gebhart/patrepeval huggingface dataset:
Synthesis, Antitubercular Activity and Mechanism of Resistance of Highly Effective Thiacetazone Analogues (2013)

Defining the pharmacological target(s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC) is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61) or HadC (at Val85, Lys157 or Thr123), which are components of the β-hydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors.
Recent Advances in Bioink Design for 3D Bioprinting of Tissues and Organs (2017)

There is a growing demand for alternative fabrication approaches to develop tissues and organs as conventional techniques are not capable of fabricating constructs with required structural, mechanical, and biological complexity. 3D bioprinting offers great potential to fabricate highly complex constructs with precise control of structure, mechanics, and biological matter [i.e., cells and extracellular matrix (ECM) components]. 3D bioprinting is an additive manufacturing approach that utilizes a "bioink" to fabricate devices and scaffolds in a layer-by-layer manner. 3D bioprinting allows printing of a cell suspension into a tissue construct with or without a scaffold support. The most common bioinks are cell-laden hydrogels, decellulerized ECM-based solutions, and cell suspensions. In this mini review, a brief description and comparison of the bioprinting methods, including extrusion-based, droplet-based, and laser-based bioprinting, with particular focus on bioink design requirements are presented. We also present the current state of the art in bioink design including the challenges and future directions.
Prognostic Importance of Elevated Jugular Venous Pressure and a Third Heart Sound in Patients with Heart Failure (2001)

In patients with heart failure, elevated jugular venous pressure and a third heart sound are each independently associated with adverse outcomes, including progression of heart failure. Clinical assessment for these findings is currently feasible and clinically meaningful.
Fractionated nuclear extracts from hamster cells catalyze cell-free recombination at selective sequences between adenovirus DNA and a hamster preinsertion site. (1993)

We have explored the mechanism of adenovirus type 12 (Ad12) DNA integration because of its importance for viral oncogenesis and as an example of insertional recombination. We have used a fractionated cell-free system from nuclear extracts of hamster cells and have partly purified nuclear proteins that could catalyze in vitro recombination. As recombination partners, the 20,880- to 24,049-nucleotide Pst I D fragment of Ad12 DNA and the hamster preinsertion sequence p7 from the Ad12-induced tumor CLAC1 have proven to recombine at higher frequencies than randomly selected adenoviral or cellular DNA sequences. A preinsertion sequence might carry elements essential in eliciting recombination. Patch homologies between the recombination partners seem to play a role in the selection of sites for recombination in vivo and in the cell-free system. Nuclear extracts from BHK21 cells were prepared by incubating the nuclei in 0.42 M (NH4)2SO4 and fractionated by Sephacryl S-300 gel filtration, followed by chromatography on Mono S and Mono Q columns. The purified products active in recombination contained a limited number of different protein bands, as determined by polyacrylamide gel electrophoresis and silver staining. The most highly purified fraction IV had helicase and topoisomerase I activities. We used two different methods to assess the in vitro generation of hamster DNA-Ad12 DNA recombinants upon incubation with the purified protein fractions: (i) transfection of the recombination products into recA- strains of Escherichia coli and (ii) the polymerase chain reaction by using amplification primers unique for each of the two recombination partners. In p7 hamster DNA, the nucleotide sequence 5'-CCTCTCCG-3' or similar sequences served repeatedly as a preferred recombination target for Ad12 DNA in the tumor CLAC1 and in five independent cell-free recombination experiments.
Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study (1995)

These results are consistent with the existence of a schizophrenia spectrum in which these five disorders are manifestations, of varying severity, of the same underlying vulnerability. This vulnerability is strongly transmitted within families.
Ultrastructural effects of pressure stress to the nucleus in Saccharomyces cerevisiae: a study by immunoelectron microscopy using frozen thin sections (1995)

The effects of hydrostatic pressure on subcellular structures, particularly the nucleus, of Saccharomyces cerevisiae were investigated by immunoelectron microscopy. Cells were treated with hydrostatic pressure from 0.1 to 400 MPa for 10 min at room temperature. Frozen thin sections of the cells revealed that spindle pole bodies disappeared at 100 MPa. At 150 MPa, the deposition of gold panicles for anti α-tubulin was noticed in the nucleus, although the filamentous structure of microtubules was lost. At 200 MPa, fewer gold particles were scattered in the nucleus and the nuclear membrane in several portions was also observed to be open at 300 MPa. These results show that elements of the nuclear division apparatus were susceptible to pressure stress, particularly spindle pole bodies and microtubules. The damage to spindle pole bodies, microtubules, and nuclear membrane caused by pressure stress was followed by the inhibition of nuclear division. After the release of pressure, the spindle pole bodies and microtubules of pressurized cells at below 200 MPa regained their normal appearance at 24 h.
Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both (2017)

This review considers master protocols, which involve the study of one or more interventions in multiple diseases or of a single disease with multiple interventions.
Chemistry of Thienopyridines. XXIV. Two Transformations of Thieno[ 2,3‐b] pyridine 7‐Oxide (1976)

Abstract Refluxing thieno[2,3‐b ]pyridine 7‐oxide ( 1 ) with aeetic anhydride plus subsequent hydrolysis produced a mixture of thieno[2,3‐b]pyrid‐6(7 H )one ( 2 ) (13%) and 5‐hydroxythieno[2,3‐b]‐pyridine ( 4 ) (4%). Refluxing 1 with phosphorus oxychloride yielded a mixture of 4‐ and 6‐chloro‐thieno[2,3‐b]pyridines, ( 5 ) (54%) and ( 6 ) (31%), respectively. Compound 6 was also obtained directly from 2 (31%). A mechanistic rationalization for the isomerization of 1 to form 2 and 4 is presented. Marked differences in the mass spectral fragmentations of these three isomeric compounds are noted.
Colony-stimulating factor (CSF) radioimmunoassay: detection of a CSF subclass stimulating macrophage production. (1979)

Colony-stimulating factors (CSFs) stimulate the differentiation of immature precursor cells to mature granulocytes and macrophages. Purified 125I-labeled murine L cell CSF has been used to develop a radioimmunoassay (RIA) that detects a subclass of CSFs that stimulates macrophage production. Murine CSF preparations that contain this subclass of CSF complete for all of the CSF binding sites on anti-L cell CSF antibody. With the exception of mouse serum, which can contain inhibitors of the bioassay, there is complete correspondence between activities determined by RIA and those determined by bioassay. The RIA is slightly more sensitive than the bioassay, detecting approximately 0.3 fmol of purified L cell CSF. It also detect this subclass of CSF in chickens, rats, and humans. In the mouse, the subclass is distinguished from other CSFs by a murine cell bioassay dose-response curve in which 90% of the response occurs over a 10-fold (rather than a 100-fold) increase in concentration, by stimulating the formation of colonies containing a high proportion of mononuclear (rather than granulocytic) cells, and by certain physical characteristics.
The Flk1-Cre-Mediated Deletion of ETV2 Defines Its Narrow Temporal Requirement During Embryonic Hematopoietic Development (2012)

During embryonic development, the emergence of hematopoiesis and vasculogenesis is tightly associated, with many transcription factors implicated in both developmental processes. Among those factors, ETV2 acts at the top of the hierarchy and controls the formation of both lineages. However, it is not known at which stage of mesoderm development ETV2 is acting and whether ETV2 activity is further required once mesodermal precursors have been specified to the hematopoietic and endothelial fates. In this study, we characterize the developmental window during which ETV2 expression is required for hematopoietic and endothelial development. Using cre-mediated deletion of ETV2, we demonstrate that ETV2 is acting prior to or at the time of FLK1 expression in mesodermal precursors to initiate the hematopoietic and endothelial program. Using the in vitro differentiation of embryonic stem cells as a model system, we further show that ETV2 re-expression in Etv2(-/-) Flk1-negative precursors drives hematopoiesis specification and switches on the expression of most genes known to be implicated in hematopoietic and endothelial development. Among the downstream targets of ETV2, we identify the transcription factors SCL, GATA2, and FLI1 known to operate a recursive loop controlling hematopoietic development. Surprisingly, SCL re-expression in Etv2(-/-) cells fully rescues hematopoiesis, while the re-expression of FLI1 or GATA2 promotes only a very limited rescue. Altogether, our data establish that ETV2 is required very transiently to specify mesodermal precursors to hematopoiesis and vasculogenesis and that SCL is one of the key downstream targets of ETV2 in controlling hematopoietic specification.
Role of type III homology repeats in cell adhesive function within the cell-binding domain of fibronectin. (1991)

Recombinant fibronectin (FN) fragments and their mutant proteins were produced to elucidate the role of type III homology repeats in cell adhesive activity within the cell-binding domain of FN. Cell adhesive activity of the 11.5-kDa fragment, the cell attachment site of the cell-binding domain, was less than 0.1% that of native FN despite the presence of the Arg-Gly-Asp-Ser sequence. The activity increased as type III homology repeats were added to the N terminus of the 11.5-kDa fragment, and a 52-kDa fragment with four additional type III repeats had almost the same activity of native FN. Deletion of Arg-Gly-Asp from the fully active fragments completely abolished the cell adhesive activity. Deletion of one or two repeats from the 52-kDa fragment affected the extent of the cell adhesive activity, the degree of the effect being inversely correlated with the distance of the deletion from the type III repeat containing Arg-Gly-Asp-Ser. Rearrangement of type III repeats caused much loss of activity. These results suggest that the number and kinds of type III repeats and their correct alignment rather than the putative synergistic site decide the extent of the specific cell adhesive activity.
New Aspects on the Preparation of 1,3-Dibromo-5,5-dimethylhydantoin (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNew Aspects on the Preparation of 1,3-Dibromo-5,5-dimethylhydantoinItzhak Markish and Onn ArradCite this: Ind. Eng. Chem. Res. 1995, 34, 6, 2125–2127Publication Date (Print):June 1, 1995Publication History Published online1 May 2002Published inissue 1 June 1995https://pubs.acs.org/doi/10.1021/ie00045a022https://doi.org/10.1021/ie00045a022research-articleACS PublicationsRequest reuse permissionsArticle Views665Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Reciprocal regulation of glucose and glutamine utilization by cultured human diploid fibroblasts (1978)

Human diploid fibroblasts utilize both glucose and glutamine as energy sources. The utilization of glutamine by fibroblasts is regulated by glucose, and vice versa. This conclusion is supported by the following observations: (1) essentially identical growth rates were observed in Eagle's minimum essential medium (MEM)3 in which the glucose concentration was either 5.5 mM or was maintained between 25 and 40 micrometer, (2) the total glutamine utilization by fibroblasts increase at least 30% in medium with 25 micrometer to 70 micrometer glucose compared to medium with 5.5 mM glucose, while the rate of glutamine-1 or 5-14C oxidation to CO2 increased 5-fold as the glucose concentration was decreased to zero, (3) 2 mM glutamine inhibited glucose-6-14C oxidation by 88% and stimulated glucose-1-14C by 77% in log phase cells and (4) glutamine oxidation in normal medium contributed approximately 30% of the energy requirement of human diploid fibroblasts.
SPECS (2015)

Processor implementation errata remain a problem, and worse, a subset of these bugs are security-critical. We classified 7 years of errata from recent commercial processors to understand the magnitude and severity of this problem, and found that of 301 errata analyzed, 28 are security-critical. We propose the SECURITY-CRITICAL PROCESSOR ER- RATA CATCHING SYSTEM (SPECS) as a low-overhead solution to this problem. SPECS employs a dynamic verification strategy that is made lightweight by limiting protection to only security-critical processor state. As a proof-of- concept, we implement a hardware prototype of SPECS in an open source processor. Using this prototype, we evaluate SPECS against a set of 14 bugs inspired by the types of security-critical errata we discovered in the classification phase. The evaluation shows that SPECS is 86% effective as a defense when deployed using only ISA-level state; incurs less than 5% area and power overhead; and has no software run-time overhead.
Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point (2017)

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
Performance evaluation of a direct-sequence spread-spectrum multiple-access system with microscopic and macroscopic diversity in mobile radio environment (2002)

Bit error rates of a direct-sequence spread-spectrum multiple-access (DS/SSMA) system employing microscopic and macroscopic diversity in conjunction with forward error correction (FEC) channel coding are evaluated. The radio link is modeled as an additive white Gaussian noise channel with Rayleigh fading and log-normal shadowing. The performance of the maximal ratio combining (MRC) with coherent binary phase shift keying (BPSK) demodulation is compared with that of the postdetection combining with noncoherent differential phase shift keying (DPSK) demodulation, in which these two types of microscopic diversities are combined with macroscopic selection diversity.
Design of Potential Neuraminidase Inhibitors By Dehydration, Deoxygenation and Epimerization of Siastatin B (1992)

Abstract Rationally designed analogs of siastatin B able to mimic oxocarbenium ion of neuraminic acid, an intermediate in the reaction catalyzed by the enzyme, were synthesized. Those types represented the improvement over siastatin B.
Microsatellite mutation rates are equivalent in normal and telomerase-immortalized human fibroblasts. (2001)

Telomerase-expressing human fibroblasts generally have the same properties as normal cells, except that they have an indefinite life span in culture. We have introduced a dinucleotide repeat sequence into the telomerase-expressing hTERT-1604 cell line and characterized the rates and types of frameshift mutations within this microsatellite. These data have been compared with those in diploid fibroblasts with a finite life span. The rates of mutation were found to be similar in the two cell types, indicating that DNA mismatch repair and other cellular processes responsible for maintenance of mutational stability are not disrupted by telomerase immortalization.
A microassay for colony-stimulating factor based on thymidine incorporation. (1984)

A variety of growth factors and lectins were tested; only colony-stimulating factors CSF-1, Interleukin 3, and a T-lymphocyte GM CSF induced colony formation in semisolid medium and stimulated thymidine incorporation in liquid culture. All other growth factors and lectins were inactive in both assays. Factor-stimulated thymidine incorporation was detectable 24 hours after stimulation and reached maximal levels 4-6 days after stimulation. A convenient microassay for measuring CSF activity has been developed, enabling a large number of samples to be screened qualitatively in 2 days and permitting CSF activity to be measured quantitatively in 4-5 days. This microassay can supplement the clonal-cell assay method and be especially useful as an initial screening assay for CSF activity.
Ion channel genes and human neurological disease: Recent progress, prospects, and challenges (1999)

What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are "paroxysmal disorders" whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.
Lymphoid Development in Mice Congenitally Lacking T Cell Receptor αβ-Expressing Cells (1992)

Vertebrate T cells express either an alpha beta or gamma delta T cell receptor (TCR). The developmental relatedness of the two cell types is unresolved. alpha beta + T cells respond to specific pathogens by collaborating with immunoglobulin-producing B cells in distinct lymphoid organs such as the spleen and Peyer's patches. The precise influence of alpha beta + T cells on B cell development is poorly understood. To investigate the developmental effects of alpha beta + T cells on B cells and gamma delta + T cells, mice homozygous for a disrupted TCR alpha gene were generated. The homozygotes showed elimination of alpha beta + T cells and the loss of thymic medullae. Despite this, gamma delta + T cells developed in normal numbers, and there was an increase in splenic B cells.
Development of an ion trap / linear time‐of‐flight mass spectrometer with electrospray ionization for micro‐column liquid chromatography detection (1995)

Abstract A linear time‐of‐flight (TOF) mass spectrometer equipped with a quadrupole ion trap for ion storage was developed for mass analysis of ions generated by electrospray ionization (ESI). With this technique, the continuous ion beam from the ESI source is collimated by a set of focusing lenses into the ion trap where the ions are accumulated for a predetermined period of time. Extraction of the ions into the flight tube of the TOF mass spectrometer is achieved by applying a short duration voltage pulse to the exit endcap of the ion trap. The extraction frequency is variable, but is typically set at 10 Hz. It was shown that with a linear TOF mass spectrometer, mass resolution in the range of 600–950 can be routinely obtained. It was also demonstrated that a complete mass spectrum of bradykinin can be obtained with a direct injection of 75 fmol, or 0.5 μL of 150 nM of sample solution. Buffer gas pressure and the energy of the ions entering the ion trap, were found to be the key parameters in obtaining this sensitivity and resolution. In addition, the ESI ion trap/TOF system was developed and applied for microcolumn liquid chromatography detection of a simple protein mixture. © 1995 John Wiley &amp; Sons, Inc.