gebhart/patrepeval huggingface dataset:
Adjunctive therapies and immunomodulating agents for severe influenza (2013)

The value of adjunctive immunomodulatory therapies in treating severe influenza and other respiratory viral infections remains uncertain. Although often used, systemic corticosteroids may increase the risk of mortality and morbidity (e.g. secondary infections) in severe influenza and other viral infections, especially if there is delay or lack of effective antiviral therapy. Non-randomized studies suggest that convalescent plasma appears useful as add-on therapy for patients with severe acute respiratory syndrome, avian influenza A(H5N1), and influenza A (H1N1) 2009 pandemic [A(H1N1)pdm09), but it is limited by its availability. A recent randomized controlled trial (RCT) comparing hyperimmune globulin prepared from convalescent plasma against normal intravenous gammaglobulin (IVIG) manufactured before 2009 as control in patients with severe A(H1N1)pdm09 infection on standard antiviral treatment has shown that the hyperimmune globulin group who received treatment within 5 days of symptom onset had a lower viral load and reduced mortality compared with the controls. A number of agents with immunomodulatory effects (e.g. acute use of statins, N-acetylcysteine, macrolides, PPAR agonists, IVIG, celecoxib, mesalazine) have been proposed for influenza management. However, more animal and detailed human observational studies and preferably RCTs controlling for the effects of antiviral therapy and disease severity are needed for evaluating these agents. The role of plasmapheresis and hemoperfusion as rescue therapy also merits more investigation.
Uridine reverses the toxicity of 3'-azido-3'-deoxythymidine in normal human granulocyte-macrophage progenitor cells in vitro without impairment of antiretroviral activity (1988)

We evaluated the effects of natural purine and pyrimidine nucleosides on protection from or reversal of 3'-azido-3'-deoxythymidine (AZT) cytotoxicity in human bone marrow progenitor cells by using clonogenic assays. The selectivity of the "protection" or "rescue" agents was examined in evaluating the antiretroviral activity of AZT in combination with these modulating agents and of AZT alone. Following exposure of human granulocyte-macrophage progenitor cells for 2 h to 5 microM AZT (70% inhibitory concentration), increasing concentrations of potential rescue agents were added. Cells were cultured, and colony formation was assessed after 14 days. At concentrations of up to 50 microM no natural 2'-deoxynucleosides, including thymidine, were able to reverse the toxic effects of AZT. Dose-dependent reversal was observed with uridine and cytidine, and essentially complete reversal was achieved with 50 microM uridine. In the protection studies, 100 microM thymidine almost completely antagonized the inhibition of granulocyte-macrophage colony formation produced by 1 microM AZT (50% inhibitory concentration), and 50 microM uridine effected 60% protection against a toxic concentration of AZT (5 microM) (70% inhibitory concentration). The antiretroviral activity of AZT in human peripheral blood mononuclear cells, assessed by revere transcriptase assays, was substantially decreased in the presence of thymidine, whereas no impairment of suppression of viral replication was observed in the presence of uridine in combination with AZT at a molar ratio (uridine/AZT) as high as 10,000. This demonstration of the capacity of uridine to selectively rescue human bone marrow progenitor cells from the cytotoxicity of AZT suggests that use of uridine rescue regimen with AZT may have potential therapeutic benefit in the treatment of acquired immunodeficiency syndrome.
Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development (2018)

Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific "signal transducer and activator of transcription" (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention.
Local and Global Structural Properties of the HIV-MN V3 Loop (1995)

Studies of the feasibility of a subunit vaccine to protect against human immunodeficiency virus (HIV) infection have principally focused on the third variable (V3) loop. The principal neutralizing determinant (PND) of HIV-1 is located inside the V3 loop of the surface envelope glycoprotein, gp120. However, progress toward a PND-based vaccine has been impeded by the amino acid sequence variability in the V3 loops of different HIV isolates. Theoretical studies revealed that the variability in sequence and structure of the V3 loop is confined to the N- and C-terminal sides of the conserved GPG crest. This leaves three regions of the V3 loop conserved both in sequence and secondary structure. We present the results of NMR studies that test the validity of our theoretical predictions. Structural studies are reported for the HIV-V3 loop (HIV-MN) in the linear and cyclic (S-S-bridged) forms. For the V3 loop sequence of the HIV-MN isolate, the three conserved secondary structural elements are as underlined below: turns turn helix CTRPNYNKRKRIHIGPGRAFYTTKNIIGTIROAHC Finally, the conformational requirement of the PND in the V3 loop-antibody interaction is tested by monitoring the monoclonal antibody binding to the HIV-MN V3 loop in the linear and cyclic forms by enzyme-linked immunosorbent assay. The binding data reveal that the cyclic V3 loop is a better ligand for the monoclonal antibodies than the linear form although the latter has the same sequence. This means that the monoclonal antibodies recognize the PNDs as conformational epitopes.
A General Method for Palladium-Catalyzed Reactions of Primary Sulfonamides with Aryl Nonaflates (2011)

A general method for Pd-catalyzed sulfonamidation of aryl nonafluorobutanesulfonates (aryl nonaflates) is described. A biaryl phosphine ligand, t-BuXPhos, formed the most active catalyst, and K(3)PO(4) in tert-amyl alcohol was found to be the optimal base-solvent combination for the reaction. The reaction conditions were tolerant of various functional groups such as cyano, nitro, ester, aldehyde, ketone, chloride, carbamate, and phenol. Heterocyclic aryl nonaflates were found to be suitable coupling partners. High yields of the coupled products were obtained from the reactions between inherently disfavored substrates such as electron-rich nonaflates and electron-poor sulfonamides. Kinetic data suggest reductive elimination to be the rate-limiting step for the reaction. The only limitation of this methodology that we have identified is the inability of 2,6-disubstituted aryl nonaflates to efficiently participate in the reaction.
Origin and kinetics of pulmonary macrophages during an inflammatory reaction induced by intravenous administration of heat-killed bacillus Calmette-Guérin. (1981)

This report gives a quantitative description of the kinetics of the pulmonary macrophages and their direct precursors during the acute inflammatory reaction in the lungs induced by intravenous injection of heat-killed bacillus Calmette-Guérin (BCG) into specific-pathogen-free mice. After BCG injection, the total number of pulmonary macrophages isolated by lavage and subsequent enzyme digestion of lung tissue increased to 225% of normal within 12 h and, after a minor decrease, rose to a maximum of 250% of normal at 96 h, followed by a decrease to 150% at 144 h, the end of the observation period. The number of circulating monocytes doubled in the first 48 h and stayed close to that level. In vivo and in vitro labeling with [3H]-thymidine showed that an influx of monocytes transforming into pulmonary macrophages was mainly responsible for the population increase. A temporary increase in the number of locally dividing pulmonary macrophages--manifested by an increased in vitro labeling index, reaching a maximum of 9.6% 72 h after BCG injection--made a minor contribution to the population increase. All pulmonary macrophages were classified according to morphological criteria as alveolar-macrophage-like (AML) or non-alveolar-macrophage-like (NAML), and their respective characteristics were established. The in vivo labeling data showed NAML to represent exudate macrophages derived from circulating monocytes entering the interstitial tissue, and these cells changed morphologically into AML upon entering the alveolar hypophase. This mechanism was confirmed by the finding that the interstitially deposited BCG were found first inside NAML and later in AML. The in vivo labeling data showed that local production was mainly a result of division of macrophages that were morphologically identical with normal alveolar macrophages. The former cells, however, derived most probably recently from the circulation, because the turnover of the total population was very high before local macrophage production became maximal. In mice treated with HC before the injection of BCG, this population increase was absent, because of virtual abolition of the initial monocyte influx and absence of the increased local production of macrophages. Calculations showed that the monocyte influx in the first 48 h amounted to approximately 4 x 10(6) cells, i.e., eight times that found in the normal steady state, and that the efflux of pulmonary macrophages in that period amounted to approximately 3.5 x 10(6) cells, i.e., seven times the normal efflux. The local production over the total period of 144 h was only three times that found normally. The results of these quantitative studies show that the increase of the pulmonary macrophage population during an acute inflammation is brought about mainly by monocyte influx and to a minor extent by a temporary increased local production of macrophages. Disposal of interstitially deposited BCG occurred by phagocytosis by local macrophages and the subsequent efflux of the latter.
Steps in maturation of influenza A virus neuraminidase (1995)

We have studied the maturation of the influenza A virus neuraminidase (NA), using monoclonal antibodies (MAbs) with different conformational specificities against the head domains of the N8 NA. The results obtained with radioimmunoprecipitation, together with previously published information, suggest the following steps in maturation of this molecule. First, the folding of the nascent NA leads to formation of the epitope recognized by MAb N8-10, a step that depends on the formation of intramolecular disulfide bonds. Second, monomers form dimers by an intermolecular disulfide linkage in the stalk, with a t1/2 of 2.5 min. Third, the epitope recognized by MAb N8-82 appears after dimerization, suggesting that oligomeric NAs may undergo conformational change with a t1/2 of 8 min. Finally, a tetramer-specific epitope recognized by MAb N8-4 appears on the NA with a t1/2 of 13 min. Epitope detection by MAb N8-4 was inhibited by tunicamycin treatment, suggesting that glycosylation of this molecule is required for proper tetramerization. Each of these proposed steps occurs in the endoplasmic reticulum of host cells, as demonstrated by treatment of virus-infected cells with brefeldin A or carbonyl cyanide m-chlorophenylhydrazine; subsequently, tetrameric NA is transported to the Golgi apparatus, where oligosaccharide processing is completed. Our findings also provide a possible explanation--lack of a functionally active conformation--for the absence of enzymatic function by NA monomers.
Comparative Study of High performance Braun’s Multiplier using FPGAs (2012)

Multiplication is one of the essential operations in Digital Signal Processing (DSP) applications like Fast Fourier Transform (FFT), Digital filters etc. With the advancements in technology, research is still going on to design a multiplier that consumes less power or has high speed or occupies less area or a combination of these in a single multiplier. This makes the multipliers to be used for high speed or low power VLSI applications. The Braun's multiplier is one of the parallel array multiplier which is used for unsigned numbers multiplication. The dynamic power of the multiplier can be reduced by using the bypassing techniques. The delay can be reduced by replacing the ripple carry adder in the last stage by fast adders like Carry look ahead adder and Kogge stone adder. This paper presents a comparative study among different types of bypassing multipliers for 4*4, 8*8 and 16*16 bits and their architectural modifications using different FPGAs like Spartan -3E, Virtex -4, Virtex -5 and Virtex -6 Lower power using Xilinx 13.2 ISE tool from which we get the delay and the dynamic power and cell area reports are obtained using RTL Compiler from Cadence in 90 nm technology.
Tetracycline-controlled transcription in eukaryotes: novel transactivators with graded transactivation potential (1997)

Several tetracycline-controlled transactivators (tTA) were generated which differ in their activation potential by >3 orders of magnitude. The transactivators are fusions between the Tet repressor and minimal transcriptional activation domains derived from Herpes simplex virus protein 16 (VP16). By reducing the VP16 moiety of the previously described tTA to 12 amino acids, potential targets for interactions with various cellular transcription factors were eliminated, as were potential epitopes which may elicit a cellular immune response. When compared with the originally described tTA, these new transactivators are tolerated at higher intracellular concentrations. This will facilitate establishment of tet regulatory systems under a variety of conditions, but particularly when cell type-restricted tetracycline-controlled gene expression is to be achieved in transgenic organisms via homologous recombination.
In vitro activity of CI-934, a quinolone carboxylic acid active against gram-positive and -negative bacteria (1985)

CI-934 is a totally synthetic difluorinated quinolinecarboxylic acid with an ethyl-amino-methyl pyrrolidine side chain, which has broad-spectrum antibacterial activity, including particular potency directed against streptococci and staphylococci. The CI-934 MIC (micrograms per milliliter) for 90% of the strains tested was 0.4 (range, 0.2 to 0.8) for a group of streptococci (pneumococci, viridans streptococci, Streptococcus faecalis, and Lancefield groups A, B, and C), 0.2 (0.05 to 0.2) for staphylococci (including methicillin-resistant Staphylococcus aureus), 0.025 (less than or equal to 0.003 to 0.025) for Haemophilus influenzae and Neisseria gonorrhoeae, 1.6 (0.1 to 25) for Enterobacteriaceae, 25 (3.1 to 25) for Pseudomonas aeruginosa, and 1.6 (0.05 to 3.1) for non-Bacteroides anaerobe species. CI-934 was equally active in vitro against multi-drug-resistant and -sensitive isolates, and cross-resistance was not apparent. Potency increased with alkalinity and was somewhat lower in urine. CI-934 was bactericidal. Inhibitory activity was generally unaffected by anaerobiosis, light, changes in inoculum size or cation concentration, or addition of human serum or sodium cholate.
Using Time-Frequency Analysis of the Photoplethysmographic Waveform to Detect the Withdrawal of 900 mL of Blood (2012)

A time-frequency spectral method detected blood loss in spontaneously breathing subjects before the onset of significant changes in heart rate or blood pressure. Spectral amplitudes at the heart rate frequency band were found to significantly decrease during blood loss in spontaneously breathing subjects, whereas those at the breathing rate frequency band did not significantly change. This technique may serve as a valuable tool in intraoperative and trauma settings to detect and monitor hemorrhage.
Endothelial cells augment T cell interleukin 2 production by a contact-dependent mechanism involving CD2/LFA-3 interaction. (1990)

We have demonstrated that endothelial cells (EC) augment IL-2 production by PHA-stimulated PBMC or purified CD4+ T cells and that the increase is apparent both in the amount of soluble IL-2 secreted and in the level of specific mRNA detectable by Northern blot hybridization. The ability of EC to affect levels of IL-2 cannot be reproduced by soluble factors, including the cytokines IL-1, IL-6, IFN-gamma, or TNF, conditioned medium from resting EC or IL-1, IFN-gamma- or TNF-treated EC, or from resting PBMC + EC cultures. Separation of the EC and PBMC by a Transwell membrane demonstrated that cell contact was required for augmentation of IL-2 synthesis and that this effect was unlikely to be mediated by a short-lived soluble signal. The cell-cell interaction required the ligand pair CD2/LFA-3, since augmentation could be inhibited by antibodies to these structures. Antibodies to ICAM-1, LFA-1, CD4, and MHC class II were without effect. A contact-dependent pathway involving CD2/LFA-3 interactions also may be used by EC to augment IL-2 production from T cells stimulated more specifically through the TCR/CD3 complex with antibody OKT3. This pathway provides a proliferative advantage to T cells stimulated with OKT3 in the presence of EC and may also be involved in the proliferative response of resting T cells to allogeneic class II MHC-expressing EC. We propose that EC augmentation of T cell IL-2 synthesis may be critical in the ability of EC to elicit primary T cell antigen responses and may have consequences for the development of localized cell-mediated immune reactions.
Parallel consensual neural networks (2002)

A neural network architecture is proposed and applied in classification of remote sensing/geographic data from multiple sources. The architecture is called the parallel consensual neural network, and its relation to hierarchical and ensemble neural networks is discussed. The parallel consensual neural network architecture is based on statistical consensus theory. The input data are transformed several times. The different transformed data are applied as if they were independent inputs, and are classified using stage neural networks. The outputs from the stage networks are weighted and combined to make a decision. Experimental results based on remote sensing data and geographic data are given. The performance of the consensual neural network architecture is compared to that of a two-layer (one hidden layer) conjugate-gradient backpropagation neural network. The results compare favorably in terms of classification accuracy to the backpropagation method.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
An intrinsically stable antibody scFv fragment can tolerate the loss of both disulfide bonds and fold correctly (1998)

A fully functional cysteine-free derivative of the intrinsically stable anti-HER2 scFv fragment hu4D5-8 was generated by replacing the disulfide forming cysteine residues in VH and VL with the amino acid combination valine-alanine in both domains. The antigen binding properties, determined by ELISA and BIAcore measurements, were not affected by removal of the disulfide bonds. The thermodynamic stability of the disulfide-containing scFv of 8.1 kcal/mol is decreased upon complete reduction of both disulfides to 2.7 kcal/mol, while that of the valine-alanine variant is somewhat higher (about 3.8 kcal/ mol). Our results suggest that, in principle, a disulfide-free fully functional derivative of any scFv can be obtained, as long as the corresponding disulfide-containing scFv has a high enough thermodynamic stability.
Iron Supplementation in Preterm Infants: A Study Comparing the Effect and Tolerance of a Fe2+ and a Nonionic FeIII Compound (2000)

The more widely used divalent forms of iron (Fe2+) supplementation often lead to gastrointestinal symptoms in preterm infants although little is known about the use of nonionic trivalent iron preparations (FeIII) in these patients. It is especially under this nonionic form that dietary iron is available. For this reason, a randomized controlled study was undertaken to compare the efficacy and the extent of possible side effects in two groups of preterm infants. In one group, the elemental iron was given in the Fe2+ form, while the other group received a nonionic trivalent iron (FeIII) complexed with polysaccharides of low molecular weight. Both groups received 7.5 mg elemental iron daily. Measured parameters in the two study groups did not differ significantly throughout the study period of 14 weeks. Both forms of iron supplementation were well tolerated. However, vomiting, diarrhea, or constipation occurred slightly more often in the group receiving iron supplementation in the Fe2+ form without reaching statistical difference. The authors found a nonionic trivalent polysaccharide-iron complex given as iron supplementation as effective as the generally more favored ferrous sulphate. Since iron therapy is mandatory in the preterm infant, the use of trivalent iron complexes can be considered as a good alternative.
Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling (2011)

The successful treatment of certain autoimmune conditions with the humanized anti-IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.
Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine (1995)

This review illustrates that NSAID-induced large bowel toxicity can cause significant morbidity in some patients, ranging from profuse diarrhea, chronic blood loss, and iron deficiency anemia to fatality. The pathogenesis is likely multifactorial and is thought to be related to inhibition of prostaglandin synthesis. Because NSAIDS are widely prescribed and some are available without a prescription, heightened awareness of these toxicologic manifestations throughout the GI tract may reduce morbidity.