensal bacteria are present in vast numbers.2 The colon is colonised with approximately 1012 organisms/g intestinal contents, making us walking culture media because the bacteria outnumber our own cells! The benefits of commensal bacteria are well known: they help us digest cellulose and salvage energy, synthesise vitamin K, and fill up the microbiological niche that might otherwise be exploited by less benign microbes. Of course, commensals can become pathogens in the right setting, such as debilitated or immunocompromised patients, but on the whole it is impressive how well we coexist with our microbial passengers.

Our bodies have adapted in many ways to achieve this harmonious mutualism with our commensals. The evidence for this comes …
A British Perspective (1995)

Multilateralism in security matters is implicitly assumed in the UK, in so far as the possibility of purely national military action is seen as very small. Even the Falklands campaign could not have been mounted without political and security support from the EC, and military and political support from the US. Multilateralism is also positively valued, especially when it is associated with collective security operations under United Nations auspices. Thus most of the debates in Britain about the development of a future security system for Europe have focused on institutional/functional matters, i.e. which organizations should do what at what point in their institutional development; which states should comprise their membership; and what roles should be played by international staffs. Abstract matters of who exercises leadership in initiating or directing missions have not been addressed. This chapter thus begins with a general appraisal of British views on institutional issues before turning to particular questions of leadership and initiative.
Oncogene‐associated tumor antigens as targets for immunotherapy (1989)

Cellular antigens encoded by tumor viruses and some antigens encoded by cellular oncogenes offer advantages as targets for immunotherapy by being inextricably associated with the neoplastic phenotype. For example, monoclonal antibodies (MAb) specific for an antigen encoded by the neu oncogene have a direct inhibitory effect on proliferation of antigen-positive tumor cells. Many of the oncogene-encoded cell surface molecules are growth factor receptors, as are some tumor-associated differentiation antigens (TADAs). Therefore, it is not surprising that their level of cancer specificity is similar. There have been some promising findings from using TADAs as targets for various forms of immunotherapy, and one would expect the results to further improve by targeting to molecules that are more directly involved in cell proliferation and/or in maintaining the malignant state.
Major Surface Protein 2 of Anaplasma phagocytophilum Facilitates Adherence to Granulocytes (2003)

Anaplasma phagocytophilum is an obligate intracellular bacterium that infects myeloid cells in the mammalian host. Msp2 (p44) is the major immunodominant outer-membrane protein of these bacteria. We hypothesized that Msp2 acts as an adhesin for A. phagocytophilum entry into granulocytes. This potential role was investigated by blocking binding with Msp2 monoclonal antibodies and by antagonizing binding and propagation with recombinant Msp2 (rMsp2) in vitro. With HL-60 cells, fresh human peripheral blood neutrophils, and a cell line devoid of the fucosylated platelet selectin glycoprotein ligand 1 (PSGL-1) receptor for A. phagocytophilum or one that was transfected to express this ligand, Msp2 monoclonal antibody and rMsp2 used as the antagonist caused concentration-dependent reductions in bacterial adhesion (P < 0.007 and P < 0.02, respectively) and propagation (P < 0.05 and P < 0.001), although inhibition of adhesion or propagation was moderate and incomplete. Likewise, rMsp2 bound to surfaces of the transfected cell at a level similar to that of extracellular A. phagocytophilum and significantly (P < 0.05) beyond that of nontransfected cells. Moreover, a dose-dependent reduction (P < 0.019) in PSGL-1 monoclonal antibody binding to HL-60 cells was elicited with rMsp2. We conclude that Msp2s of A. phagocytophilum are involved in bacterial adhesion to ligands on host myeloid cells before intracellular infection.
A yeast mitogen-activated protein kinase homolog (Mpk1p) mediates signalling by protein kinase C. (1993)

Mitogen-activated protein (MAP) kinases are activated in response to a variety of stimuli through a protein kinase cascade that results in their phosphorylation on tyrosine and threonine residues. The molecular nature of this cascade is just beginning to emerge. Here we report the isolation of a Saccharomyces cerevisiae gene encoding a functional analog of mammalian MAP kinases, designated MPK1 (for MAP kinase). The MPK1 gene was isolated as a dosage-dependent suppressor of the cell lysis defect associated with deletion of the BCK1 gene. The BCK1 gene is also predicted to encode a protein kinase which has been proposed to function downstream of the protein kinase C isozyme encoded by PKC1. The MPK1 gene possesses a 1.5-kb uninterrupted open reading frame predicted to encode a 53-kDa protein. The predicted Mpk1 protein (Mpk1p) shares 48 to 50% sequence identity with Xenopus MAP kinase and with the yeast mating pheromone response pathway components, Fus3p and Kss1p. Deletion of MPK1 resulted in a temperature-dependent cell lysis defect that was virtually indistinguishable from that resulting from deletion of BCK1, suggesting that the protein kinases encoded by these genes function in a common pathway. Expression of Xenopus MAP kinase suppressed the defect associated with loss of MPK1 but not the mating-related defects associated with loss of FUS3 or KSS1, indicating functional conservation between the former two protein kinases. Mutation of the presumptive phosphorylated tyrosine and threonine residues of Mpk1p individually to phenylalanine and alanine, respectively, severely impaired Mpk1p function. Additional epistasis experiments, and the overall architectural similarity between the PKC1-mediated pathway and the pheromone response pathway, suggest that Pkc1p regulates a protein kinase cascade in which Bck1p activates a pair of protein kinases, designated Mkk1p and Mkk2p (for MAP kinase-kinase), which in turn activate Mpk1p.
Staphylococcus aureus protein A binding to von Willebrand factor A1 domain is mediated by conserved IgG binding regions (2006)

Protein A (Spa) is a surface-associated protein of Staphylococcus aureus best known for its ability to bind to the Fc region of IgG. Spa also binds strongly to the Fab region of the immunoglobulins bearing V(H)3 heavy chains and to von Willebrand factor (vWF). Previous studies have suggested that the protein A-vWF interaction is important in S. aureus adherence to platelets under conditions of shear stress. We demonstrate that Spa expression is sufficient for adherence of bacteria to immobilized vWF under low fluid shear. The full length recombinant Ig-binding region of protein A, Spa-EDABC, fused to glutathione-S-transferase (GST), bound recombinant vWF in a dose-dependent and saturable fashion with half maximal binding of about 30 nm in immunosorbent assays. Full length-Spa did not bind recombinant vWF A3 domain but displayed binding to recombinant vWF domains A1 and D'-D3 (half maximal binding at 100 nm and 250 nm, respectively). Each recombinant protein A Ig-binding domain bound to the A1 domain in a similar manner to the full length-Spa molecule (half maximal binding 100 nm). Amino acid substitutions were introduced in the GST-SpaD protein at sites known to be involved in IgG Fc or in V(H)3 Fab binding. Mutants altered in residues that recognized IgG Fc but not those that recognized V(H)3 Fab had reduced binding to vWF A1 and D'-D3. This indicated that both vWF regions recognized a region on helices I and II that overlapped the IgG Fc binding site.
A one-step coupled amplification and oligonucleotide ligation procedure for multiplex genetic typing. (1995)

A new technique, coupled amplification and oligonucleotide ligation (CAL), has been developed that allows for simultaneous multiplex amplification and genotyping of DNA. CAL is a biphasic method that combines in one assay DNA amplification by PCR with DNA genotyping by the oligonucleotide ligation assay (OLA). By virtue of a difference in the melting temperatures of PCR primer-target DNA and OLA probe-target DNA hybrids, the method allows preferential amplification of DNA during stage I and oligonucleotide ligation during stage II of the reaction. In stage I, target DNA is amplified using high-melting primers (Tm values between 68 degrees C and 89 degrees C) in a two-step PCR cycle that employs a 94 degrees C denaturation step and a 72 degrees C anneal-elongation step. In stage II, genotyping of PCR products by competitive oligonucleotide ligation with oligonucleotide probes (Tm values between 51 degrees C and 67 degrees C) located between the PCR primers is accomplished by several cycles of denaturation at 94 degrees C followed by anneal-ligation at 55 degrees C. Ligation products are fluorochrome-labeled at their 3' ends and analyzed electrophoretically on a fluorescent DNA sequencer. The CAL procedure has been used successfully to analyze human genomic DNA for cystic fibrosis (CF) alleles. Because product detection occurs concurrently with target amplification, the technique is rapid, highly sensitive, and specific and requires minimal sample processing.
Cortical remyelination: A new target for repair therapies in multiple sclerosis (2012)

Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
Recombinant adenoviruses with large deletions generated by Cre-mediated excision exhibit different biological properties compared with first-generation vectors in vitro and in vivo (1996)

In vivo gene transfer of recombinant E1-deficient adenoviruses results in early and late viral gene expression that elicits a host immune response, limiting the duration of transgene expression and the use of adenoviruses for gene therapy. The prokaryotic Cre-lox P recombination system was adapted to generate recombinant adenoviruses with extended deletions in the viral genome (referred to here as deleted viruses) in order to minimize expression of immunogenic and/or cytotoxic viral proteins. As an example, an adenovirus with a 25-kb deletion that lacked E1, E2, E3, and late gene expression with viral titers similar to those achieved with first-generation vectors and less than 0.5% contamination with E1-deficient virus was produced. Gene transfer was similar in HeLa cells, mouse hepatoma cells, and primary mouse hepatocytes in vitro and in vivo as determined by measuring reporter gene expression and DNA transfer. However, transgene expression and deleted viral DNA concentrations were not stable and declined to undetectable levels much more rapidly than those found for first-generation vectors. Intravenous administration of deleted vectors in mice resulted in no hepatocellular injury relative to that seen with first-generation vectors. The mechanism for stability of first-generation adenovirus vectors (E1a deleted) appeared to be linked in part to their ability to replicate in transduced cells in vivo and in vitro. Furthermore, the deleted vectors were stabilized in the presence of undeleted first-generation adenovirus vectors. These results have important consequences for the development of these and other nonintegrating vectors for gene therapy.
Poly(I:C) Enhances the Susceptibility of Leukemic Cells to NK Cell Cytotoxicity and Phagocytosis by DC (2011)

α active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.
Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1) (2019)

We previously disclosed a series of type I 1/2 inhibitors of NF-κB inducing kinase (NIK). Inhibition of NIK by these compounds was found to be strongly dependent on the inclusion and absolute stereochemistry of a propargyl tertiary alcohol as it forms critical hydrogen bonds (H-bonds) with NIK. We report that inhibition of protein kinase D1 (PKD1) by this class of compounds is not dependent on H-bond interactions of this tertiary alcohol. This feature was leveraged in the design of highly selective inhibitors of PKD1 that no longer inhibit NIK. A structure-based hypothesis based on the position and flexibility of the α-C-helix of PKD1 vs NIK is presented.
A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents (2015)

Systemic absorption and metabolism of drugs in the small intestine, metabolism by the liver as well as excretion by the kidney are key determinants of efficacy and safety for therapeutic candidates. However, these systemic responses of applied substances lack in most in vitro assays. In this study, a microphysiological system maintaining the functionality of four organs over 28 days in co-culture has been established at a minute but standardized microsystem scale. Preformed human intestine and skin models have been integrated into the four-organ-chip on standard cell culture inserts at a size 100,000-fold smaller than their human counterpart organs. A 3D-based spheroid, equivalent to ten liver lobules, mimics liver function. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. A peristaltic on-chip micropump ensures pulsatile media flow interconnecting the four tissue culture compartments through microfluidic channels. A second microfluidic circuit ensures drainage of the fluid excreted through the kidney epithelial cell layer. This four-organ-chip system assures near to physiological fluid-to-tissue ratios. In-depth metabolic and gene analysis revealed the establishment of reproducible homeostasis among the co-cultures within two to four days, sustainable over at least 28 days independent of the individual human cell line or tissue donor background used for each organ equivalent. Lastly, 3D imaging two-photon microscopy visualised details of spatiotemporal segregation of the two microfluidic flows by proximal tubule epithelia. To our knowledge, this study is the first approach to establish a system for in vitro microfluidic ADME profiling and repeated dose systemic toxicity testing of drug candidates over 28 days.
Molecular basis for modulated regulation of gene expression in the arginine regulon ofEscherichia coliK-12 (1983)

We compare the nucleotide sequences of the regulatory regions of five genes or groups of genes of the arginine regulon of Escherichia coli K-12: argF, argI, argR, the bipolar argECBH operon and the carAB operon. All these regions harbour one or two copies of a conserved 18 bp sequence which appears to constitute the basic arginine operator sequence (ARG box). We discuss the influence of ARG box copy number, degree of dyad symmetry, base composition, and position relative to the cognate promoter site on the derepression-repression ratios of the genes of the regulon. A novel hypothesis, based on structural considerations, is also put forward to account for the absence ot attenuation control.
Procainamide Dosage Schedules, Plasma Concentrations, and Clinical Effects (1971)

The relationship of dosage to plasma concentration of procainamide varied greatly among 186 patients. This variation resulted from individual differences in completeness of absorption, distribution space, and elimination rate. Plasma concentrations correlated well with therapeutic and toxic effects. The usually effective antiarrhythmic concentration was 4 to 8 mg/liter; in occasional patients, 8 to 16 mg/liter was more effective. Toxic manifestations were very rare with concentrations of less than 12 mg/liter, but common with concentrations of more than 16 mg/liter. In most patients, procainamide hydrochloride in a daily dose of 50 mg/kg of body weight produces therapeutic plasma concentrations. Three-hour dosage intervals are required to prevent fluctuations of plasma level exceeding 50%. In urgent situations, a parenteral priming dose should be given. In patients with cardiac or renal failure and when usual doses fail or toxic manifestations appear, determinations of plasma levels are useful guides to dosage.
Task-dependence of Activity/ Bite-force Relations and its Impact on Estimation of Chewing Force from EMG (2002)

Estimation of chewing force from electromyograms (EMGs) calibrated in isometric biting yielded strikingly high force values. We tested the hypothesis that EMG-based force predictions are excessive because of differing activity/bite-force relations in mastication and isometric biting. In nine patients, unilateral bite forces and EMGs of 4 elevator muscles were recorded during chewing and isometric clenching on a bite-fork. We estimated chewing force by substituting chewing EMGs of each muscle into isometric activity/bite-force regressions. The estimates were compared with actual chewing forces recorded by intra-oral transducers. In all muscles except the balancing-side masseter, the activity/bite-force ratio was significantly higher in chewing than in isometric biting. The actual mean chewing force amounted to 220 N, while EMG-based estimates ranged from 273 to 475 N, depending on the muscle used for estimation. The results indicate that different activity/force characteristics in dynamic and isometric biting can cause overestimation when chewing force is predicted from masticatory EMGs.
Hepatitis C virus NS3-4A protease inhibitors: countering viral subversion in vitro and showing promise in the clinic. (2006)

Hepatitis C virus (HCV) NS3.4A protease inhibitors have potential for treating chronic HCV disease. Robust antiviral effects have been reported for the three HCV NS3.4A inhibitors (BILN-2061 (ciluprevir), telaprevir (VX-950; Vertex Pharmaceuticals Inc./Janssen Pharnmaceutica NV/Mitsubishi Pharma Corp.) and SCH-503034; Schering-Plough Research Institute) that have been studied in clinical trials to date in HCV-infected patients, and new inhibitor molecules continue to appear on the horizon. Herein, toe relate the remarkable progress of these drug candidates to recent evidence that suggests HCV might depend on NS3.4A protease to subvert multiple innate cellular defense mechanisms.
Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)–Fc Fusion Protein (1997)

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist — a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc).