gebhart/patrepeval huggingface dataset:
Alkylsulfonyltoluene Derivatives (Diuretics. I.) (1962)

Alkylsulfonyltoluenesulfonamides and their derivatives bearing a chlorine and an amino group on the benzene rings, or a variety of substituents on the nitrogen atom were synthesized. All compounds were evaluated for diuretic activity.
Increased protein expression through improved ribosome-binding sites obtained by library mutagenesis. (1994)

This report describes a method whereby library mutagenesis combined with drug selection was used to generate unique and efficient ribosome-binding sites (RBS) for expressing recombinant proteins in Escherichia coli. The RBS was deleted from a vector expressing beta-lactamase and replaced with a 16-base sequence containing a library of mutations. Selection of the library with ampicillin yielded several unique RBS sequences that were more efficient than ompA RBS for expressing a bacterial (beta-lactamase) and a mammalian protein (single-chain Fv antibody). The described approach provides a practical means to improve recombinant protein expression and, also, provides new sequences to further evaluate the complex regulatory mechanism underlying translation initiation.
Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease (2011)

Neurofibrillary tangles, composed of insoluble aggregates of the microtubule-associated protein Tau, are a pathological hallmark of Alzheimer disease (AD) and other tauopathies. However, recent evidence indicates that neuronal dysfunction precedes the formation of these insoluble fibrillar deposits, suggesting that earlier prefibrillar Tau aggregates may be neurotoxic. To determine the composition of these aggregates, we have employed a photochemical cross-linking technique to examine intermolecular interactions of full-length Tau in vitro. Using this method, we demonstrate that dimerization is an early event in the Tau aggregation process and that these dimers self-associate to form larger oligomeric aggregates. Moreover, using these stabilized Tau aggregates as immunogens, we generated a monoclonal antibody that selectively recognizes Tau dimers and higher order oligomeric aggregates but shows little reactivity to Tau filaments in vitro. Immunostaining indicates that these dimers/oligomers are markedly elevated in AD, appearing in early pathological inclusions such as neuropil threads and pretangle neurons as well as colocalizing with other early markers of Tau pathogenesis. Taken as a whole, the work presented herein demonstrates the existence of alternative Tau aggregates that precede formation of fibrillar Tau pathologies and raises the possibility that these hierarchical oligomeric forms of Tau may contribute to neurodegeneration.
Design and Pharmacological Characterization of Inhibitors of Amantadine-Resistant Mutants of the M2 Ion Channel of Influenza A Virus (2009)

The A/M2 proton channel of influenza A virus is a target for the anti-influenza drugs amantadine and rimantadine, whose effectiveness was diminished by the appearance of naturally occurring point mutants in the A/M2 channel pore, among which the most common are S31N, V27A, and L26F. We have synthesized and characterized the properties of a series of compounds, originally derived from the A/M2 inhibitor BL-1743. A lead compound emerging from these investigations, spiro[5.5]undecan-3-amine, is an effective inhibitor of wild-type A/M2 channels and L26F and V27A mutant ion channels in vitro and also inhibits replication of recombinant mutant viruses bearing these mutations in plaque reduction assays. Differences in the inhibition kinetics between BL-1743, known to bind inside the A/M2 channel pore, and amantadine were exploited to demonstrate competition between these compounds, consistent with the conclusion that amantadine binds inside the channel pore. Inhibition by all of these compounds was shown to be voltage-independent, suggesting that their charged groups are within the N-terminal half of the pore, prior to the selectivity filter that defines the region over which the transmembrane potential occurs. These findings not only help to define the location and mechanism of binding of M2 channel-blocking drugs but also demonstrate the feasibility of discovering new inhibitors that target this binding site in a number of amantadine-resistant mutants.
Regulation of cholesterol 7 alpha-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat (1991)

Cholesterol 7 alpha-hydroxylase catalyzes the rate-limiting step in the bile acid biosynthetic pathway. Regulation of this pathway is thought to occur solely as a result of a negative feedback control mechanism that is dependent upon the flux and composition of bile salts undergoing enterohepatic circulation. We have used the chronic biliary diverted (CBD) rat model to study the mechanism of regulation of cholesterol 7 alpha-hydroxylase by taurocholate. As compared to nonoperated controls, CBD rats exhibited a 4.2-fold increase in cholesterol 7 alpha-hydroxylase-specific activity, a 4.5-fold increase in enzyme mass, a 10-fold increase in steady-state mRNA levels, and a 3.4-fold increase in transcriptional (nuclear "run-on") activity. Intraduodenal infusion of taurocholate at a rate of 36 mumol/100 g/h for 48 h in CBD rats caused a significant (p less than 0.05) decrease (64%) in cholesterol 7 alpha-hydroxylase-specific activity, mass (72%), steady-state mRNA levels (74%), and transcriptional activity (57%) as compared to CBD controls. Cholesterol feeding increased cholesterol 7 alpha-hydroxylase-specific activity (288%), poly(A) RNA levels (291%), and transcriptional activity (220%) as compared to control animals. These results provide convincing evidence that bile salts, either directly or indirectly, down-regulate in vivo transcription of the cholesterol 7 alpha-hydroxylase gene, which is probably the major mechanism regulating the levels of this enzyme. The results of this study also suggest that the promoter for cholesterol 7 alpha-hydroxylase may have both bile salt- and sterol-responsive elements.
PDE4 inhibitors: a review of current developments (2005 – 2009) (2009)

This review summarizes the clinical development of PDE4 inhibitors since 2005 and the associated patent literature with a focus on strategies applied to minimize systemic adverse effects. In sum, although a significant number of new drugs designed for improved tolerability entered clinical trials, so far none of them fulfilled expectations and best progress has been achieved recently with the oral, non-isoform selective PDE4 inhibitor roflumilast.
Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms (2000)

Men with coronary artery disease have significantly lower levels of androgens than normal controls, challenging the preconception that physiologically high levels of androgens in men account for their increased relative risk for coronary artery disease.
Cloning and Heterologous Expression of the Epothilone Gene Cluster (2000)

The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol. The gene cluster responsible for epothilone biosynthesis in the myxobacterium Sorangium cellulosum was cloned and completely sequenced. It encodes six multifunctional proteins composed of a loading module, one nonribosomal peptide synthetase module, eight polyketide synthase modules, and a P450 epoxidase that converts desoxyepothilone into epothilone. Concomitant expression of these genes in the actinomycete Streptomyces coelicolor produced epothilones A and B. Streptomyces coelicolor is more amenable to strain improvement and grows about 10-fold as rapidly as the natural producer, so this heterologous expression system portends a plentiful supply of this important agent.
Delivery of testosterone replacement therapy. (2003)

Optimal testosterone replacement therapy remains a considerable challenge for the estimated five out of 1000 men in the general community with androgen deficiency. Oral delivery is not possible due to rapid first pass metabolism and short half-life. Testosterone derivatives have been developed to enhance intrinsic androgenic potency, prolong duration of action, or improve oral bioavailability of synthetic androgens. Structural modification of testosterone include 17 beta-esterification, 17 alpha-alkylation, 1-methylation, addition of a 19-normethyl group, and 7 alpha-methylation. Currently, oral (testosterone undecanoate), transcutaneous (Andropatch, Virormone, Testoderm (ALZA Corp), Testogel), sublingual (testosterone cyclodextrin), intramuscular (Sustanon, Primoteston Depot), and fused crystalline testosterone pellet preparations are available for clinical use. Transbuccal testosterone systems have also been developed for clinical use and require twice daily application. Suspensions of biodegradable microspheres consisting of a polyglycolide-lactide matrix laden with testosterone can deliver stable, physiological levels of testosterone for 2 to 3 months. Micronized testosterone has low oral bioavailability requiring high daily doses. 7 alpha-Methyl 19-nortestosterone, a potent, synthetic androgen free of hepatotoxicity, has tissue-specific selectivity, being susceptible to aromatization but not 5 alpha-reduction, thereby potentially avoiding intraprostatic androgen amplification.
Enhanced Stability of Electrohydrodynamic Jets through Gas Ionization (2008)

Theoretical predictions of the nonaxisymmetric instability growth rate of an electrohydrodynamic jet based on the measured total current overestimate experimental values. We show that this apparent discrepancy is the result of gas ionization in the surrounding gas and its effect on the surface charge density of the jet. As a result of gas ionization, a sudden drop in the instability growth rate occurs below a critical electrode separation, yielding highly stable jets that can be used for nano- to microscale printing.
Bases and Basic Materials in Industrial and Environmental Chemistry: A Review of Commercial Processes (2009)

The practical application of liquids and solid bases in industrial and environmental processes is reviewed. Liquid bases include water solutions of metal hydroxides such as caustics and potash, amines, phosphorus compounds and other molecular bases, solutions and slurries of alkali and alkaline-earth carbonates, organic solutions of organometallics, and superbases. Solid bases include basic clays, alkaline-earth oxides, alkali metals containing oxides and zeolites, synthetic hydrotalcites, rare-earth oxides and mixed oxides, impregnated carbons, and supported alkali metals. Some health and safety considerations are discussed, together with process features. Conclusions about the future use of bases and the perspective of a more massive application of solid bases are offered.
The role of monocyte chemotactic protein-1 in intraperitoneal adhesion formation (1998)

Abdomino-pelvic adhesions arise from infection, endometriosis, or peritoneal injury during surgery, and represent a significant source of morbidity in women of reproductive age. Monocyte chemotactic protein-1 (MCP-1) plays a role in the chemotaxis of mononuclear cells and fibroblasts in a murine wound repair model. To evaluate the role of MCP-1 in intraperitoneal adhesion formation, we investigated peritoneal fluid MCP-1 levels of women undergoing laparoscopy. Patients without endometriosis were divided into two groups: normal fertile women undergoing bilateral tubal ligation without intraperitoneal adhesions (n=14) and women with pelvic adhesions (n=8). Patients with endometriosis were arranged into two groups: women with (n=17) and without (n=17) adhesions. Peritoneal fluid MCP-1 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Peritoneal biopsy samples were immunostained for the detection of MCP-1 protein and macrophages, and were also processed for the presence of MCP-1 mRNA expression. Among women without endometriosis, the median peritoneal fluid MCP-1 level was 144 pg/ml (range 54-261) in women without adhesions and was 336 pg/ml (range 130-2494) in women with adhesions (P=0.01). There was a significant correlation between adhesion scores and MCP-1 levels (r=0.50; P=0.018). Among women with endometriosis, peritoneal fluid MCP-1 levels significantly correlated with the stage of the disease. The presence or absence of adhesions did not significantly affect the peritoneal fluid MCP-1 levels in this group of women. In summary, we have found that women with adhesions have elevated peritoneal fluid MCP-1 levels. However, we were not able to show an incremental effect of adhesions on peritoneal fluid MCP-1 levels of patients with endometriosis. Thus, we conclude that factors besides the intraperitoneal adhesions contribute to the elevated peritoneal fluid MCP-1 levels in patients with endometriosis.
A data glove based sensor interface to expressively control musical processes (2011)

Flexible sensors can find many useful applications detecting vibrations, contacts and impacts, air and liquid flows, pressures and compressions, displacements and motions. So they are utilized in the fields of robotic, medical, fitness, assistive technology, gaming, etc. But we want here point out the adoption of such sensors for realizing a data glove, capable to associate a sound to each single movement of every joint of the fingers of a human hand. In addition force sensing resistors, applied to each fingertip, measure the pressure applied on a surface when the hands mimic the gestures of a pianist. Previous works were already devoted to play sounds according to body movements, but as far as we know, to this aim no works take advantage on the measure of the complete degrees of freedom of a human hand. To this end, we present an innovative data glove based sensor interface that allows an electronic music composer to plan and conduct the musical expressivity of a performer. For musical expressivity we mean all those execution techniques and modalities that a performer has to follow in order to satisfy common musical aesthetics, as well as the desiderata of the composer. The proposed interface or virtual musical instrument is able to transform input parameters, supplied by hand movement, in many sound synthesis parameters. Especially, we focus our attention on mapping strategies based on Neural Network to solve the problem of music expressivity.
Monocytes use either CD11/CD18 or VLA-4 to migrate across human endothelium in vitro. (1994)

Monocytes traverse the endothelial lining of blood vessels and migrate into both normal and inflamed tissues. An in vitro model of a vascular wall, consisting of HUVEC cultured on acellular human amniotic tissue, was employed to examine the roles of several adhesion molecules in diapedesis of monocytes. Approximately half of the monocytes added to this system traversed the endothelium in a time-dependent fashion, completing their migration within 2 h. Pretreatment of HUVEC with IL-1 beta for 4 h increased the rate of adhesion of monocytes, but did not alter the number that ultimately migrated. A mAb to CD18, ts1/18, greatly inhibited adhesion and migration of monocytes when the monocytes were incubated with unstimulated HUVEC monolayers for 20 min. Much less inhibition was observed when the incubation period was increased to 2 h or when HUVEC were pretreated with IL-1 beta. A mAb to VLA-4, HP1/2, had little or no inhibitory effect in all cases. The combination of ts1/18 and HP1/2 greatly inhibited (up to 98%) adhesion and migration of monocytes across both unstimulated and IL-1 beta-stimulated monolayers. Additional inhibition experiments indicated that VLA-4 interacted with unstimulated endothelium by binding to VCAM-1 and, to a much lesser extent, fibronectin. These results suggest that monocytes are capable of interacting with endothelium during diapedesis via either CD11/CD18- or VLA-4-dependent pathways.
A Common Fold Mediates Vertebrate Defense and Bacterial Attack (2007)

Proteins containing membrane attack complex/perforin (MACPF) domains play important roles in vertebrate immunity, embryonic development, and neural-cell migration. In vertebrates, the ninth component of complement and perforin form oligomeric pores that lyse bacteria and kill virus-infected cells, respectively. However, the mechanism of MACPF function is unknown. We determined the crystal structure of a bacterial MACPF protein, Plu-MACPF from Photorhabdus luminescens, to 2.0 angstrom resolution. The MACPF domain reveals structural similarity with poreforming cholesterol-dependent cytolysins (CDCs) from Gram-positive bacteria. This suggests that lytic MACPF proteins may use a CDC-like mechanism to form pores and disrupt cell membranes. Sequence similarity between bacterial and vertebrate MACPF domains suggests that the fold of the CDCs, a family of proteins important for bacterial pathogenesis, is probably used by vertebrates for defense against infection.
Type IV pili‐dependent gliding motility in the Gram‐positive pathogen Clostridium perfringens and other Clostridia (2006)

Bacteria can swim in liquid media by flagellar rotation and can move on surfaces via gliding or twitching motility. One type of gliding motility involves the extension, attachment and retraction of type IV pili (TFP), which pull the bacterium towards the site of attachment. TFP-dependent gliding motility has been seen in many Gram-negative bacteria but not in Gram-positive bacteria. Recently, the genome sequences of three strains of Clostridium perfringens have been completed and we identified gene products involved in producing TFP in each strain. Here we show that C. perfringens produces TFP and moves with an unusual form of gliding motility involving groups of densely packed cells moving away from the edge of a colony in curvilinear flares. Mutations introduced into the pilT and pilC genes of C. perfringens abolished motility and surface localization of TFP. Genes encoding TFP are also found in the genomes of all nine Clostridium species sequenced thus far and we demonstrated that Clostridium beijerinckii can move via gliding motility. It has recently been proposed that the Clostridia are the oldest Eubacterial class and the ubiquity of TFP in this class suggests that a Clostridia-like ancestor possessed TFP, which evolved into the forms seen in many Gram-negative species.
Importance of the Two Interferon-stimulated Response Element (ISRE) Sequences in the Regulation of the Human Indoleamine 2,3-Dioxygenase Gene (1996)

Indoleamine 2,3-dioxygenase (INDO) is the rate-limiting enzyme in the catabolism of the essential amino acid L-tryptophan. It is induced strongly in many cell lines following interferon-gamma treatment. We report the cloning and characterization of the full-length human INDO promoter. This promoter is 1,245 base pairs long and includes two interferon-stimulated response elements (ISRE) separated by an approximately 1-kilobase sequence. The presence of these two ISREs is critical for maximum INDO promoter activity (50-fold induction). When the ISREs are present in two separate fragments cloned upstream of the chloramphenicol acetyltransferase (CAT) reporter vector, the INDO promoter activity drops significantly (7-fold induction). 5' end deletions of the wild type promoter sequence indicate that removal of the ISRE (ISRE1) at position -1126 reduces the induction level to approximately 25-fold. This activity does not change appreciably when the promoter is deleted down to position -241. Furthermore, site-directed mutagenesis of ISRE1 also decreases the promoter activity in a similar way. When ISRE1 is kept intact, deletion of the second ISRE (ISRE2) at position -111 leads to only 11-fold induction of the promoter. A similar result is obtained when substitution mutations are introduced in ISRE2. Deletion of a 748-base pair sequence between the two ISREs only shows a slight decrease in the INDO promoter activity. These data indicate that the two ISRE sequences are required for the full transcriptional induction of the interferon-gamma-inducible human INDO gene. INDO activity is not induced in the hepatic cell line HepG2. An analysis of INDO-CAT activity in this cell line indicated that the lack of INDO activity was at the transcriptional level and could reflect either the presence of a repressor or lack of a transcription factor. This lack of induction could be correlated with a truncated or unstable IRF-1. However, the levels of IRF-2, JAK2, and STAT 91 were similar in both ME180 and HepG2 cells.
Effect of combinations of acyclovir with vidarabine or its 5'-monophosphate on herpes simplex viruses in cell culture and in mice (1982)

The combination of various concentrations of acyclovir and vidarabine or its 5'-monophosphate usually produced an additive interaction with various strains of herpes simplex virus types 1 and 2 in Vero cells. Similarly, certain combinations of these drugs were more effective than the individual drugs in decreasing the mortality and increasing the mean day of death of mice inoculated intracerebrally with herpes simplex virus type 2. Neither antagonism nor interference was noted for any of the in vitro or in vivo combinations. The increased antiviral activity was determined not to be secondary to toxic effects of the drugs. Although viruses resistant to either vidarabine or acyclovir developed readily in cell culture, no evidence of cross-resistance was obtained. Furthermore, in the presence of the two drugs, mutants resistant to vidarabine, acyclovir, or vidarabine/acyclovir could not be isolated. These findings suggest that combinations with these antivirals, which are currently being evaluated singly for the therapy of severe forms of herpetic infection, could prove clinically useful if increasing numbers of resistant viral strains are observed.
Current-induced vortex-vortex switching in a nanopillar comprising two Co nano-rings (2007)

The authors fabricated a current-perpendicular-to-plane pseudo-spin-valve nanopillar comprising a thick and a thin Co rings with deep submicron lateral sizes. The dc current can effectively induce the flux-closure vortex states in the rings with desired chiralities. Abrupt transitions between the vortex states are also realized by the dc current and detected with the giant magnetoresistance effect. Both Oersted field and spin-transfer torque are found important to the magnetic transitions, but the former is dominant. They can be designed to cooperate with each other in the vortex-to-vortex transitions by carefully setting the chirality of the vortex state in the thick Co ring.