gebhart/patrepeval huggingface dataset:
Studies of adhesion molecules mediating interactions between cells of peripheral nervous system indicate a major role for L1 in mediating sensory neuron growth on Schwann cells in culture. (1988)

The involvement of the adhesion molecules L1, N-CAM, and J1 in adhesion and neurite outgrowth in the peripheral nervous system was investigated. We prepared Schwann cells and fibroblasts (from sciatic nerves) and neurons (from dorsal root ganglia) from 1-d mice. These cells were allowed to interact with each other in a short-term adhesion assay. We also measured outgrowth of dorsal root ganglion neurons on Schwann cell and fibroblast monolayers. Schwann cells (which express L1, N-CAM, and J1) adhered most strongly to dorsal root ganglion neurons by an L1-dependent mechanism and less by N-CAM and J1. Schwann cell-Schwann cell adhesion was mediated by L1 and N-CAM, but not J1. Adhesion of fibroblasts (which express N-CAM, but not L1 or J1) to neurons or Schwann cells was mediated by L1 and N-CAM and not J1. However, inhibition by L1 and N-CAM antibodies was found to be less pronounced with fibroblasts than with Schwann cells. N-CAM was also strongly involved in fibroblast-fibroblast adhesion. Neurite outgrowth was most extensive on Schwann cells and less on fibroblasts. A difference in extent of neurite elongation was seen between small- (10-20 microns) and large- (20-35 microns) diameter neurons, with the larger neurons tending to exhibit longer neurites. Fab fragments of polyclonal L1, N-CAM, and J1 antibodies exerted slightly different inhibitory effects on neurite outgrowth, depending on whether the neurites were derived from small or large neurons. L1 antibodies interfered most strikingly with neurite outgrowth on Schwann cells (inhibition of 88% for small and 76% for large neurons), while no inhibition was detectable on fibroblasts. Similarly, although to a smaller extent than L1, N-CAM appeared to be involved in neurite outgrowth on Schwann cells and not on fibroblasts. Antibodies to J1 only showed a very small effect on neurite outgrowth of large neurons on Schwann cells. These observations show for the first time that identified adhesion molecules are potent mediators of glia-dependent neurite formation and attribute to L1 a predominant role in neurite outgrowth on Schwann cells which may be instrumental in regeneration.
Prolyl 4-Hydroxylation of α-Fibrinogen (2009)

Plasma proteome analysis requires sufficient power to compare numerous samples and detect changes in protein modification, because the protein content of human samples varies significantly among individuals, and many plasma proteins undergo changes in the bloodstream. A label-free proteomics platform developed in our laboratory, termed "Two-Dimensional Image Converted Analysis of Liquid chromatography and mass spectrometry (2DICAL)," is capable of these tasks. Here, we describe successful detection of novel prolyl hydroxylation of alpha-fibrinogen using 2DICAL, based on comparison of plasma samples of 38 pancreatic cancer patients and 39 healthy subjects. Using a newly generated monoclonal antibody 11A5, we confirmed the increase in prolyl-hydroxylated alpha-fibrinogen plasma levels and identified prolyl 4-hydroxylase A1 as a key enzyme for the modification. Competitive enzyme-linked immunosorbent assay of 685 blood samples revealed dynamic changes in prolyl-hydroxylated alpha-fibrinogen plasma level depending on clinical status. Prolyl-hydroxylated alpha-fibrinogen is presumably controlled by multiple biological mechanisms, which remain to be clarified in future studies.
Avoidance of pseudogene interference in the detection of 3′ deletions in PMS2 (2011)

Lynch syndrome is characterized by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. In PMS2, detection of mutations is confounded by numerous pseudogenes. Detection of 3' deletions is particularly complicated by the pseudogene PMS2CL, which has strong similarity to PMS2 exons 9 and 11-15, due to extensive gene conversion. A newly designed multiplex ligation-dependent probe amplification (MLPA) kit incorporates probes for variants found in both PMS2 and PMS2CL. This provides detection of deletions, but does not allow localization of deletions to the gene or pseudogene. To address this, we have developed a methodology incorporating reference samples with known copy numbers of variants, and paired MLPA results with sequencing of PMS2 and PMS2CL. We tested a subset of clinically indicated samples for which mutations were either unidentified or not fully characterized using existing methods. We identified eight unrelated patients with deletions encompassing exons 9-15, 11-15, 13-15, 14-15, and 15. By incorporating specific, characterized reference samples and sequencing the gene and pseudogene it is possible to identify deletions in this region of PMS2 and provide clinically relevant results. This methodology represents a significant advance in the diagnosis of patients with Lynch syndrome caused by PMS2 mutations.
Suppression of neutrophil and endothelial activation by substance P receptor blockade in the Mg-deficient rat. (2003)

The regulatory role of substance-P (SP) on neutrophil and endothelium activation as well as nitric oxide (NO) production induced by Mg-deficiency was examined. Male Sprague-Dawley rats (180 g) were fed either a Mg-deficient (MgD) or Mg-sufficient (MgS) diet for 3 weeks. Enriched neutrophil fractions (> 85%) isolated from whole blood of the Mg-deficient rats displayed an 11-fold (p < 0.001) higher basal superoxide anion producing activity (assayed as SOD-inhibitable cytochrome c reduction) compared to that obtained from the MgS rats. Treatment of the MgD rats with the specific SP-receptor (SPR) blocker, L-703,606 (1 mg/kg/day as s.c. implanted sustained-release pellets) attenuated the superoxide anion producing activity by 75% (p < 0.025). In parallel, circulating prostacyclin (PGI2) level (assayed as 6-keto-PGF-1alpha) was elevated 13-fold in the MgD rats, but was reduced 90% by L-703,606 treatment. Concomitantly, plasma NO products (nitrate + nitrite), which increased 2.2-fold during Mg-deficiency, were completely suppressed by the SPR blockade. When the isolated hearts were subjected to ischemia/ reperfusion stress, NO products were elevated 2.4-fold in the effluent of the MgD group compared to MgS; such heightened NO release was also attenuated after in vivo treatment with the SPR blocker. In conclusion, SP plays a direct role in promoting activation of the neutrophil and endothelium as well as induction of NO production; these processes might participate in the oxidative stress that contributes to the depletion of blood glutathione and cardiac pathology.
On frequency-domain and time-domain phase unwrapping (1987)

Time-domain phase unwrapping of analytic or complex functions of time is an unavoidable operation when processing such signals within an FM-modeling framework or when attempting to establish the instantaneous frequency of such signals. With the help of an alternate derivation of his equations, Tribolet's frequency-domain phase unwrapping algorithm is easily rewritten for time-domain application. The time derivative of the argument of the signal, a quantity needed in these modified equations, is developed and furthermore recognized to be proportional to the instantaneous frequency of the signal.
INTRACEREBRAL RADIO STIMULATION AND RECORDING IN COMPLETELY FREE PATIENTS (1968)

DELGADO, JOSÉ M. R. M.D.; MARK, VERNON M.D.; SWEET, WILLIAM M.D.; ERVIN, FRANK M.D.; WEISS, GERHARD B. E. E.; BACH-Y-RITA, GEORGE M.D.; HAGIWARA, RIOJI M.D. Author Information
From the circumsporozoite protein to the RTS,S/AS candidate vaccine (2010)

The RTS,S/AS01(E) malaria vaccine candidate has recently entered Phase 3 testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline and partners and collaborators. The vaccine has been developed to protect young children and infants living in Sub-Saharan Africa against clinical and severe disease caused by Plasmodium falciparum infection. Over the past 9 years, RTS,S/AS has been evaluated in multiple Phase 2 studies. The vaccine was shown to have a favorable safety profile and to be well tolerated in all age groups in which it was tested, including the intended target population of infants and young children in Sub-Saharan Africa. Data obtained so far suggest that RTS,S/AS can be co-administered with other vaccines included in the routine Expanded Program of Immunization (EPI). In Phase 2 testing, the vaccine candidate was shown to confer significant protection against P. falciparum infection and clinical disease, including severe malaria. Furthermore, a trend towards an indirect beneficial effect of the vaccine on non-malarial morbidities has been observed in several trials. In this paper, we will describe the genesis of the RTS,S/AS concept, including the rationale for selecting the circumsporozoite protein (CSP) as the target antigen. Early development history of the vaccine will be briefly described. We will present the most salient results from recent Phase 2 studies conducted in the target pediatric population, which have led to the decision to progress RTS,S/AS to Phase 3 testing. If the Phase 3 results confirm the observations made during Phase 2 testing, the RTS,S/AS vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, would have a major public-health impact in Sub-Saharan Africa.
SYNTHESIS OF C1–C6 FRAGMENT FOR EPOTHILONE A VIA LIPASE-CATALYZED OPTICAL RESOLUTION (2001)

Synthesis of 5-oxo-(3S)-hydroxy-4,4-dimethylheptanoic acid (1), C1–C6 fragment of epothilone A, is described. Racemic tert-butyl 5-oxo-(3S)-acetoxy-4,4-dimethylheptanoate (5) was prepared by acylation of enamine followed by aldol condensation. Optical resolution of the heptanoate 5 was carried out by lipase catalyzed hydrolysis (yield 50%, > 98% e.e.).
Discriminative, generative and imitative learning (2002)

I propose a common framework that combines three different paradigms in machine learning: generative, discriminative and imitative learning. A generative probabilistic distribution is a principled way to model many machine learning and machine perception problems. Therein, one provides domain specific knowledge in terms of structure and parameter priors over the joint space of variables. Bayesian networks and Bayesian statistics provide a rich and flexible language for specifying this knowledge and subsequently refining it with data and observations. The final result is a distribution that is a good generator of novel exemplars.
Exacerbation of arthritis by IL-1 in rat joints previously injured by peptidoglycan-polysaccharide. (1988)

The arthropathic activity of mouse recombinant IL-1 (mrIL-1) after intraarticular (i.a.) injection into rat ankles was investigated. Nanogram quantities of either mrIL-1 alpha or mrIL-1 beta induced an acute transient arthritis. Arthritis induced by i.a. mrIL-1 developed more rapidly and was more severe in ankles previously injured by i.a. injection of group A streptococcal peptidoglycan-polysaccharide (PG-APS) fragments. In addition, a protracted pain response, as judged by severe limping, occurred 60 to 90 min after mrIL-1 injection into joints previously injured by PG-APS or 4 to 6 h after mrIL-1 injection into naive joints. The severity of arthritis was related to the mrIL-1 dose. Arthropathic activity of mrIL-1 alpha was neutralized by goat anti-mouse IL-1 alpha IgG, and the activity of both the alpha and beta preparations was heat labile. Repeated episodes of acute inflammation were induced by repeated i.a. injection of mrIL-1. In naive ankles this led to chronic synovitis without histologic evidence of erosions. However, in joints previously injured by PG-APS, repeated mrIL-1 injection induced a more severe chronic synovitis with a 50% incidence of early pannus formation and limited marginal erosions of cartilage and subchondral bone. Thus, mrIL-1 induces an acute exacerbation of arthritis in joints previously injured by PG-APS and repeated exposure of these joints to mrIL-1 promotes chronic erosive synovitis. These studies provide evidence for an in vivo function of IL-1 and are consistent with its role as one of the mediators in the local regulation of inflammation in recurrences of arthritis induced by bacterial cell wall polymers.
4‐Aminoquinoline‐Triazine‐Based Hybrids with Improved In Vitro Antimalarial Activity Against CQ‐Sensitive and CQ‐Resistant Strains of Plasmodium falciparum (2013)

A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-chloroquinolines yielded a series of new 7-chloro-4-aminoquinoline-triazine hybrids exhibiting high in vitro activity against W2 (chloroquine-resistant) and D6 (chloroquine-sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine-resistant strains (W2 clone) of P. falciparum.
Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody (2015)

Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.
Role of Rab3 GDP/GTP Exchange Protein in Synaptic Vesicle Trafficking at the Mouse Neuromuscular Junction (2001)

The Rab3 small G protein family consists of four members, Rab3A, -3B, -3C, and -3D. Of these members, Rab3A regulates Ca(2+)-dependent neurotransmitter release. These small G proteins are activated by Rab3 GDP/GTP exchange protein (Rab3 GEP). To determine the function of Rab3 GEP during neurotransmitter release, we have knocked out Rab3 GEP in mice. Rab3 GEP-/- mice developed normally but died immediately after birth. Embryos at E18.5 showed no evoked action potentials of the diaphragm and gastrocnemius muscles in response to electrical stimulation of the phrenic and sciatic nerves, respectively. In contrast, axonal conduction of the spinal cord and the phrenic nerve was not impaired. Total numbers of synaptic vesicles, especially those docked at the presynaptic plasma membrane, were reduced at the neuromuscular junction approximately 10-fold compared with controls, whereas postsynaptic structures and functions appeared normal. Thus, Rab3 GEP is essential for neurotransmitter release and probably for formation and trafficking of the synaptic vesicles.
Functional studies of the PI(3)-kinase signalling pathway employing synthetic and expressed siRNA (2003)

RNA interference (RNAi) is a RNA-mediated sequence-specific gene silencing mechanism. Recently, this mechanism has been used to down-regulate protein expression in mammalian cells by applying synthetic- or vector-generated small interfering RNAs (siRNAs). However, for the evaluation of this new knockdown technology, it is crucial to demonstrate biological consequences beyond protein level reduction. Here, we demonstrate that this new siRNA-based technology is suitable to analyse protein functions using the phosphatidylinositol (PI) 3-kinase signal transduction pathway as a model system. We demonstrate stable and transient siRNA-mediated knockdown of one of the PI 3-kinase catalytic subunits, p110beta, which leads to inhibition of invasive cell growth in vitro as well as in a tumour model system. Importantly, this result is consistent with loss-of-function phenotypes induced by conventional RNase H-dependent antisense molecules or treatment with the PI 3-kinase inhibitor LY294002. RNAi knockdown of the downstream kinases Akt1 and Akt2 does not reduce cell growth on extracellular matrix. Our data show that synthetic siRNAs, as well as vector-based expression of siRNAs, are a powerful new tool to interfere with signal transduction processes for the elucidation of gene function in mammalian cells.
Protective effects of SP600125 in a diet-induced rat model of non-alcoholic steatohepatitis (2009)

OBJECTIVE. To investigate the protective effect of SP600125, a selective c-Jun N-terminal kinase inhibitor, in a diet-induced rat model of non-alcoholic steatohepatitis (NASH). MATERIAL AND METHODS. Sprague-Dawley rats were randomly divided into three groups: a normal control group (NC group), a high-fat model group (HF group) and an SP600125 treatment group (SP group). All animals were subjected to a percutaneous superior mesenteric vein retention catheter operation and fed with a standard diet for 10 days. The HF group was then fed with an HF diet and treated with dimethyl sulfoxide while the SP group was fed with an HF diet and treated with SP600125 (50 mg/kg) once per day. RESULTS. Feeding rats with an HF diet established a model of NASH, with varying degrees of hepatic steatosis and hepatic inflammation. SP600125 treatment substantially decreased the incidence of insulin resistance, reduced lipotoxicity, inhibited oxidative stress and alleviated hepatocellular injury. CONCLUSIONS. SP600125 has the potential to remarkably attenuate steatosis and inflammation and may be a novel therapeutic drug against NASH.
Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity (2000)

Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens.
Preventing privilege escalation (2003)

A review of the English literature has yielded 39 cases of polyorchidism suitable for consideration in this review, and we add one more. The patients may be grouped according to the location of the aberrant testicular mass or the anatomic arrangement of their collecting systems.
Genome Sequence of Brucella abortus Vaccine Strain S19 Compared to Virulent Strains Yields Candidate Virulence Genes (2008)

The Brucella abortus strain S19, a spontaneously attenuated strain, has been used as a vaccine strain in vaccination of cattle against brucellosis for six decades. Despite many studies, the physiological and molecular mechanisms causing the attenuation are not known. We have applied pyrosequencing technology together with conventional sequencing to rapidly and comprehensively determine the complete genome sequence of the attenuated Brucella abortus vaccine strain S19. The main goal of this study is to identify candidate virulence genes by systematic comparative analysis of the attenuated strain with the published genome sequences of two virulent and closely related strains of B. abortus, 9-941 and 2308. The two S19 chromosomes are 2,122,487 and 1,161,449 bp in length. A total of 3062 genes were identified and annotated. Pairwise and reciprocal genome comparisons resulted in a total of 263 genes that were non-identical between the S19 genome and any of the two virulent strains. Amongst these, 45 genes were consistently different between the attenuated strain and the two virulent strains but were identical amongst the virulent strains, which included only two of the 236 genes that have been implicated as virulence factors in literature. The functional analyses of the differences have revealed a total of 24 genes that may be associated with the loss of virulence in S19. Of particular relevance are four genes with more than 60 bp consistent difference in S19 compared to both the virulent strains, which, in the virulent strains, encode an outer membrane protein and three proteins involved in erythritol uptake or metabolism.
Interleukin-6, Fibrin D-Dimer, and Coagulation Factors VII and XIIa in Prediction of Coronary Heart Disease (2004)

Fibrin D-dimer may be a stronger predictor of coronary risk than inflammatory markers, perhaps through its ability to stimulate monocyte release of IL-6.
Simplified Assay of Amrinone in Plasma by High-Performance Liquid Chromatography (1990)

An isocratic high-performance liquid chromatography method for the assay of plasma amrinone is described. Plasma amrinone is extracted using protein precipitation with an internal standard, separated with a reverse phase column, and detected using ultraviolet absorption. Each run is completed within 10 min. The assay can detect amrinone concentrations between 0.5 and 10.0 micrograms/ml, within the accepted therapeutic range. The assay has a within-day coefficient of variation of less than 5% and a day-to-day coefficient of variation of less than 10% in the therapeutic range of amrinone. This technique is an accurate, simple, and rapid method for the determination of amrinone concentrations in plasma.