gebhart/patrepeval huggingface dataset:
Using build-integrated static checking to preserve correctness invariants (2004)

A key missing link in the creation of secure and robust systems is finding a ost effective way to demonstrate and preserve correspondence between a software design and its implementation. This paper explores the use of software model checking techniques to validate selected design invariants in the EROS operating system kernel. Several global consistency policies in the EROS kernel can be expressed as finite state automata. Using the MOPS static hecker, we have been able to validate the EROS kernel implementation against these automata. In the process, we have confirmed the practical utility of the basic verification technique, identified a number of desirable enhancements in MOPS, and located bugs in the EROS implementation.A key contribution of this paper is establishing that it is practical to integrate software model checking into normal development lifestyle. Model hecking is efficient enough that it does not add noticeably to our build times. This allows us to view it as a tool for error prevention rather than detection. Our work with EROS and MOPS suggests that domain specific application of software model hecking is a practical and powerful technique for software assurance and maintenance.
Conformational implications of enzymatic proline hydroxylation in collagen. (1982)

In 1979 it was proposed that prolyl hydroxylase (prolyl-glycyl-peptide,2-oxoglutarate:oxygen oxidoreductase, EC 1.14.11.2) recognizes the beta-turn conformation in nascent procollagen chains and that the hydroxylation process involves a conformational change resulting in "straightening" of the beta-turn segments into the linear triple-helical conformation of native collagen. We present experimental data that verify both these postulates. The following peptides were synthesized and studied for their conformation and interaction with prolyl hydroxylase: tBoc-Pro-Gly-Ala-OH, tBoc-Pro-Gly-Val-OH, tBoc-Gly-Val-Pro-Gly-Val-OH, and tBoc-Pro-DAla-Ala-OH. Spectral data showed that these peptides preferred a beta-turn conformation. All of them acted as inhibitors of the enzyme; the pentapeptide also acted as a substrate. To mimic the biosynthetic event, a collagen model polypeptide, (Pro-Pro-Gly)10, was incubated at 37 degrees C with purified prolyl hydroxylase and the necessary cosubstrates and cofactors at pH 7.8. A progressive change from the initially nonhelical to the triple-helical conformation, as monitored by CD spectra and gel filtration, occurred during the course of proline hydroxylation. In addition to leading to increased thermal stability of the triple-helical conformation in (Pro-Pro-Gly)10 and (Pro-Pro-Gly)5, the enzymatic incorporation of the hydroxyproline residues was found to enable these polypeptides to fold into this conformation faster than the unhydroxylated counterparts. These conformational implications of proline hydroxylation in collagen may also be of use in the study of the complement subcomponent Clq and of acetylcholine esterase which contain collagen-like regions in them.
Room-temperature epitaxial growth of AlN films (2002)

We have grown AlN films on nearly-lattice-matched (Mn,Zn)Fe2O4 (111) substrates by pulsed-laser deposition at room temperature and investigated their structural properties using reflection high-energy electron diffraction (RHEED), grazing incidence angle x-ray reflectivity (GIXR), grazing incidence angle x-ray diffraction (GIXD), and atomic force microscope. We have found that AlN grows epitaxially even at room temperature. In situ RHEED observations have shown that the room-temperature growth of AlN starts with the two-dimensional mode followed by a transition to the three-dimensional mode at the film thickness of 2 nm. GIXR and GIXD measurements have revealed that the heterointerface between AlN and (Mn,Zn)Fe2O4 is abrupt and approximately 90% of the lattice mismatch is released at the interface due to the introduction of crystalline defects such as misfit dislocations. These results indicate that the present technique solves one of the two major problems with heteroepitaxial growths of group III nitrides (mismatch in the thermal expansion coefficients) and alleviates the other problem (mismatch in the lattice constants).
Effect of Silver Carp Hypophthalmichthys molitrix and Freshwater Mussel Elliptio complanata Filtration on the Phytoplankton Community of Partitioned Aquaculture System Units (2004)

Abstract Growers produce over 2.8 million kg of catfish (over $350 million wholesale revenue) annually in the United States. The microbiology of the phytoplankton community in culture water affects the growth and flavor of the catfish and is a consideration for growers. Filter feeders, like silver carp and freshwater mussels, in controlled growth systems are used to adjust the phytoplankton species. Our goal was to successfully control the algal populations with filter feeders in catfish production. We used silver carp Hypophthalmichthys molitrix as a filter feeder in Partitioned Aquaculture System (PAS) water. Silver carp completely eliminated the cyanobacteria Microcystis by size and biovolume reduction. This created the desired effect of small green algae dominating the algal community. A significant but opposite change was observed when freshwater mussels Elliptio complanata filtered PAS water resulting in Microcystis biovolume and size dominance in the PAS; a less desirable algal community. This study also showed an immediate shift in the phytoplankton community when silver carp and mussels were interchanged between PAS waters. The size‐selective filtration by the two filter‐feeding taxa was important in determining the composition of the PAS phytoplankton community, and it was apparent that filtration with silver carp successfully depleted undesirable algae.
Occurrence and Biosynthesis of Endogenous Cannabinoid Precursor,N-Arachidonoyl Phosphatidylethanolamine, in Rat Brain (1997)

It has been suggested that anandamide (N-arachidonoylethanolamine), an endogenous cannabinoid substance, may be produced through Ca2+-stimulated hydrolysis of the phosphatidylethanolamine (PE) derivative N-arachidonoyl PE. The presence of N-arachidonoyl PE in adult brain tissue and the enzyme pathways that underlie its biosynthesis are, however, still undetermined. We report here that rat brain tissue contains both anandamide (11 +/- 7 pmol/gm wet tissue) and N-arachidonoyl PE (22 +/- 16 pmol/gm), as assessed by gas chromatography/mass spectrometry. We describe a N-acyltransferase activity in brain that catalyzes the biosynthesis of N-arachidonoyl PE by transferring an arachidonate group from the sn-1 carbon of phospholipids to the amino group of PE. We also show that sn-1 arachidonoyl phospholipids are present in brain, where they constitute approximately 0.5% of total phospholipids. N-acyltransferase activity is Ca2+ dependent and is enriched in brain and testis. Within the brain, N-acyltransferase activity is highest in brainstem; intermediate in cortex, striatum, hippocampus, medulla, and cerebellum; and lowest in thalamus, hypothalamus, and olfactory bulb. Pharmacological inhibition of N-acyltransferase activity in primary cultures of cortical neurons prevents Ca2+-stimulated N-arachidonoyl PE biosynthesis. Our results demonstrate, therefore, that rat brain tissue contains the complement of enzymatic activity and lipid substrates necessary for the biosynthesis of the anandamide precursor N-arachidonoyl PE. They also suggest that biosynthesis of N-arachidonoyl PE and formation of anandamide are tightly coupled processes, which may concomitantly be stimulated by elevations in intracellular Ca2+ occurring during neural activity.
Sporeformers as Human Probiotics: Bacillus, Sporolactobacillus , and Brevibacillus (2003)

The value of exogenously supplied live bacteria for the maintenance of health in humans has been recognized both scientifically in the published literature and commercially in the availability of probiotic products. Although many bacteria characterized as probiotics are strains of Lactobacillus or Bifidobacterium, sporeforming bacteria, primarily of the genus Bacillus and related genera, have also been studied and commercialized as probiotics. This article reviews the characterization, efficacy, and safety of sporeformers used as probiotics.
Characterization of a novel structural member, LukE‐LukD, of the bi‐component staphylococcal leucotoxins family (1998)

A new member of the staphylococcal bi-component leucotoxins family, LukE (32 kDa) and LukD (34.3 kDa) has been characterized from Staphylococcus aureus strain Newman. LukE was 58-68% identical with the class S proteins, whereas LukD was 71-77% identical with the class F proteins of the family. A partial immunoreactivity with the various affinity-purified antibodies specific for the other proteins was observed. Immunoprecipitation assay and gene probing confirmed a 30% frequency among human clinical isolates, differing from the distribution of the other known leucotoxins (P<0.005). LukE+LukD was as effective as the Panton-Valentine leucocidin for inducing dermonecrosis when injected in the rabbit skin, but not hemolytic and poorly leucotoxic compared to other leucotoxins expressed by Staphylococcus aureus.
Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. (1990)

The turnover and processing of the Alzheimer beta/A4 amyloid precursor protein (beta APP) has been studied in PC12 cells after treatment with agents that regulate protein phosphorylation. Phorbol 12,13-dibutyrate, an agent that stimulates protein kinase C, decreased the levels of mature beta APP and increased the levels of 15- and 19-kDa peptides. These peptides appeared to be COOH-terminal fragments of beta APP, which arose when phorbol 12,13-dibutyrate increased the rate of proteolytic processing of mature forms of beta APP. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also led to decreased levels of mature beta APP and increased levels of the 15- and 19-kDa peptides. H-7, an inhibitor of protein kinase C and of several other protein kinases, apparently decreased the rate of proteolytic processing of mature beta APP. The sizes of the putative COOH-terminal fragments observed after treatment with either phorbol 12,13-dibutyrate or okadaic acid suggest that one or both may contain the entire beta/A4 region of beta APP and thus be amyloidogenic. Our results support the hypothesis that abnormal protein phosphorylation may play a role in the development of the cerebral amyloidosis that accompanies Alzheimer disease.
MicroRNAs of the immune system (2010)

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to complementary target mRNAs and either promoting their decay or inhibiting their translation. Most eukaryotic genomes studied encode miRNAs, which are processed from longer noncoding transcripts through pathways conserved from fungi to plants to animals. miRNAs are now understood to be key mediators of developmental transitions in a number of model organisms. With respect to the immune system, miRNAs affect all facets of immune system development, from hematopoiesis to activation in response to infection during both the innate and the adaptive immune response. At the same time, miRNA dysregulation is a central event in the development and pathophysiology of a number of cancers of the immune system. Here we will discuss our current understanding of this general regulatory mechanism, focusing on its involvement in inflammation and in oncogenesis.
The influence of zinc on apoptosis. (1995)

This review summarizes the evidence that apoptosis is modulated by intracellular excess or deficiency of Zn2+, considers mechanisms whereby Zn2+ may influence apoptosis, and delineates gaps in current knowledge and opportunities for research. The experimental evidence supports four major conclusions: [1] Zinc deficiency, resulting from dietary deprivation of mice, or exposure of cultured cells to membrane-permeable Zn(2+)-chelators, can induce apoptosis; [2] Zinc supplementation, either by pretreating mice with ZnSO4, or adding Zn2+ to the media of cell cultures, can prevent apoptotic death. Zn2+ protects against the apoptosis induced by diverse physical, chemical, or immunologic stimuli in cultured cells of lymphoid, hepatic, or neoplastic origin; [3] Zn2+ does not affect the triggering events or earliest signs of apoptosis, but acts later in the apoptotic pathway, preventing endonucleosomal fragmentation and subsequent cytolysis; and [4] An intracellular pool of chelatable Zn2+ plays a critical role in apoptosis, possibly by modulating the activation or activity of endonuclease(s). These conclusions should alert pharmacologists and physicians to the potential therapeutic applications of zinc compounds and zinc chelators in clinical disorders and diseases that involve apoptosis, and to the relevance of zinc nutrition in such conditions.
In Situ Gene Therapy for Adenocarcinoma of the Prostate: A Phase I Clinical Trial (1999)

For patients with local recurrence of prostate cancer after definitive irradiation therapy there is no treatment widely considered safe and effective. After extensive preclinical testing of prodrug gene therapy in vitro and in vivo, we conducted a phase I dose escalation clinical trial of intraprostatic injection of a replication-deficient adenovirus (ADV) containing the herpes simplex virus thymidine kinase gene (HSV-tk) injected directly into the prostate, followed by intravenous administration of the prodrug ganciclovir (GCV). Our goal was to determine safe dose levels of the vector for future trials of efficacy. Patients with a rising serum prostate-specific antigen (PSA) level and biopsy confirmation of local recurrence of prostate cancer without evidence of metastases one or more years after definitive irradiation therapy were eligible for the trial. After giving informed consent, patients received injections of increasing concentrations of ADV/HSA-tk in 1 ml into the prostate under ultrasound guidance. Ganciclovir was then given intravenously for 14 days (5 mg/kg every 12 hr). Patients were monitored closely for evidence of toxicity and for response to therapy. Eighteen patients were treated at 4 escalating doses: group 1 (n = 4) received 1 x 10(8) infectious units (IU); group 2 (n = 5) received 1 x 10(9) IU; group 3 (n = 4) received 1 x 10(10) IU; group 4 (n = 5) received 1 x 10(11) IU. Vector was detected by PCR of urine samples after treatment, increasing in frequency and duration (up to 32 days) as the dose increased. All cultures of blood and urine specimens were negative for growth of adenovirus. Minimal toxicity (grade 1-2) was encountered in four patients. One patient at the highest dose level developed spontaneously reversible grade 4 thrombocytopenia and grade 3 hepatotoxicity. Three patients achieved an objective response, one each at the three highest dose levels, documented by a fall in serum PSA levels by 50% or more, sustained for 6 weeks to 1 year. This study is the first to demonstrate the safety of ADV/HSV-tk plus GCV gene therapy in human prostate cancer and the first to demonstrate anticancer activity of gene therapy in patients with prostate cancer. Further trials are underway to identify the optimal distribution of vector within the prostate and to explore the safety of repeat courses of gene therapy.
An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells (2009)

The chemokine receptor CXCR4 is expressed by malignant cells in ovarian cancer and is implicated in their growth and spread. We report here a unique mechanism of action of a small peptide antagonist of CXCR4 on ovarian cancer cells: induction of cell death by mitotic catastrophe. CTCE-9908 inhibited ovarian cancer cell migration to CXCL12, but on longer incubation, caused cell death in CXCR4-positive cells. CTCE-9908 did not cause apoptosis or cellular senescence, but induced multinucleation, G(2)-M arrest, and abnormal mitosis in ovarian cancer cells. This suggests that cell death was caused by mitotic catastrophe. Using microarray and Western blot analysis, we showed that CTCE-9908 deregulated DNA damage checkpoint proteins and spindle assembly checkpoint proteins at G(2)-M phases of the cell cycle. Combination treatment of CTCE-9908 and the drug paclitaxel led to an additive cytotoxicity that also involved mitotic catastrophe. We conclude that CTCE-9908 has a unique mechanism of action in ovarian cancer cells that seems to be CXCR4 specific.
Possible association of β‐arrestin 2 gene with methamphetamine use disorder, but not schizophrenia (2006)

Recent investigations suggest that the AKT/glycogen synthase kinase 3 (GSK3) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine (METH) use disorder. One important molecule related to this cascade is β‐arrestin 2 (ARRB2). We therefore conducted a genetic case–control association analysis of the gene for ARRB2 with schizophrenia and METH use disorder in a Japanese population (547 people with schizophrenia, 177 with METH use disorder and 546 controls). A possible association of ‘tag single nucleotide polymorphisms (SNPs)’ was found in METH use disorder (rs1045280: P genotype = 0.0118, P allele = 0.00351; rs2036657: P allele = 0.0431; rs4790694: P genotype = 0.0167, P allele = 0.0202), but no association was found with schizophrenia. We also evaluated the gene–gene interactions among ARRB2, AKT1, and GSK3B, which we previously reported for each of these diseases. However, no interaction was seen in our samples. This is the first association analysis of ARRB2, and our results indicate that ARRB2 may play a role in the pathophysiology of METH use disorder.
Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression (2014)

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.
Spinal Stenosis and Neurogenic Claudication (1996)

Neurogenic claudication is diagnosed from a classical history and complementary spinal imaging. The abnormal signs may be few. It should be distinguished from intermittent claudication (peripheral vascular disease), referred pain from the back or root pain that is aggravated by walking, and psychological distress. Pathologically, a developmentally small canal is usually affected by multiple levels of segmental degenerative change, with venous pooling in the cauda equina between two levels of low pressure stenosis. There is probably then a failure of arterial vasodilatation of the congested roots in response to exercise, with symptoms in the legs when walking. Once established, symptoms tend neither to improve nor deteriorate. Conservative management is reasonable. Otherwise decompression at the most significant stenotic level is probably adequate to obtain a good surgical result.
5-Aminolevulinic Acid-based Photochemical Internalization of the Immunotoxin MOC31-gelonin Generates Synergistic Cytotoxic Effects In Vitro¶ (2001)

Photochemical internalization (PCI) is a novel method for the endosomal or lysosomal release of membrane-impermeable molecules into the cytosol of target cells. This novel technology is based on the photodynamically induced rupture of endocytic vesicles preloaded with molecules of therapeutic interest. PCI of the ribosome-inactivating plant toxin gelonin and the immunotoxin monoclonal antibody 31 (MOC31) gelonin has been performed previously by the use of the endocytic vesicle-localizing photosensitizers TPPS2a and AIPcS2a and light, demonstrating synergistic toxicity against the more than 20 different cell lines tested, most of them of neoplastic origin. In this study we demonstrate that 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) is also capable of inducing PCI of MOC31-gelonin in the human colon adenocarcinoma cell line WiDr. The cells were incubated with 1 mM 5-ALA for up to 8 h in serum-free medium and from 24 to 96 h in serum-containing medium. Fluorescence microscopical studies indicate a partial plasma membrane localization of PpIX when 5-ALA was applied under serum-free conditions. This plasma membrane localization was not seen when 5-ALA was given in the presence of serum. There was a granular component of the PpIX localization in addition to a diffuse cytoplasmic localization. The granular component resembled the localization of the fluorescent dye conjugate Alexa-gelonin and the lysosomal localizing dye acridine orange. Our present results provide evidence for an endocytic vesicle-associated fraction of PpIX after 5-ALA incubation of the WiDr cells. We demonstrate that PCI, by combining 5-ALA, MOC31-gelonin and light, induces a synergistic cytotoxic effect against the WiDr cells.