gebhart/patrepeval huggingface dataset:
Murine Models of Sepsis and Trauma: Can We Bridge the Gap? (2017)

Sepsis and trauma are both leading causes of death in the United States and represent major public health challenges. Murine models have largely been used in sepsis and trauma research to better understand the pathophysiological changes that occur after an insult and to develop potential life-saving therapeutic agents. Mice are favorable subjects for this type of research given the variety of readily available strains including inbred, outbred, and transgenic strains. In addition, they are relatively easy to maintain and have a high fecundity. However, pharmacological therapies demonstrating promise in preclinical mouse models of sepsis and trauma often fail to demonstrate similar efficacy in human clinical trials, prompting considerable criticism surrounding the capacity of murine models to recapitulate complex human diseases like sepsis and traumatic injury. Fundamental differences between the two species include, but are not limited to, the divergence of the transcriptomic response, the mismatch of temporal response patterns, differences in both innate and adaptive immunity, and heterogeneity within the human population in comparison to the homogeneity of highly inbred mouse strains. Given the ongoing controversy, this narrative review aims to not only highlight the historical importance of the mouse as an animal research model but also highlight the current benefits and limitations of the model as it pertains to sepsis and trauma. Lastly, this review will propose future directions that may promote further use of the model.
Differences in replication of attenuated and neurovirulent polioviruses in human neuroblastoma cell line SH-SY5Y (1989)

A base change from C to U at position 472 of the 5' noncoding region of the poliovirus genome is known to be a major determinant of attenuation in the P3/Sabin vaccine strain. To determine the biochemical basis for the attenuated phenotype imparted by this mutation, a cell line in which replication of neurovirulent and attenuated viruses could be distinguished was identified. A pair of P3/Sabin-P2/Lansing viral recombinants that differ only at position 472 was used; the viruses replicated equally well in HeLa cells, but the virus with a U at base 472 was attenuated in mice. In the human neuroblastoma cell line SH-SY5Y, recombinants with a U at base 472 replicated to approximately 10-fold-lower titers than did neurovirulent viruses with a C at this position. Analysis of viral RNA and protein synthesis indicated that translation of the attenuated viral RNA was specifically reduced in SH-SY5Y cells.
Toxicities of Immunotherapy for the Practitioner (2015)

The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell-mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities.
[Comprehensive quality control method for total flavonoid of Fructus Aurantii]. (2011)

The method reported in this paper can be used effectively for the quality control of total flavonoid of Fructus Aurantii.
Codon Usage in Higher Plants, Green Algae, and Cyanobacteria (1990)

Codon usage is the selective and nonrandom use of synonymous codons by an organism to encode the amino acids in the genes for its proteins. During the last few years, a large number of plant genes have been cloned and sequenced, which now permits a meaningful comparison of codon usage in higher plants, algae, and cyanobacteria. For the nuclear and organellar genes of these organisms, a small set of preferred codons are used for encoding proteins. Codon usage is different for each genome type with the variation mainly occurring in choices between codons ending in cytidine (C) or guanosine (G) versus those ending in adenosine (A) or uridine (U). For organellar genomes, chloroplastic and mitochrondrial proteins are encoded mainly with codons ending in A or U. In most cyanobacteria and the nuclei of green algae, proteins are encoded preferentially with codons ending in C or G. Although only a few nuclear genes of higher plants have been sequenced, a clear distinction between Magnoliopsida (dicot) and Liliopsida (monocot) codon usage is evident. Dicot genes use a set of 44 preferred codons with a slight preference for codons ending in A or U. Monocot codon usage is more restricted with an average of 38 codons preferred, which are predominantly those ending in C or G. But two classes of genes can be recognized in monocots. One set of monocot genes uses codons similar to those in dicots, while the other genes are highly biased toward codons ending in C or G with a pattern similar to nuclear genes of green algae. Codon usage is discussed in relation to evolution of plants and prospects for intergenic transfer of particular genes.
Anti-IgM-mediated B cell signaling. Molecular analysis of ligand binding requisites for human B cell clonal expansion and tolerance. (1988)

The ligand binding requisites for membrane IgM-mediated signaling of human B lymphocyte clonal expansion and B cell tolerance were investigated with a well-characterized set of soluble murine anti-human IgM mAbs. Evaluation of the impact of mu chain domain specificity, affinity, and binding stoichiometry for membrane IgM on antibody-induced regulation of normal and leukemic B cell DNA synthesis revealed that the ligand binding requisites for inducing or, alternatively, suppressing B cell DNA synthesis are significantly different. First, while the induction of S phase entry required micrograms/ml concentrations of ligand, orders of magnitude lower concentrations of ligand sufficed for inhibitory signaling. Second, while an upper affinity threshold for achieving maximal stimulation of B cell DNA synthesis was never detected, inhibitory signaling by bivalent ligands appeared to become relatively affinity independent at Fab binding affinities greater than 7.0 x 10(6) M-1. Third, while a C mu 1-specific mAb with an enhanced incidence of monogamous binding to mIgM was ineffective at inducing B cell DNA synthesis, the antibody was not significantly compromised in ability to initiate inhibitory signals. These differences could be observed in a clonal B cell population which positively or negatively responded to mIgM ligation depending upon its state of activation. The accumulated observations indicate that the ligand binding requisites for inhibitory signal transduction in human B lymphocytes are much less rigorous than those for stimulatory signal transduction and suggest that many physiologically relevant anti-Ig antibodies are more likely to function in the negative feedback regulation of B cell responses than in the direct triggering of human B cell clonal expansion.
Patterns of p53 G->T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke (2001)

It is unquestionable that the major cause of lung cancer is cigarette smoking. p53 mutations are common in lung cancers from smokers but less common in non-smokers. A large fraction of the p53 mutations in lung cancers are G-->T transversions, a type of mutation that is infrequent in other tumors aside from hepatocellular carcinoma. Previous studies have indicated that there is a good correlation between G-->T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon (PAH) adducts along the p53 gene. The origin of p53 mutations in lung cancer has been questioned by recent reports suggesting that there are no significant differences in p53 mutation spectra between smokers and non-smokers and between lung cancers and non-lung cancers [S.N. Rodin and A.S. Rodin (2000) Human lung cancer and p53: The interplay between mutagenesis and selection. P:roc. Natl Acad. Sci. USA, 97, 12244-12249]. We have re-assessed these issues by using the latest update of the p53 mutation database of the International Agency for Research on Cancer (14 051 entries) as well as recent data from the primary literature on non-smokers. We come to the conclusion that the p53 mutation spectra are different between smokers and non-smokers and that this difference is highly statistically significant (G-->T transversions are 30 versus 10%; P < 0.0001, chi2 test). A similar difference is seen between lung cancers and non-lung cancers. At a number of mutational hotspots common to all cancers, a large fraction of the mutations are G-->T transversions in lung cancers but are almost exclusively G-->A transitions in non-lung cancers. Our data reinforce the notion that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.
Evaluation of 1-octen-3-ol and carbon dioxide as attractants for mosquitoes associated with irrigated rice fields in Arkansas. (1991)

Field studies were conducted to determine the responses of mosquitoes associated with irrigated riceland in Arkansas to 1-octen-3-ol (octenol), carbon dioxide (CO2) and combinations of both. Octenol was released at 4.1 (wick in) and 41.1 (wick out) mg/h and CO2 at 200, 500 and 1,000 ml/min. Octenol alone did not result in a significant (P greater than 0.05) increased response for any species relative to unbaited traps. An increase in CO2 release rate generally resulted in an increase in collection size. All octenol + CO2 combinations increased the collections of Coquillettidia perturbans, Culex salinarius and Psorophora columbiae relative to equivalent CO2 release rates alone. Mixed responses for these same treatment combinations were obtained for Anopheles crucians, An. quadrimaculatus and Cx. erraticus.
Multiple Roles for Slits in the Control of Cell Migration in the Rostral Migratory Stream (2004)

The subventricular zone (SVZ) contains undifferentiated cells, which proliferate and generate olfactory bulb (OB) interneurons. Throughout life, these cells leave the SVZ and migrate along the rostral migratory stream (RMS) to the OB where they differentiate. In vitro, the septum and the choroid plexus (CP) secrete repulsive factors that could orient the migration of OB precursors. Slit1 and Slit2, two known chemorepellents for developing axons, can mimic this effect. We show here that the Slit receptors Robo2 and Robo3/Rig-1 are expressed in the SVZ and the RMS and that Slit1 and Slit2 are still present in the adult septum. Using Slit1/2-deficient mice, we found that Slit1 and Slit2 are responsible for both the septum and the CP repulsive activity in vitro. In adult mice lacking Slit1, small chains of SVZ-derived cells migrate caudally into the corpus callosum, supporting a role for Slits in orienting the migration of SVZ cells. Surprisingly, in adult mice, Slit1 was also expressed by type A and type C cells in the SVZ and RMS, suggesting that Slit1 could act cell autonomously. This hypothesis was tested using cultures of SVZ explants or isolated neurospheres from Slit1-/- or Slit1+/- mice. In both types of cultures, the migration of SVZ cells was altered in the absence of Slit1. This suggests that the regulation of the migration of OB precursors by Slit proteins is complex and not limited to repulsion.
Treatment of metastatic breast cancer with paclitaxel and doxorubicin. (1995)

The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) against untreated and previously treated metastatic breast cancer (documented in anthracycline-resistant disease and in extensively pretreated patients as well) has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered in either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to a 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two ongoing European trials that have achieved promising preliminary results. In Milan, a phase I trial has achieved a preliminary response rate exceeding 90% in 30 chemotherapy-naive patients treated with an alternating schedule of paclitaxel over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicity is leukopenia and mucositis. Furthermore, congestive heart failure has occurred in six patients. We are conducting a phase I/II study in minimally pretreated patients, with a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks. Of 24 patients evaluable for response, five have achieved partial responses and three complete responses. (Another five partial and two complete responses need confirmation.) Of the two dose levels now given, all responses occurred at the higher paclitaxel/doxorubicin level, 175 and 60 mg/m2, respectively. Despite grades 3 and 4 neutropenia in 31% and 60% of courses, respectively, only six patients have been hospitalized for febrile neutropenia. Of concern, the left ventricular ejection fraction has decreased to below normal in six patients and two have developed symptomatic congestive heart failure. Whether lowering the peak doxorubicin concentration will preclude this effect, which has been observed only in the studies using short infusions of both drugs, is under investigation.
Ultra-Wide Bandwidth Design for Very-Low Voltage Substrate-Removed Electro-optic Intensity Modulators (2012)

Ultra-wide bandwidth, very-low drive voltage modulator design is presented. Design combines buried electrodes made of doped semiconductors and dielectrics with very large dielectric constant dispersion. 0.4 V Vπ device with bandwidth exceeding 100 GHz is possible.
Semi-Chronic Motorized Microdrive and Control Algorithm for Autonomously Isolating and Maintaining Optimal Extracellular Action Potentials (2004)

A system was developed that can autonomously position recording electrodes to isolate and maintain optimal quality extracellular signals. The system consists of a novel motorized miniature recording microdrive and a control algorithm. The microdrive was designed for chronic operation and can independently position four glass-coated Pt-Ir electrodes with micrometer precision over a 5-mm range using small (3 mm diam) piezoelectric linear actuators. The autonomous positioning algorithm is designed to detect, align, and cluster action potentials and then command the microdrive to optimize and maintain the neural signal. This system is shown to be capable of autonomous operation in monkey cortical tissue.
Cre-stimulated recombination atloxP-containing DNA sequences placed into the mammalian genome (1989)

The cre gene of coliphage P1 encodes a 38 kDa protein which efficiently promotes both intra- and intermolecular recombination at specific 34 bp sites called loxP. To demonstrate that the Cre protein can promote DNA recombination at loxP sites resident on a mammalian chromosome, a mouse cell line was constructed containing two directly repeated loxP sites flanking a 2.5 kb yeast DNA fragment and inserted between the SV40 promoter and the neo structural gene to disrupt expression of the neo gene. Expression of the cre gene in this cell line results in excision of the intervening yeast DNA and thus permits sufficient expression of the neo gene to allow cell growth in high concentrations of G418. Southern analysis indicated that Cre-mediated excision occurred at the loxP sites. In the absence of the cre gene such excisive events are quite rare. Cre-mediated recombination should thus be quite useful in effecting a variety of genomic rearrangements in eukaryotic cells.
Managing and manipulating carbocations in biology: terpenoid cyclase structure and mechanism (1998)

Terpenoid cyclases catalyze remarkably complex cyclization cascades that are initiated by the formation of a highly reactive carbocation in a polyisoprene substrate. Recent crystal structures of terpenoid cyclases show how these enzymes provide a template for binding and stabilizing the flexible substrate in the precise orientation required for catalysis, trigger carbocation formation, chaperone the conformations of the reactive carbocation intermediates through a unique cyclization sequence, and sequester and stabilize carbocations from premature quenching. Notably, terpenoid cyclases and catalytic antibodies have converged to similar chemical and structural strategies for managing highly reactive carbocations in polyisoprene cyclization cascades.
In-vitro release characteristics of tetracycline HCl, khellin and nicotinamide adenine dineculeotide from halloysite; a cylindrical mineral (2001)

The use of halloysite clay as a low cost alternative to more traditional microencapsulation systems is reported. Halloysite is an alumino-silicate clay which demonstrates a predominately cylindrical geometry, uniquely characterized by a hollow core or series of voids with diameters ranging from 16-50 nm. These nanoscale-to-mesoscale microcylinders are capable of entrapping active agents within the core lumen as well as within any void spaces contained in the multilayered walls of the cylinder. Some of the active agents associated with the clay are also bound to the external surfaces of the clay. Delivery of the active agent is first by desorption of the active agent from the exterior surfaces and exposed ends of the microcylinders, and is followed by a second more prolonged phase dominated by pore diffusion from the ends of the cylinders. Halloysite is capable of retaining and releasing a range of active ingredients. Both hydrophilic and hydrophobic agents may be entrapped following appropriate pre-treatment of the clay to render it lipophilic. Here, a unique low cost alternative microcylindrical delivery system: the clay mineral halloysite, is investigated.
Synergistic Assembly of Heavy Metal Clusters and Luminescent Organic Bridging Ligands in Metal–Organic Frameworks for Highly Efficient X-ray Scintillation (2014)

We have designed two metal-organic frameworks (MOFs) to efficiently convert X-ray to visible-light luminescence. The MOFs are constructed from M6(μ3-O)4(μ3-OH)4(carboxylate)12 (M = Hf or Zr) secondary building units (SBUs) and anthracene-based dicarboxylate bridging ligands. The high atomic number of Zr and Hf in the SBUs serves as effective X-ray antenna by absorbing X-ray photons and converting them to fast electrons through the photoelectric effect. The generated electrons then excite multiple anthracene-based emitters in the MOF through inelastic scattering, leading to efficient generation of detectable photons in the visible spectrum. The MOF materials thus serve as efficient X-ray scintillators via synergistic X-ray absorption by the metal-cluster SBUs and optical emission by the bridging ligands.
CD 69 expression during selection and maturation of CD4+8+ thymocytes (1993)

We have analyzed the inducibility of protein kinase C (PKC)-dependent expression of CD 69 molecules in T cell receptor (TCR) transgenic thymocytes developing in the presence or absence of selecting, class I major histocompatibility complex (MHC) molecules. Small CD4+8+ thymocytes developing in the absence of selecting MHC molecules could not be induced to express CD 69 by TCR cross-linking even after spontaneous in vitro up-regulation of their TCR level which resulted in enhanced Ca++ flux. In contrast, a small proportion of CD4+8+TCRlow and most TCRhigh (CD4+8+ and CD4-8+) thymocytes developing in the presence of selecting MHC ligands could be induced to express CD 69 upon TCR cross-linking. Unlike the anti-TCR antibody, phorbol 12-myristate 13-acetate--a direct activator of PKC--induced the expression of CD 69 on all thymocytes. These results suggest that positive selection of CD4+8+ thymocytes results on coupling of TCR-mediated signals to the CD 69 expression pathway. In vitro analysis of thymocytes before and after positive selection suggests that (1) positive selection does not immediately result in resistance to deletion and (2) that sustained TCR ligation is needed to promote maturation of positively selected CD4+8+ thymocytes resulting in gradual loss of the sensitivity to deletion and acquisition of the ability to proliferate in response to TCR-mediated signals.
1-Methyl-1-azacyclohexa-2,3-diene(N−B)borane − Generation and Interception of an Unsymmetrical Isodihydropyridine (2001)

3-Bromo-1-methyl-1,2,5,6-tetrahydropyridine(N−B)borane (7) was prepared from 3-bromopyridine by conversion to 3-bromo-1-methylpyridinium iodide, hydrogenation of the latter with sodium tetrahydroborate and treatment of the resulting 3-bromo-1-methyl-1,2,5,6-tetrahydropyridine (6) with borane−dimethyl sulfide. Whereas no trapping product of the possible intermediate 1-methyl-1-azacyclohexa-2,3-diene (4) could be observed on treatment of 6 with potassium tert-butoxide in the presence of furan, the subjection of 7 to the same conditions produced the hexahydroepoxyquinoline derivatives 8a−c. Treatment of 7, dissolved in styrene, with sodium bis(trimethylsilyl)amide furnished the hexahydrocyclobutapyridine derivatives 9a−c. The six-membered cycloallene 1-methyl-1-azacyclohexa-2,3-diene(N−B)borane (10) must be regarded as the key intermediate en route to 8 and 9.
Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro (1994)

The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.