gebhart/patrepeval huggingface dataset:
Multiporosity/Multipermeability Inclined-Wellbore Solutions With Mudcake Effects (2018)

Summary This paper investigates the effects of mudcake and formation multiporosity/multipermeability on the evolution of a safe-drilling mudweight window. The analytical poroelastic solutions for an inclined wellbore drilled through a multiporosity/multipermeability porous medium were derived, taking into account the mudcake buildup on the wellbore wall. A multiporosity/multipermeability porous medium consists of an overlapping of N distinct porous-continuum networks, each of which has its own geomechanical and petrophysical properties. Wellbore collapse and fracturing are investigated by studying a dual-porosity naturally fractured weak sandstone. The first porosity is matrix porosity, and the second porosity is the fractures. In addition, a triple-porosity source shale with multiple scales of natural fractures was modeled. The first porosity corresponds to the shale matrix one, and two scales of fracture distribution account for the other two sets of porosity. The Drucker and Prager (1952) criterion is applied to analyze wellbore collapse and shear failure, whereas the tensile strengths of both formations are considered, conservatively, as negligible. The safe-drilling mud-weight window is calculated to illustrate the time-dependent effects of formation N-porosity/N-permeability nature and the wellbore-wall boundary conditions (with/without mudcake). On the one hand, natural fractures narrow the safe-drilling mud-weight window by degrading rock strength and facilitating hydraulic-pressure invasion. On the other hand, the mudcake leads to a wider safe-drilling mud-weight window by generating compressive effective radial stress on the wellbore wall and impeding hydraulic-pressure invasion. Mudcake thickness and mudcake permeability are found to have significant effects. The drilling-mud design to build a mudcake on the wellbore wall is essential when drilling through difficult naturally fractured formations.
Selective induction of toxicity to human cells expressing human immunodeficiency virus type 1 Tat by a conditionally cytotoxic adenovirus vector. (1990)

The human immunodeficiency viruses (HIVs) primarily infect CD4+ T lymphocytes, leading eventually to the development of a systemic immune dysfunction termed acquired immunodeficiency syndrome (AIDS). An attractive strategy to combat HIV-mediated pathogenesis would be to eliminate the initial pool of infected cells and thus prevent disease progression. We have engineered a replication-defective, conditionally cytotoxic adenovirus vector, Ad-tk, whose action is dependent on the targeted expression of the herpes simplex virus type 1 thymidine kinase gene (tk), cloned downstream of the HIV-1 long terminal repeat, in human cells expressing the HIV-1 transcriptional activator Tat. Infection of Tat-expressing human HeLa or Jurkat cells with Ad-tk resulted in high-level tk expression, which was not deleterious to the viability of these cells. However, in the presence of the antiherpetic nucleoside analog ganciclovir, Ad-tk infection resulted in a massive reduction in the viability of these Tat-expressing cell lines. As adenoviruses are natural passengers of the human lymphoid system, our results suggest adenovirus vector-based strategies for the targeted expression, under the control of cis-responsive HIV regulatory elements, of cytotoxic agents in HIV-infected cells for the therapy of HIV-mediated pathogenesis.
A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea (2012)

The canonical Wnt/β-catenin signaling pathway is known to play crucial roles in organogenesis by regulating both proliferation and differentiation. In the inner ear, this pathway has been shown to regulate the size of the otic placode from which the cochlea will arise; however, direct activity of canonical Wnt signaling as well as its function during cochlear mechanosensory hair cell development had yet to be identified. Using TCF/Lef:H2B-GFP reporter mice and transfection of an independent TCF/Lef reporter construct, we describe the pattern of canonical Wnt activity in the developing mouse cochlea. We show that prior to terminal mitosis, canonical Wnt activity is high in early prosensory cells from which hair cells and support cells will differentiate, and activity becomes reduced as development progresses. Using an in vitro model we demonstrate that Wnt/β-catenin signaling regulates both proliferation and hair cell differentiation within the developing cochlear duct. Inhibition of Wnt/β-catenin signaling blocks proliferation during early mitotic phases of development and inhibits hair cell formation in the differentiating organ of Corti. Conversely, activation increases the number of hair cells that differentiate and induces proliferation in prosensory cells, causing an expansion of the Sox2-positive prosensory domain. We further demonstrate that the induced proliferation of Sox2-positive cells may be mediated by the cell cycle regulator cyclin D1. Lastly, we provide evidence that the mitotic Sox2-positive cells are competent to differentiate into hair cells. Combined, our data suggest that Wnt/β-catenin signaling has a dual function in cochlear development, regulating both proliferation and hair cell differentiation.
Multigene Knockout Utilizing Off-Target Mutations of the CRISPR/Cas9 System in Rice (2014)

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated endonuclease 9 (CRISPR/Cas9) system has been demonstrated to be a robust genome engineering tool in a variety of organisms including plants. However, it has been shown that the CRISPR/Cas9 system cleaves genomic DNA sequences containing mismatches to the guide RNA strand. We expected that this low specificity could be exploited to induce multihomeologous and multiparalogous gene knockouts. In the case of polyploid plants, simultaneous modification of multiple homeologous genes, i.e. genes with similar but not identical DNA sequences, is often needed to obtain a desired phenotype. Even in diploid plants, disruption of multiparalogous genes, which have functional redundancy, is often needed. To validate the applicability of the CRISPR/Cas9 system to target mutagenesis of paralogous genes in rice, we designed a single-guide RNA (sgRNA) that recognized 20 bp sequences of cyclin-dependent kinase B2 (CDKB2) as an on-target locus. These 20 bp possess similarity to other rice CDK genes (CDKA1, CDKA2 and CDKB1) with different numbers of mismatches. We analyzed mutations in these four CDK genes in plants regenerated from Cas9/sgRNA-transformed calli and revealed that single, double and triple mutants of CDKA2, CDKB1 and CDKB2 can be created by a single sgRNA.
High-Resolution Scanning X-ray Diffraction Microscopy (2008)

Coherent diffractive imaging (CDI) and scanning transmission x-ray microscopy (STXM) are two popular microscopy techniques that have evolved quite independently. CDI promises to reach resolutions below 10 nanometers, but the reconstruction procedures put stringent requirements on data quality and sample preparation. In contrast, STXM features straightforward data analysis, but its resolution is limited by the spot size on the specimen. We demonstrate a ptychographic imaging method that bridges the gap between CDI and STXM by measuring complete diffraction patterns at each point of a STXM scan. The high penetration power of x-rays in combination with the high spatial resolution will allow investigation of a wide range of complex mesoscopic life and material science specimens, such as embedded semiconductor devices or cellular networks.
Enzyme immunoassay of neocarzinostatin using .BETA.-galactosidase as label. (1981)

A novel convenient procedure was introduced for enzyme labelling of neocarzinostatin (NCS) with beta-D-galactosidase using a new hetero-bifunctional reagent N-(gamma-maleimidobutyryloxy) succinimide (GMBS). With the enzyme labelled NCS and a rabbit anti-NCS serum which was elicited in a rabbit immunized with NCS in complete Freund's adjuvant, a highly sensitive enzyme immunoassay which can quantify a femto mol order NCS was developed. Accuracy and precision of the assay as well as a comparison with the immunodiffussion method were studied with satisfactory results. This enzyme immunoassay of NCS was applicable to monitoring serum NCS levels of patients in clinical treatment of the antitumor agent.
Ambient Mass Spectrometry (2006)

A recent innovation in mass spectrometry is the ability to record mass spectra on ordinary samples, in their native environment, without sample preparation or preseparation by creating ions outside the instrument. In desorption electrospray ionization (DESI), the principal method described here, electrically charged droplets are directed at the ambient object of interest; they release ions from the surface, which are then vacuumed through the air into a conventional mass spectrometer. Extremely rapid analysis is coupled with high sensitivity and high chemical specificity. These characteristics are advantageously applied to high-throughput metabolomics, explosives detection, natural products discovery, and biological tissue imaging, among other applications. Future possible uses of DESI for in vivo clinical analysis and its adaptation to portable mass spectrometers are described.
Relevance of Solid‐state Properties for Pharmaceutical Products (2006)

This chapter contains sections titled: Introduction Drug Discovery and Development Bioavailability of Solids Phases of Development and Solid-state Research Salt Selection Polymorph Screening Crystallization Process Development Formulation Method Development Solid-state and Life Cycle Management Conclusions References
Effect of Gaseous Impurities on the Electrochemical Reduction of CO2 on Copper Electrodes (2009)

Effects of impurities such as NO2 and SO2 with or without co-presence of O2 were studied in electrochemical reduction of CO2 on Cu in 0.5 M KHCO3 or 2 M KCl electrolyte in LS (liquid-solid) or GLS (gas-liquid-solid) cell. The effects of gaseous impurities are complex depending on geometry, flow rate, and speciation in solution. Generally, less than or equal to 1667 ppm of exposure NO2 is either beneficial or neutral - dissolved nitrate is beneficial, but nitrite and ammonia are detrimental. Less than or equal to 104 ppm of exposure of SO2 is either mildly detrimental or neutral - dissolved sulfide is extremely detrimental, but sulfate is beneficial. Oxygen can be detrimental (co-reductant or catalyst oxidant) or beneficial (oxidation of dissolved sulfide species) depending on LS or GLS geometry.
Chemically Modified Solid-State Nanopores (2007)

Nanopores are extremely sensitive single-molecule sensors. Recently, electron beams have been used to fabricate synthetic nanopores in thin solid-state membranes with subnanometer resolution. Here we report a new class of chemically modified nanopore sensors. We describe two approaches for monolayer coating of nanopores: (1) self-assembly from solution, in which nanopores approximately 10 nm diameter can be reproducibly coated, and (2) self-assembly under voltage-driven electrolyte flow, in which we are able to coat 5 nm nanopores. We present an extensive characterization of coated nanopores, their stability, reactivity, and pH response.
Detrusor muscle and sphincteric response to anorectal stimulation in spinal cord injury. (1979)

Twelve patients with spinal cord injuries were studied to determine whether the anal sphincter could be used as an index of urethral sphincter activity and to determine the bladder and striated sphincter response to anal and rectal stimulation. Electromyogram (emg) needle electrodes were placed in the external urethral sphincter, external anal sphincter and levator ani. The output of a cystometer was simultaneously recorded on the printout so that the relationship of the striated muscle response to distension of the bladder could be observed. The response to inserting a finger into the external anal canal, external anal sphincter stretch and rectal balloon distension was also observed. The external urethral and anal sphincter activity was closely linked during bladder contraction and anorectal stimulation. The levator ani showed divergent activity. Stretch of the external anal sphincter caused an initial period of increased striated muscle activity, then in 10 of 12 patients abrupt and often marked inhibition of both sphincters and levator ani developed with continued stretch. Ongoing bladder contractions were inhibited and a decrease in bladder tone developed in 7 of 12. Stretch of the rectum produced results similar to those with anal stretch except that bladder facilitation was seen in 4 of 12 patients.
The major dust mite allergen Der p 2 is differentially distributed after intratracheal delivery in sensitised and non-sensitised mice (2004)

The major dust mite allergen Der p 2 is differentially distributed after intratracheal delivery in sensitised and non-sensitised mice
Phase I Dose Escalation and Pharmacokinetic Study of BI 2536, a Novel Polo-Like Kinase 1 Inhibitor, in Patients With Advanced Solid Tumors (2008)

The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed.
Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples (2011)

The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.
Differential trafficking of Src, Lyn, Yes and Fyn is specified by the state of palmitoylation in the SH4 domain (2009)

Src-family tyrosine kinases (SFKs), which participate in a variety of signal transduction events, are known to localize to the cytoplasmic face of the plasma membrane through lipid modification. Recently, we showed that Lyn, an SFK member, is exocytosed to the plasma membrane via the Golgi region along the secretory pathway. We show here that SFK trafficking is specified by the palmitoylation state. Yes is also a monopalmitoylated SFK and is biosynthetically transported from the Golgi pool of caveolin to the plasma membrane. This pathway can be inhibited in the trans-Golgi network (TGN)-to-cell surface delivery by temperature block at 19 degrees C or dominant-negative Rab11 GTPase. A large fraction of Fyn, a dually palmitoylated SFK, is directly targeted to the plasma membrane irrespective of temperature block of TGN exit. Fyn(C6S), which lacks the second palmitoylation site, is able to traffic in the same way as Lyn and Yes. Moreover, construction of Yes(S6C) and chimeric Lyn or Yes with the Fyn N-terminus further substantiates the importance of the dual palmitoylation site for plasma membrane targeting. Taken together with our recent finding that Src, a nonpalmitoylated SFK, is rapidly exchanged between the plasma membrane and late endosomes/lysosomes, these results suggest that SFK trafficking is specified by the palmitoylation state in the SH4 domain.
Opsonization of Apoptotic Cells and Its Effect on Macrophage and T Cell Immune Responses (2003)

Genetic studies in mice indicate that predisposition to lupus-like diseases is caused by at least three mechanisms: (1) alterations in the threshold of activation of lymphocytes or macrophages; (2) defective signaling for activation-induced cell death; and (3) reduced clearance of apoptotic cells. To define the mechanisms whereby lupus develops in mice with deficiencies in either C1q, serum amyloid P component (SAP, the mouse counterpart of C-reactive protein, or CRP), or serum IgM, we studied the efficiency of phagocytosis of apoptotic cells using serum with varying levels of C1q, CRP, or IgM; we also examined the immune response to ingestion of dying cells under these conditions. Deficiency of C1q led to impaired macrophage phagocytosis of apoptotic cells, whereas CRP augmented phagocytosis, largely through recruitment of the early complement components. Like CRP, normal polyclonal IgM bound to apoptotic cells and activated complement on the cell surface. Similarly, direct binding as well as absorption experiments revealed that CRP and IgM antibodies had a similar ligand recognition specificity, namely lysophospholipids containing phosphorylcholine. IL-12 provides a pivotal link between macrophages and the T cell response to ingested material. We observed that necrotic cells induced IL-12 p40 expression, whereas phagocytosis of apoptotic cells profoundly reduced IL-12 production from stimulated macrophages. Furthermore, soluble factors from macrophages that had ingested apoptotic cells suppressed interferon-gamma production by activated T cells. These findings suggest that phospholipid exposure on apoptotic cells promotes opsonization by serum proteins leading to activation of complement, macrophage ingestion, and T cell suppression. We discuss how deficient opsonization or processing of dying cells leads to autoimmunity.
TCR Signaling Emerges from the Sum of Many Parts (2012)

"How does T cell receptor signaling begin?" Answering this question requires an understanding of how the parts of the molecular machinery that mediates this process fit and work together. Ultimately this molecular architecture must (i) trigger the relay of information from the TCR-pMHC interface to the signaling substrates of the CD3 molecules and (ii) bring the kinases that modify these substrates in close proximity to interact, initiate, and sustain signaling. In this contribution we will discuss advances of the last decade that have increased our understanding of the complex machinery and interactions that underlie this type of signaling.
Evaluation of a Coagulation Assay Determining the Activity State of Factor VII in Plasma (1983)

A coagulation assay is described that allows the measurement of the degree of activation of factor VII in circulating blood. The test is based on the use of both bovine and human brain thromboplastin, together with an artificial factor VII-deficient plasma. The latter can be prepared on a relatively large scale which makes it possible to measure factor VII activation in large series of patients. The determination of factor VII activation during incubation at 4 degrees C of plasma of women using oral contraceptives shows that the test described adequately measures factor VII activation. Differences in the time course of factor VII activation during this incubation in glass and plastic containers are found and implicate that rigorous standardization of blood sampling and test conditions is necessary. A possible mechanism that causes this critical dependence upon the test conditions is discussed.
The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells (2004)

Interactions between the novel benzamide histone deacetylase (HDAC) inhibitor MS-275 and fludarabine were examined in lymphoid and myeloid human leukemia cells in relation to mitochondrial injury, signal transduction events, and apoptosis. Prior exposure of Jurkat lymphoblastic leukemia cells to a marginally toxic concentration of MS-275 (e.g., 500 nM) for 24 h sharply increased mitochondrial injury, caspase activation, and apoptosis in response to a minimally toxic concentration of fludarabine (500 nM), resulting in highly synergistic antileukemic interactions and loss of clonogenic survival. Simultaneous exposure to MS-275 and fludarabine also led to synergistic effects, but these were not as pronounced as observed with sequential treatment. Similar interactions were noted in the case of (a) other human leukemia cell lines (e.g., U937, CCRF-CEM); (b) other HDAC inhibitors (e.g., sodium butyrate); and (c) other nucleoside analogues (e.g., 1-beta-D-arabinofuranosylcytosine, gemcitabine). Potentiation of fludarabine lethality by MS-275 was associated with acetylation of histones H3 and H4, down-regulation of the antiapoptotic proteins XIAP and Mcl-1, enhanced cytosolic release of proapoptotic mitochondrial proteins (e.g., cytochrome c, Smac/DIABLO, and apoptosis-inducing factor), and caspase activation. It was also accompanied by the caspase-dependent down-regulation of p27(KIP1), cyclins A, E, and D(1), and cleavage and diminished phosphorylation of retinoblastoma protein. However, increased lethality of the combination was not associated with enhanced fludarabine triphosphate formation or DNA incorporation and occurred despite a slight reduction in the S-phase fraction. Prior exposure to MS-275 attenuated fludarabine-mediated activation of MEK1/2, extracellular signal-regulated kinase, and Akt, and enhanced c-Jun NH(2)-terminal kinase phosphorylation; furthermore, inducible expression of constitutively active MEK1/2 or Akt significantly diminished MS-275/fludarabine-induced lethality. Combined exposure of cells to MS-275 and fludarabine was associated with a significant increase in generation of reactive oxygen species; moreover, both the increase in reactive oxygen species and apoptosis were largely attenuated by coadministration of the free radical scavenger L-N-acetylcysteine. Finally, prior administration of MS-275 markedly potentiated fludarabine-mediated generation of the proapoptotic lipid second messenger ceramide. Taken together, these findings indicate that the HDAC inhibitor MS-275 induces multiple perturbations in signal transduction, survival, and cell cycle regulatory pathways that lower the threshold for fludarabine-mediated mitochondrial injury and apoptosis in human leukemia cells. They also provide insights into possible mechanisms by which novel, clinically relevant HDAC inhibitors might be used to enhance the antileukemic activity of established nucleoside analogues such as fludarabine.