gebhart/patrepeval huggingface dataset:
Specific in situ Hybridization of the Intracellular Organism of Porcine Proliferative Enteropathy (1994)

The identity of the intracellular bacteria found in the enterocytes of pigs with proliferative enteropathy was investigated using specific DNA probes to various Campylobacter species and to a novel organism, ileal symbiont intracellularis. The ilea from pigs (Nos. 1-7) that were diagnosed by routine histopathology as having proliferative enteropathy were used. Diagnosis was made on the basis of proliferation of the enterocytes on hematoxylin and eosin-stained sections and the presence of large numbers of intracellular curved organisms on Warthin-Starry silver-stained sections. Four of these pigs (Nos. 1-4) had the chronic form of the disease, porcine intestinal adenomatosis, and three (Nos. 5-7) had the acute form, proliferative hemorrhagic enteropathy. An additional three normal pigs (Nos. 8-10) were obtained from three separate farms with no history of proliferative enteropathy. Frozen ileal sections were examined by in situ hybridization with DNA probes specific for ileal symbiont intracellularis and the three porcine intestinal Campylobacter species, C. coli, C. hyointestinalis, and C. mucosalis. In all seven pigs with either the intestinal adenomatosis or hemorrhagic enteropathy form of the disease, a DNA probe specific for ileal symbiont intracellularis hybridized to localized foci in the apical cytoplasm of ileal enterocytes. These hybridization sites corresponded to the location of intracellular bacteria in silver-stained sections of adjacent tissue. Sections from the three normal pigs tested with this probe and from all pigs tested with the Campylobacter species-specific DNA probes showed no specific hybridization reactions. The identity of the intracellular organism in these diseased pigs is ileal symbiont intracellularis.
Synthesis and Melt Self-Assembly of PS–PMMA–PLA Triblock Bottlebrush Copolymers (2014)

Polystyrene–poly(methyl methacrylate)–polylactide (PS–PMMA–PLA) triblock bottlebrush copolymer with nearly symmetric volume fractions was synthesized by grafting from a symmetrical triblock backbone and the resulting melt was characterized by scanning electron microscopy and small-angle X-ray scattering. The copolymer backbone was prepared by sequential reversible addition–fragmentation chain transfer (RAFT) polymerization of solketal methacrylate (SM), 2-(bromoisobutyryl)ethyl methacrylate (BIEM), and 5-(trimethylsilyl)-4-pentyn-1-ol methacrylate (TPYM). PMMA branches were grafted by atom transfer radical polymerization from the poly(BIEM) segment, PS branches were grafted by RAFT polymerization from the poly(TPYM) block after installment of the RAFT agents, while PLA side chains were grafted from the deprotected poly(SM) block. The resulting copolymer was found to exhibit a lamellae morphology with a domain spacing of 79 nm. Differential scanning calorimetry analysis indicated that PMMA was preferentially mixing with PS while phase separating from PLA domains.
Identification of potentially useful combinations of epidermal growth factor receptor tyrosine kinase antagonists with conventional cytotoxic agents using median effect analysis (2006)

Targeted therapy for breast carcinoma has achieved a major advance with the use of trastuzumab in Her2/neu-positive tumors. The epidermal growth factor receptor superfamily thus becomes an attractive target for therapeutic agents. As the epidermal growth factor receptor tyrosine kinase family has a conformational binding site, which allows small molecules to interfere with its function, we have explored the effects of a dual kinase (epidermal growth factor receptor-1 and epidermal growth factor receptor-2) inhibitor (GW282974X) with a variety of cytotoxic agents looking for synergistic effects in vitro. Using a median effect model in four breast cancer cell lines in vitro, cytotoxic agents commonly used in treatment of human malignant disease were combined with trastuzumab or one of two epidermal growth factor receptor tyrosine kinase inhibitors in a 72-h culture and then analyzed for cytotoxic effect by 3-[26]-2,5-diphenyl-tetrazolium bromide assay. Combination index values within one standard deviation of unity were considered additive, less than unity as synergistic and more than unity as antagonistic. Synergistic results were confirmed by curve shift analysis and by an enzyme-linked immunosorbent assay measuring apoptosis by cytoplasmic histone-associated DNA fragments. Quantitative real-time polymerase chain reaction analysis was used to measure the expression of three of the critical enzymes in 5'-deoxy-5-fluorouridine metabolism and activity: thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidine synthase. 5'-Deoxy-5-fluorouridine with GW282974X demonstrated global synergy, both in high and low expressing epidermal growth factor receptor breast cancer cell lines. These results were confirmed by apoptosis assay and cell counts. RNA quantification following treatment with the dual kinase inhibitor suggested reduction in thymidine synthase levels to be a potential mechanism of synergy. The triplet of trastuzumab, GW282974X and 5'-deoxy-5-fluorouridine, and the triplet of GW282974X, epirubicin and 5'-deoxy-5-fluorouridine were highly synergistic in low expression cells (MCF7/wt) and high expression cells (MCF7/adr). These experiments suggest further studies of the dual kinase inhibitor with selected cytotoxics such as 5'-deoxy-5-fluorouridine are warranted.
Providing nighttime pharmaceutical services through telepharmacy (2002)

A nighttime telepharmacy service serving a community hospital is described. At a 340-bed acute care community hospital, the level of nighttime activity related to medication use did not support the establishment of a full night pharmacy shift. After-hours access to medications was mostly the responsibility of nursing and medical staff using a separate night closet, automated dispensing machines, and limited floor stock. Pharmacists reviewed new orders and missing doses during the following day shift. An innovative practice model that combined an outsourced telepharmacy service and the traditional oncall pharmacist service was implemented to improve services at night. Prospective order review, drug information services, and clinical pharmacy consultations were all provided under the new model. Nurses and physicians used the service extensively. A total of 1039 drug orders were reviewed by the telepharmacy service during the first three months, with 29% of these orders representing high-risk therapies. Most orders were submitted by the critical care areas, the medical-surgical units, and the emergency department. Feedback from the hospital staff concerning the service was favorable, and physician leaders asked that the service be expanded to take oral orders from physicians at night. A nighttime telepharmacy service was successfully implemented at a community hospital to provide medication order review, resolution of drug-related problems, and drug information and clinical pharmacy services.
GSK-3 inhibitors and insulin receptor signaling in health, disease, and therapeutics (2009)

GSK-3 is constitutively active in nonstimulated cells; multiple signalings negatively regulate GSK-3 via GSK-3 phosphorylation, subcellular (i.e. cytoplasmic; nuclear; mitochondrial) localization, and interaction with other proteins. GSK-3 alpha (51 kDa)/-3 beta (47 kDa) are encoded by different genes. Dysregulated hyperactivity of GSK-3 is associated with various diseases; in vivo and in vitro studies have increasingly implicated that GSK-3 inhibitors are promising therapeutics in diabetes mellitus, inflammation, tumorigenesis, psychiatric/neurodegenerative diseases, ischemia, and stem cell regeneration. Importantly, GSK-3 is the common target for various classical therapeutic drugs. In adrenal chromaffin cells, GSK-3 inhibition caused up-regulation of voltage-dependent Nav1.7 sodium channel, enhancing voltage-dependent calcium channel gating and catecholamine exocytosis; conversely, chronic treatment with GSK-3 inhibitors caused down-regulation of insulin receptor, IRS-1, IRS-2, and Akt1 levels. In this review, I will focus on these recent topics. Comprehensive review articles about lithium (1), GSK-3 and GSK-3 inhibitors (2-4), and the inhibition of Wnt/GSK-3beta>/beta-catenin signaling pathway by therapeutic drugs (5) are useful. Chemical structures of GSK-3 inhibitors are listed in the review articles (2, 4).
Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemotherapy or chemotherapy alone (2006)

Rituximab with or without chemotherapy was found to have major activity in patients with SMZL. These results may be associated with high levels of cellular CD20 antigen sites. Rituximab should be the treatment of choice, at least in older patients with SMZL who have comorbid diseases.
Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation--a novel mechanism for the cardioprotective effects of PPAR agonists (2008)

Our results demonstrated that hypercholesterolaemia and MPO overexpression are causally related and that PPARgamma agonists may have great therapeutic value in ischaemic heart disease patients with multiple complications such as hypercholesterolaemia and diabetes.
Distributed, parallel simulation of multiple, deliberative agents (2000)

Multi agent systems comprise multiple, deliberative agents embedded in and recreating patterns of interactions. Each agent's execution consumes considerable storage and calculation capacities. For testing multi agent systems, distributed parallel simulation techniques are required that take the dynamic pattern of composition and interaction of multi-agent systems into account. Analyzing the behavior of agents in virtual, dynamic environments necessitates relating the simulation time to the actual execution time of agents. Since the execution time of deliberative components can hardly be foretold, conservative techniques based on lookahead are not applicable. On the other hand, optimistic techniques become very expensive if mobile agents and the creation and deletion of model components are affected by a rollback. The developed simulation layer of JAMES (a Java Based Agent Modeling Environment for Simulation) implements a moderately optimistic strategy which splits simulation and external deliberation into different threads and allows simulation and deliberation to proceed concurrently by utilizing simulation events as synchronization points.
Immunohistochemical Localization of Extracellular Matrix Proteins in Cerebral Vessels in Chronic Hypertension (1996)

Vascular hypertrophy or vascular remodeling are both associated with an increase in the extracellular matrix of cerebral arteries and arterioles in chronic hypertension. Rats with chronic renal hypertension were studied to determine whether the extracellular matrix proteins--collagen IV, laminin, and fibronectin--are increased in the thick-walled cerebral vessels in brain and those associated with areas of blood-brain barrier (BBB) breakdown to protein. The latter was detected by extravasation of endogenous serum proteins in brain. Serum proteins and the extracellular matrix proteins--fibronectin, laminin, and collagen IV--were detected by immunohistochemistry. Hypertensive rats having blood pressures over 150 mm Hg showed mild to moderate degrees of mural thickening of pial and intracerebral arterioles. In addition, these vessels demonstrated increased immunoreactivity with collagen IV, fibronectin, and laminin antisera. This occurred concomitant with the development of hypertension and prior to the observation of BBB breakdown to protein. Four rats having mean maximum systolic blood pressures in excess of 220 mm Hg developed multifocal areas of increased vascular permeability to endogenous serum proteins in the boundary zones of the territories supplied by the major cerebral arteries. The arterioles in these areas showed a severe degree of vascular thickening, which was due to medial hyperplasia/hypertrophy and increased mural deposition of serum proteins and the extracellular matrix proteins--laminin, fibronectin, and collagen IV. This study demonstrates that extracellular matrix proteins play an important role in the vascular response to increased intraluminal pressure. However, since this change occurs in diseases in the absence of hypertension it should be regarded as a nonspecific response of cellular components of vessel walls to injury.
Assessment of Ovarian Cancer Conditions From Exhaled Breath (2015)

Most patients with ovarian cancer (OC) are diagnosed with advanced disease stages (III to IV) and have a 5-year survival rate less than 30%. Detecting OC in its early stages before it has metastasized could increase the 5-year survival rate to 85% to 90%. Previous studies have investigated a novel approach for the detection of OC based on measuring volatile organic compounds (VOCs) in exhaled breath; these disease-specific compounds evaporate from cancer cells and enter the surrounding environment. Using this principle, trained dogs showed an ability to distinguish OC tissues or blood samples from equivalent controls with almost 100% sensitivity and specificity. Because canine OC detection is not practical for widespread clinical use, scientists developed suitably sensitive analytical instrumentation for rapid detection of OC with similar accuracy as found with dogs. This pilot study examined the possibility that exhaled breath samples can noninvasively detect and discriminate women with OC from women that have no tumor(s) and from women that have benign genital tract neoplasia. The study population was composed of 3 groups: women with OC (n = 48), tumor-free control subjects (n = 48), and women with benign genetic tract neoplasia (n = 86). Gas chromatography linked with mass spectrometry was used to determine the chemical composition of the VOCs in the breath samples. Elevated concentrations of 5 compounds (decanal, nonanal, styrene, 2-butanone, and hexadecane) were found in the VOC samples from patients with cancer compared with the cancer-free volunteers. Analysis of the same samples with tailor-made nanoarrays showed good discrimination between women with OC and women who had either no tumor or benign genital tract neoplasia (71% for accuracy, sensitivity, and specificity). Conversely, nanoarray analysis was able to distinguish between the OC patients and the tumor-free control subjects (79% sensitivity, 100% specificity, and 89% accuracy). These preliminary findings show that a negative result with nanorray analysis could identify tumor-free women and avoid unnecessary complicated or expensive tests for OC in these patients. In patients with a positive result, the test will indicate the presence of OC with high probability. Further studies are needed with larger and more diverse populations to confirm and improve these promising results.
Dissection of the ATP-binding Domain of the Chaperone hsc70 for Interaction with the Cofactor Hap46 (2001)

Several unrelated proteins are known that specifically interact with members of the mammalian hsp70 chaperone protein family independent of the hsp70 substrate-binding site. One of these is Hap46, also called BAG-1, which binds to the ATP-binding domain of hsp70 and its constitutively expressed, highly homologous counterpart hsc70, thereby affecting nucleotide binding, as well as protein folding properties, of these molecular chaperones. In an attempt to delineate the potential contact sites on hsp70/hsc70 involved in this interaction we made use of the following two independent approaches: (i) screening of membrane-bound peptide libraries based on the sequence of the ATP-binding domain and (ii) the phage-display technique with random dodecapeptides. These approaches yielded partially overlapping results and identified several possible contact regions. On the space-filling model of hsc70, the two major contact areas for Hap46 delineated in the present study are located on the same side of the molecule on either subdomain that border the central cleft harboring the nucleotide-binding site. We suggest that this bridging affects the conformation of the ATP-binding domain in a way similar to the opening of the nucleotide-binding cleft produced in the bacterial hsp70 homologue DnaK upon binding its regulatory protein GrpE.
A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents RecurrentClostridium difficileInfection (2016)

SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.
Development of superconductor electronics technology for high-end computing (2003)

This paper describes our programme to develop and demonstrate ultra-high performance single flux quantum (SFQ) VLSI technology that will enable superconducting digital processors for petaFLOPS-scale computing. In the hybrid technology, multi-threaded architecture, the computational engine to power a petaFLOPS machine at affordable power will consist of 4096 SFQ multi-chip processors, with 50 to 100 GHz clock frequency and associated cryogenic RAM. We present the superconducting technology requirements, progress to date and our plan to meet these requirements. We improved SFQ Nb VLSI by two generations, to a 8 kA cm−2, 1.25 µm junction process, incorporated new CAD tools into our methodology, demonstrated methods for recycling the bias current and data communication at speeds up to 60 Gb s−1, both on and between chips through passive transmission lines. FLUX-1 is the most ambitious project implemented in SFQ technology to date, a prototype general-purpose 8 bit microprocessor chip. We are testing the FLUX-1 chip (5K gates, 20 GHz clock) and designing a 32 bit floating-point SFQ multiplier with vector-register memory. We report correct operation of the complete stripline-connected gate library with large bias margins, as well as several larger functional units used in FLUX-1. The next stage will be an SFQ multi-processor machine. Important challenges include further reducing chip supply current and on-chip power dissipation, developing at least 64 kbit, sub-nanosecond cryogenic RAM chips, developing thermally and electrically efficient high data rate cryogenic-to-ambient input/output technology and improving Nb VLSI to increase gate density.
The Xenopus laevis Aurora-related Protein Kinase pEg2 Associates with and Phosphorylates the Kinesin-related Protein XlEg5 (1999)

We have previously reported on the cloning of XlEg5, a Xenopus laevis kinesin-related protein from the bimC family (Le Guellec, R., Paris, J., Couturier, A., Roghi, C., and Philippe, M. (1991) Mol. Cell. Biol. 11, 3395-3408) as well as pEg2, an Aurora-related serine/threonine kinase (Roghi, C., Giet, R., Uzbekov, R., Morin, N., Chartrain, I., Le Guellec, R., Couturier, A., Dorée, M., Philippe, M., and Prigent, C. (1998) J. Cell Sci. 111, 557-572). Inhibition of either XlEg5 or pEg2 activity during mitosis in Xenopus egg extract led to monopolar spindle formation. Here, we report that in Xenopus XL2 cells, pEg2 and XlEg5 are both confined to separated centrosomes in prophase, and then to the microtubule spindle poles. We also show that pEg2 co-immunoprecipitates with XlEg5 from egg extracts and XL2 cell lysates. Both proteins can directly interact in vitro, but also through the two-hybrid system. Furthermore immunoprecipitated pEg2 were found to remain active when bound to the beads and phosphorylate XlEg5 present in the precipitate. Two-dimensional mapping of XlEg5 tryptic peptides phosphorylated in vivo first confirmed that XlEg5 was phosphorylated by p34(cdc2) and next revealed that in vitro pEg2 kinase phosphorylated XlEg5 on the same stalk domain serine residue that was phosphorylated in metabolically labeled XL2 cells. The kinesin-related XlEg5 is to our knowledge the first in vivo substrate ever reported for an Aurora-related kinase.
In search of natural substrates and inhibitors of MDR pumps. (2001)

The function of microbial MDRs remains a hotly debated subject. Given the very broad substrate specificities of some MDRs, like the RND pumps that can extrude all classes of amphipathic compounds (cationic, neutral, and anionic), it seems difficult to develop a rationale for pinpointing possible natural substrates of these translocases. At the same time, several clues can be used to guide our search for natural MDR substrates. One is the fact that amphipathic cations appear to be the preferred substrates of MDRs. These substances are extruded by MDRs of all 5 known families and are the almost exclusive substrates of SMR and MF family MDRs. The universal nature of amphipathic cations as MDR substrates suggests that these were the substances that fueled the evolution of MDR pumps. Two factors apparently favored this particular class of molecules for the role of original MDR substrates--need and opportunity. Unlike other substances, amphipathic cations accumulate in the cell driven by the membrane potential, which makes cations potentially the most dangerous toxins. At the same time, amphipathic cations are highly hydrated and do not permeate the membrane as readily as neutral compounds, making it feasible to design a defense based on an efflux pump. The paucity of known cationic (non-basic) antimicrobials might be a result of using MDR-expressing microbial cells for antibiotic discovery. Plant amphipathic cations, the berberine alkaloids, are good MDR substrates. The Berberis plants produce 5'-methoxyhydnocarpin-D, an MDR inhibitor that potentiates the action of berberine. It is suggested that the further evolution of MDR pumps was determined largely by the barrier function of the membrane they reside in. Thus Gram negative bacteria have an outer membrane barrier that slows the penetration of virtually all amphipathic molecules, and transenvelope MDRs of the RND and EmrAB-type extrude their substrates across this barrier. A low permeability of the cytoplasmic membrane of yeast similarly allows for the operation of broad-specificity ABC and MF MDRs. The presence of MDR sensors that regulate the expression of some MDR pumps strongly suggests that defense against external toxins is the function of these MDRs. The BmrR transcriptional activator of the MerR family induces expression of the Bmr pump in B. subtilis and is a sensor specifically designed to recognize amphipathic cations. Similarly, the OacR repressor binds chemically unrelated cations, which leads to the expression of the QacA pump in S. aureus. In E. coli, the EmrR sensor of the MarR repressor family binds unrelated neutral molecules, allowing for expression of the transenvelope EmrAB pump.