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1
Ferreira Filho, Pedro Calixto, and Antonio Henrique Campolina Martins. "LA TRANSLATIO SEMANTICAE ET GRAMMAIRE CHEZ ALAIN DE LILLE." Revista Ética e Filosofia Política 2, no. 21 (January 10, 2019): 194–247. http://dx.doi.org/10.34019/2448-2137.2018.17866.
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Résumé : Dans le néoplatonisme grec, le fait d'avoir érigé un principe non-ontique rompt avec la supériorité de l'affirmation sur la négation lorsqu'il s'agit d'énoncer le divin. Cependant, à cause des thèses exprimées sur la transcendance radicale de l'Un, la réflexion sur le discours portant sur la divinité s'achève la plupart du temps par la dénonciation d'une inaptitude profonde du discours à signifier une quelconque réalité divine, et aboutit systématiquement à l'apologie du silence. L’apophase a comme objectif de dépouiller l’âme de toute détermination afin qu’elle puisse s’unir au Principe qui est au-delà de toute détermination. Au XIIème siècle la conscience de la supériorité de la négation sur l'affirmation in divinis, qui avait donné l’origine à la translatio nominis chez Denys et à une translatio categoriae chez Erigène, donne lieu à une théorie grammaticale que l'on a qualifiée de translatio semanticae. C'est cette question du tranfert sémantique des noms et de la proposition qui constituera l’objet d'analyse de ce chapitre. Nous nous proposons d’étudier les éléments de cette sémantique et de cette syntaxe néoplatoniciennes dans les maximes de grammaire contenues dans les Règles de Théologie d'Alain de Lille écrites au XIIème siècle.Mots-clef : Alain de Lille, grammaire, sémantique, translatio, kataphase, apophase.
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Gordon-Lipkin, Eliza, Julie S. Cohen, Siddharth Srivastava, Bruno P. Soares, Eric Levey, and Ali Fatemi. "ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis." Journal of Child Neurology 33, no. 13 (September 5, 2018): 825–31. http://dx.doi.org/10.1177/0883073818791099.
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GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.
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Wang, Y., D. C. Newton, G. B. Robb, C. L. Kau, T. L. Miller, A. H. Cheung, A. V. Hall, S. VanDamme, J. N. Wilcox, and P. A. Marsden. "RNA diversity has profound effects on the translation of neuronal nitric oxide synthase." Proceedings of the National Academy of Sciences 96, no. 21 (October 12, 1999): 12150–55. http://dx.doi.org/10.1073/pnas.96.21.12150.
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Araujo, M. "Inhibition of Nitric Oxide Synthase Causes Profound Enhancement of the Bezold-Jarisch Reflex." American Journal of Hypertension 11, no. 1 (January 1998): 66–72. http://dx.doi.org/10.1016/s0895-7061(97)00302-6.
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Wang, Xiaojing, Snezana Levic, Michael Anne Gratton, Karen Jo Doyle, Ebenezer N. Yamoah, and Anthony E. Pegg. "Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine." Journal of Biological Chemistry 284, no. 2 (November 10, 2008): 930–37. http://dx.doi.org/10.1074/jbc.m807758200.
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Aronoff, Mark, Irit Meir, Carol A. Padden, and Wendy Sandler. "The roots of linguistic organization in a new language." Interaction Studies 9, no. 1 (March 7, 2008): 133–53. http://dx.doi.org/10.1075/is.9.1.10aro.
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It is possible for a language to emerge with no direct linguistic history or outside linguistic influence. Al-Sayyid Bedouin Sign Language (ABSL) arose about 70 years ago in a small, insular community with a high incidence of profound prelingual neurosensory deafness. In ABSL, we have been able to identify the beginnings of phonology, morphology, syntax, and prosody. The linguistic elements we find in ABSL are not exclusively holistic, nor are they all compositional, but a combination of both. We do not, however, find in ABSL certain features that have been posited as essential even for a proto-language. ABSL has a highly regular syntax as well as word-internal compounding, also highly regular but quite distinct from syntax in its patterns. ABSL, however, has no discernable word-internal structure of the kind observed in more mature sign languages: no spatially organized morphology and no evident duality of phonological patterning.
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Musser, Jeffrey B., Timothy B. Bentley, Scott Griffith, Pushpa Sharma, John E. Karaian, and Paul D. Mongan. "Hemorrhagic Shock in Swine: Nitric Oxide and Potassium Sensitive Adenosine Triphosphate Channel Activation." Anesthesiology 101, no. 2 (August 1, 2004): 399–408. http://dx.doi.org/10.1097/00000542-200408000-00021.
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Background To determine the role of nitric oxide and adenosine triphosphate-sensitive potassium (KATP) vascular channels in vascular decompensation during controlled hemorrhagic shock in swine. Methods Thirty instrumented, anesthetized adolescent Yorkshire swine were subjected to controlled isobaric hemorrhage to a mean arterial pressure of 40 mmHg for 2 h (n = 6) or 4 h (n = 10) or 50 mmHg for 4 h (n = 8). An additional six animals were used as anesthetized instrumented time controls. During controlled hemorrhage, plasma and tissue samples were obtained every 30 to 60 min. Before euthanasia, tissue (carotid artery, lung, liver, and aorta) was obtained for analysis of nitrate concentrations and nitric oxide synthase activity. Isolated carotid artery ring reactivity to norepinephrine was also determined with and without glibenclamide. Results Animals hemorrhaged to 40 mmHg decompensated earlier than animals hemorrhaged to 50 mmHg. Plasma nitrate concentrations and nitric oxide synthase activity rose consistently throughout hemorrhage in both groups. However, they were substantially higher in the mean arterial pressure 40 group. Constitutive nitric oxide synthase activity was the major contributor to total nitric oxide synthase activity throughout the protocol with only the animals maintained at 40 mmHg for 4 h showing evidence of inducible nitric oxide synthase activity. Profound KATP channel activation and hyporeactivity of isolated vessel rings to norepinephrine was not observed until 4 h after the initiation of hemorrhagic shock. Only those animals with inducible nitric oxide synthase activity showed a decreased response to norepinephrine, and this hyporeactivity was reversed with the KATP channel inhibitor, glibenclamide. Conclusions The data indicate that profound KATP activation associated with increased nitric oxide concentrations and inducible nitric oxide synthase induction is a key factor in vascular smooth muscle hyporeactivity characteristic of the late decompensatory phase of hemorrhagic shock in swine.
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Hu, Qingsong, Xiaohong Wang, Joseph Lee, Abdul Mansoor, Jingbo Liu, Lepeng Zeng, Cory Swingen, et al. "Profound bioenergetic abnormalities in peri-infarct myocardial regions." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 2 (August 2006): H648—H657. http://dx.doi.org/10.1152/ajpheart.01387.2005.
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Regions of myocardial infarct (MI) are surrounded by a border zone (BZ) of normally perfused but dysfunctional myocardium. Although systolic dysfunction has been attributed to elevated wall stress in this region, there is evidence that intrinsic abnormalities of contractile performance exist in BZ myocardium. This study examined whether decreases of high-energy phosphates (HEP) and mitochondrial F1F0-ATPase (mtATPase) subunits typical of failing myocardium exist in BZ myocardium of compensated postinfarct remodeled hearts. Eight pigs were studied 6 wk after MI was produced by ligation of the left anterior descending coronary artery (LAD) distal to the second diagonal. Animals developed compensated LV remodeling with a decrease of ejection fraction from 54.6 ± 5.4% to 31 ± 2.1% (MRI) 5 wk after LAD occlusion. The remote zone (RZ) myocardium demonstrated modest decreases of ATP and mtATPase components. In contrast, BZ myocardium demonstrated profound abnormalities with ATP levels decreased to 42% of normal, and phosphocreatine-to-ATP ratio (31P-magnetic resonance spectroscopy) decreased from 2.06 ± 0.19 in normal hearts to 1.07 ± 0.10, with decreases in α-, β-, OSCP, and IF1 subunits of mtATPase, especially in the subendocardium. The reduction of myocardial creatine kinase isoform protein expression was also more severe in the BZ relative to the RZ myocardium. These abnormalities were independent of a change in mitochondrial content because the mitochondrial citrate synthase protein level was not different between the BZ and RZ. This regional heterogeneity of ATP content and expression of key enzymes in ATP production suggests that energetic insufficiency in the peri-infarct region may contribute to the transition from compensated LV remodeling to congestive heart failure.
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Ivanova, Elena. "Contrastive Analysis of Bulgarian and Russian Syntax Peculiarities." Slovene 9, no. 1 (2019): 554–63. http://dx.doi.org/10.31168/2305-6754.2019.8.1.22.
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[Rev. of: Gradinarova Alla A., Essays on the Comparative Syntax of Bulgarian and Russian, Sofia: Iztok-Zapad, 2017, 500 pp.] This article presents a review of the book by a major Bulgarian researcher of Russian, professor of Sofia University “St. Kliment Ohridski” Alla Gradinarova, whose scholarly interests focus mainly on the contrastive syntax of Bulgarian and Russian. In the new monograph, the author concentrates largely on the points of divergence in these languages stemming from their typological differences: passive voice and syntactic impersonality, word order, communicatively marked phrasal templates, various types of multi-clause structures ranging from verbal adverb phrases to complex and asyndetic sentences, etc. The contrastive analysis of the language data helps to reveal significant characteristics of the studied phenomena. This allows the use of the obtained results and data not only in typology and contrastive linguistics, but also in the study of the Russian language, as the approach of the author in her studies is based on a profound analysis of Russian data. The book constitutes a major contribution to studies in contrastive syntax of Slavic languages.
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NEWMEYER, FREDERICK J. "The Prague School and North American functionalist approaches to syntax." Journal of Linguistics 37, no. 1 (March 2001): 101–26. http://dx.doi.org/10.1017/s0022226701008593.
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Modern functionalist approaches to syntax were pioneered in the 1920s by the scholars associated with the Linguistic Circle of Prague and Prague-based functionalism is a dynamic force today. Nevertheless, citations of this work by North American functionalists are few and far between. This paper sets out to explain that state of affairs. It pinpoints the profound theoretical differences between mainstream North American and Czech approaches that have led to partisans of the former losing interest in the latter. The paper argues that, on the other hand, Praguian functional syntax has a great deal in common with more ‘formal’ functionalist approaches and with much work in formal semantics. Not surprisingly, then, recent years have seen increasing productive collaboration between North American and Western European practitioners of these approaches and members of the Prague School.
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Klaevik-Pettersen, Espen. "Full V2, no V2, residual V2." Isogloss. Open Journal of Romance Linguistics 8, no. 3 (August 31, 2022): 1–25. http://dx.doi.org/10.5565/rev/isogloss.199.
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This paper presents a new phase-based theory of verb-second and indeed a new model of the left periphery. I argue that V-to-C movement of the verb to the phase head Fin0 has profound repercussions on clausal syntax which explains well-known differences between Modern Germanic V2 languages and Modern Romance non-V2 languages with respect to topicalisation. I also explore how the proposed analysis can account for the linear restriction on the prefield in V2 languages as well as the phenomenon of ‘residual verb second’ in otherwise non-V2 languages like Modern Romance.
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Sampson, A. P., A. S. Cowburn, K. Sladek, L. Adamek, E. Nizankowska, A. Szczeklik, B. K. Lam, J. F. Penrose, K. F. Austen, and S. T. Holgate. "Profound Overexpression of Leukotriene C4 Synthase in Bronchial Biopsies from Aspirin-Intolerant Asthmatic Patients." International Archives of Allergy and Immunology 113, no. 1-3 (1997): 355–57. http://dx.doi.org/10.1159/000237600.
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Chin, Alfred C. "Neuroinflammation and the cGAS-STING pathway." Journal of Neurophysiology 121, no. 4 (April 1, 2019): 1087–91. http://dx.doi.org/10.1152/jn.00848.2018.
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The recent discovery of cyclic GMP-AMP synthase (cGAS) as the mammalian cytosolic DNA sensor has profound therapeutic implications for infection, immunology, and cancer. Because neurovirology, neuroimmunology, neuro-oncology, and neurodegeneration implicate cytosolic DNA sensing, cGAS activation and induction of the downstream signaling protein stimulator of interferon genes (STING) has become increasingly recognized as a crucial determinant of neuropathophysiology. This Neuro Forum article reviews recent advances on the role of cGAS-STING signaling in neuroinflammation and neurological disease.
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LLOYD, James R., Volker LANDSCHÜTZE, and Jens KOSSMANN. "Simultaneous antisense inhibition of two starch-synthase isoforms in potato tubers leads to accumulation of grossly modified amylopectin." Biochemical Journal 338, no. 2 (February 22, 1999): 515–21. http://dx.doi.org/10.1042/bj3380515.
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A chimaeric antisense construct was used to reduce the activities of the two major starch-synthase isoforms in potato tubers simultaneously. A range of reductions in total starch-synthase activities were found in the resulting transgenic plants, up to a maximum of 90% inhibition. The reduction in starch-synthase activity had a profound effect on the starch granules, which became extremely distorted in appearance compared with the control lines. Analysis of the starch indicated that the amounts produced in the tubers, and the amylose content of the starch, were not affected by the reduction in activity. In order to understand why the starch granules were distorted, amylopectin was isolated and the constituent chain lengths analysed. This indicated that the amylopectin was very different to that of the control. It contained more chains of fewer than 15 glucose units in length, and fewer of between 15 and 80 glucose units. In addition, the amylopectin contained more very long chains. Amylopectin from plants repressed in just one of the activities of the two starch-synthase isoforms, which we have reported upon previously, were also analysed. Using a technique different to that used previously we show that both isoforms also affect the amylopectin, but in a way that is different to when both isoforms are repressed together.
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Biller, Scott A., Michael J. Sofia, Barbara DeLange, Cornelia Forster, Eric M. Gordon, Thomas Harrity, Lois C. Rich, and Carl P. Ciosek. "The first potent inhibitor of squalene synthase: a profound contribution of an ether oxygen to inhibitor-enzyme interaction." Journal of the American Chemical Society 113, no. 22 (October 1991): 8522–24. http://dx.doi.org/10.1021/ja00022a050.
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Mracek, Tomas, Petr Pecina, Hana Nuskova, Jana Kovalcikova, Alena Pecinova, Lukas Alan, Marie Rodinova, et al. "Knockout of DAPIT protein disrupts ATP synthase oligomerisation and has a profound role in regulation of glucose homeostasis." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1859 (September 2018): e15. http://dx.doi.org/10.1016/j.bbabio.2018.09.047.
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de Koning, Ramon, Raphaël Kiekens, Mary Esther Muyoka Toili, and Geert Angenon. "Identification and Expression Analysis of the Genes Involved in the Raffinose Family Oligosaccharides Pathway of Phaseolus vulgaris and Glycine max." Plants 10, no. 7 (July 16, 2021): 1465. http://dx.doi.org/10.3390/plants10071465.
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Raffinose family oligosaccharides (RFO) play an important role in plants but are also considered to be antinutritional factors. A profound understanding of the galactinol and RFO biosynthetic gene families and the expression patterns of the individual genes is a prerequisite for the sustainable reduction of the RFO content in the seeds, without compromising normal plant development and functioning. In this paper, an overview of the annotation and genetic structure of all galactinol- and RFO biosynthesis genes is given for soybean and common bean. In common bean, three galactinol synthase genes, two raffinose synthase genes and one stachyose synthase gene were identified for the first time. To discover the expression patterns of these genes in different tissues, two expression atlases have been created through re-analysis of publicly available RNA-seq data. De novo expression analysis through an RNA-seq study during seed development of three varieties of common bean gave more insight into the expression patterns of these genes during the seed development. The results of the expression analysis suggest that different classes of galactinol- and RFO synthase genes have tissue-specific expression patterns in soybean and common bean. With the obtained knowledge, important galactinol- and RFO synthase genes that specifically play a key role in the accumulation of RFOs in the seeds are identified. These candidate genes may play a pivotal role in reducing the RFO content in the seeds of important legumes which could improve the nutritional quality of these beans and would solve the discomforts associated with their consumption.
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Bayraktar, Nesrin. "On Ebū al-Fazl Mūsā bin Haci Huseyn Iznikī’s Translation of Tha‘labī’s Qiṣaṣ al-Anbiyā." IRAN and the CAUCASUS 17, no. 2 (2013): 171–88. http://dx.doi.org/10.1163/1573384x-20130204.
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This article focuses on Iznikī’s translation of Tha‘labī’s Qiṣaṣ al-Anbiyā’ as a valuable gateway to our understanding of features of Old Anatolian Turkish. Comprising of two volumes, the manuscript is incomplete, with a missing second volume. There are two extant copies (Yozgat and Şazeli) of the first volume of the manuscript. An examination of the two copies reveals that both copies contain characteristic morphological and phonetic features of 15th century Old Anatolian Turkish. The manuscript embodies informative information concerning lexical and morphological features of Turkish of the era as well as transitional forms of Turkish. Syntactically, however, the texts carries resemblance to Arabic syntax, attributable to Iznikī’s profound command of Arabic and Persian and the original language of Tha‘labī’s work.
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Reshef, Ran, Doron Schwartz, Merav Ingbir, Alexander Shtabsky, Tamara Chernichovski, Benjamin A. Isserlin, Gil Chernin, Yoram Levo, and Idit F. Schwartz. "A profound decrease in maternal arginine uptake provokes endothelial nitration in the pregnant rat." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 3 (March 2008): H1156—H1163. http://dx.doi.org/10.1152/ajpheart.01051.2007.
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While a specific role for nitric oxide (NO) in inducing the hemodynamic alterations of pregnancy is somewhat controversial, it is widely accepted that excess NO is generated during pregnancy. l-Arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate l-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as the specific arginine transporter for endothelial NO synthase. The present study was designed to test the hypothesis that, during pregnancy, when arginine consumption by the fetus is significantly increased, compensatory changes in maternal arginine uptake affect the endothelium. Uptake of radiolabeled arginine (l-[3H]arginine) by freshly harvested maternal aortic rings from pregnant rats decreased by 65 and 30% in mid- and late pregnancy, respectively, compared with those obtained from virgin animals. This decrease was associated with a significant increase in endothelial protein nitration (the footprint of peroxynitrite generation), as shown by both Western blotting and immunohistochemistry utilizing anti-nitrotyrosine antibodies, reflecting endothelial damage. Northern blot analysis revealed that steady-state aortic CAT-1 mRNA levels did not change throughout pregnancy, whereas CAT-1 protein abundance was significantly increased, peaking at mid-pregnancy. Protein content of protein kinase C (PKC)-α, which was previously shown to decrease CAT-1 activity, increased significantly in the pregnant animals and was associated with a significant increase in CAT-1 phosphorylation. Intraperitoneal injection of α-tocopherol, a PKC-α inhibitor, prevented the decrease in arginine transport and attenuated protein nitration. In conclusion, aortic arginine uptake is reduced during pregnancy, through posttranslational modulation of CAT-1 protein, presumably via upregulation of PKC-α. The aforementioned findings are associated with an increase in protein nitration and, therefore, in selected individuals, may lead to the development of certain forms of endothelial dysfunction, like preeclampsia.
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Scanga, Charles A., Andre Bafica, Carl G. Feng, Allen W. Cheever, Sara Hieny, and Alan Sher. "MyD88-Deficient Mice Display a Profound Loss in Resistance to Mycobacterium tuberculosis Associated with Partially Impaired Th1 Cytokine and Nitric Oxide Synthase 2 Expression." Infection and Immunity 72, no. 4 (April 2004): 2400–2404. http://dx.doi.org/10.1128/iai.72.4.2400-2404.2004.
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ABSTRACT Mycobacterium tuberculosis possesses agonists for several Toll-like receptors (TLRs), yet mice with single TLR deletions are resistant to acute tuberculosis. MyD88−/− mice were used to examine whether TLRs play any role in protection against aerogenic M. tuberculosis H37Rv infection. MyD88−/− mice failed to control mycobacterial replication and rapidly succumbed. Moreover, expressions of interleukin 12, tumor necrosis factor alpha, gamma interferon, and nitric oxide synthase 2 were markedly decreased in the knockout animals. These results argue that resistance to M. tuberculosis must depend on MyD88-dependent signals mediated by an as-yet-undetermined TLR or a combination of TLRs.
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Muramatsu, Matthew K., Julie A. Brothwell, Barry D. Stein, Timothy E. Putman, Daniel D. Rockey, and David E. Nelson. "Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation." Infection and Immunity 84, no. 10 (July 18, 2016): 2791–801. http://dx.doi.org/10.1128/iai.00356-16.
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Chlamydia trachomatiscan enter a viable but nonculturable statein vitrotermed persistence. A common feature ofC. trachomatispersistence models is that reticulate bodies fail to divide and make few infectious progeny until the persistence-inducing stressor is removed. One model of persistence that has relevance to human disease involves tryptophan limitation mediated by the host enzyme indoleamine 2,3-dioxygenase, which convertsl-tryptophan toN-formylkynurenine. GenitalC. trachomatisstrains can counter tryptophan limitation because they encode a tryptophan-synthesizing enzyme. Tryptophan synthase is the only enzyme that has been confirmed to play a role in interferon gamma (IFN-γ)-induced persistence, although profound changes in chlamydial physiology and gene expression occur in the presence of persistence-inducing stressors. Thus, we screened a population of mutagenizedC. trachomatisstrains for mutants that failed to reactivate from IFN-γ-induced persistence. Six mutants were identified, and the mutations linked to the persistence phenotype in three of these were successfully mapped. One mutant had a missense mutation in tryptophan synthase; however, this mutant behaved differently from previously described synthase null mutants. Two hypothetical genes of unknown function,ctl0225andctl0694, were also identified and may be involved in amino acid transport and DNA damage repair, respectively. Our results indicate thatC. trachomatisutilizes functionally diverse genes to mediate survival during and reactivation from persistence in HeLa cells.
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Richer, Ernest. "Des enfants qui comprennent le fonctionnement de leur langue." Revue des sciences de l'éducation 4, no. 3 (October 9, 2009): 355–64. http://dx.doi.org/10.7202/900084ar.
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Depuis quelques décennies, presque toutes les disciplines scolaires ont subi des transformations en profondeur : dans l’enseignement de la langue française, pourtant, aucun changement radical n’a été opéré. Dans certaines classes de niveaux élémentaire et secondaire de la région du Saguenay, on enseigne la langue française selon une méthode d’analyse syntaxique fondée sur la linguistique structurale et destinée à simplifier, tout à la fois, et à purifier l’enseignement de notre langue. Dans cette formule pédagogique, on est très attentif à faire le départ entre les éléments qui constituent la langue (matière de la syntaxe) et les messages véhiculés par les divers énoncés possibles en français (matière de la sémantique). L’enseignement tout entier de la langue est rapporté aux données syntaxiques, qui se réduisent à six pièces réparables en cinq structures. La classe de français se révèle, dans ces conditions, une expérience agréable, voire attendue par les enfants, et notre langue y apparaît comme une réalité facile à saisir et à manipuler en raison d’un étiquetage fort réduit et du recours constant à l’observation et à la reconnaissance des faits de la langue.
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Tang, Fu-Lei, Jing Wang, Yukata Itokazu, and Robert K. Yu. "Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice." ASN Neuro 12 (January 2020): 175909142093817. http://dx.doi.org/10.1177/1759091420938175.
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Ganglioside GM3 synthase (α-2,3-sialyltransferase, ST3GAL5, GM3S) is a key enzyme involved in the biosynthesis of gangliosides. ST3GAL5 deficiency causes an absence of GM3 and all downstream biosynthetic derivatives. The affected individuals manifest deafness, severe irritability, intractable seizures, and profound intellectual disability. To investigate whether deficiency of GM3 is involved in seizure susceptibility, we induced seizures with different chemoconvulsants in ST3GAL5 knockout mice. We report here that ST3GAL5 knockout mice are hyperactive and more susceptible to seizures induced by chemoconvulsants, including kainate and pilocarpine, compared with normal controls. In the hippocampal dentate gyrus, loss of GM3 aggravates seizure-induced aberrant neurogenesis. These data indicate that GM3 and gangliosides derived from GM3 may serve as important regulators of epilepsy and may play an important role in aberrant neurogenesis associated with seizures.
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BOBB, SUSAN C., and NORIKO HOSHINO. "Fusing languages in the bilingual cognitive architecture." Bilingualism: Language and Cognition 19, no. 5 (February 11, 2016): 879–80. http://dx.doi.org/10.1017/s1366728916000109.
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Research on bilingualism has documented profound brain plasticity by which the bilingual experience reconfigures the cognitive system. These effects include temporary as well as more enduring ones, and parallel activation of a bilingual's two languages may well be a key factor at the root of these observed changes. Recent recommendations (Green, 2011) have emphasized that research on code-switching in particular could provide a fruitful avenue for investigating the nature of how a bilingual speaker selects words and ultimately produces an utterance. Findings to date illustrate that if anything, the reach of co-activation is more extensive than previously thought, extending to the phonology and syntax of languages. While the degree of permeability may compound the perceived difficulty of the selection process, it is also a testament to the documented mental agility of bilinguals.
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Bitsi, Stavroula, Houda Ali, Lauren Maskell, Samir Ounzain, Vidya Mohamed-Ali, and Vishwanie S. Budhram-Mahadeo. "Profound hyperglycemia in knockout mutant mice identifies novel function for POU4F2/Brn-3b in regulating metabolic processes." American Journal of Physiology-Endocrinology and Metabolism 310, no. 5 (March 1, 2016): E303—E312. http://dx.doi.org/10.1152/ajpendo.00211.2015.
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The POU4F2/Brn-3b transcription factor has been identified as a potentially novel regulator of key metabolic processes. Loss of this protein in Brn-3b knockout (KO) mice causes profound hyperglycemia and insulin resistance (IR), normally associated with type 2 diabetes (T2D), whereas Brn-3b is reduced in tissues taken from obese mice fed on high-fat diets (HFD), which also develop hyperglycemia and IR. Furthermore, studies in C2C12 myocytes show that Brn-3b mRNA and proteins are induced by glucose but inhibited by insulin, suggesting that this protein is itself highly regulated in responsive cells. Analysis of differential gene expression in skeletal muscle from Brn-3b KO mice showed changes in genes that are implicated in T2D such as increased glycogen synthase kinase-3β and reduced GLUT4 glucose transporter. The GLUT4 gene promoter contains multiple Brn-3b binding sites and is directly transactivated by this transcription factor in cotransfection assays, whereas chromatin immunoprecipitation assays confirm that Brn-3b binds to this promoter in vivo. In addition, correlation between GLUT4 and Brn-3b in KO tissues or in C2C12 cells strongly supports a close association between Brn-3b levels and GLUT4 expression. Since Brn-3b is regulated by metabolites and insulin, this may provide a mechanism for controlling key genes that are required for normal metabolic processes in insulin-responsive tissues and its loss may contribute to abnormal glucose uptake.
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Botica, Aurelian. "Philo of Alexandria and the Epistle to the Hebrews on the Concept of the Spiritualization of the Cult." Perichoresis 21, s1 (March 1, 2023): 40–66. http://dx.doi.org/10.2478/perc-2023-0009.
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Abstract The Epistle to the Hebrews contains one of the most unique Greek lexicology and syntax of all the New Testament writings. Behind syntax, however, there lies a very profound theological vision on topics such as Christ, Temple, holiness, perseverance and salvation. Studying Hebrews against the background of Graeco-Roman culture, the source that most contemporary scholars mention as being closest to the world of Hebrews in this context is Philo of Alexandria. Not only on philological grounds, but also in matters of methods of interpreting the Old Testament cult and in theology, Hebrews and Philo share a very common background. Analyzing the Epistle to the Hebrews comparatively, we are bound to ask whether or not comparsions such as these are warranted. In the following study we will state the state of the problem and then will examine the two sources that seem to have served as a source of inspiration for the author of Hebrews: the Old Testament and Philo of Alexandria. We will focus exclusively on the issues of the method of allegory and the spiritualization/reinterpretation of Old Testament cultic entities, since both Philo and Hebrews are characterized by these concerns. In essence, we will want to know who or what served as the most plausible source of inspiration for the author of Hebrews in the particular area of the reinterpretation of the Old Testament cult.
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Ichord, R. N., M. A. Helfaer, J. R. Kirsch, D. Wilson, and R. J. Traystman. "Nitric oxide synthase inhibition attenuates hypoglycemic cerebral hyperemia in piglets." American Journal of Physiology-Heart and Circulatory Physiology 266, no. 3 (March 1, 1994): H1062—H1068. http://dx.doi.org/10.1152/ajpheart.1994.266.3.h1062.
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We tested the hypothesis that nitric oxide (NO) mediates hypoglycemia-induced cerebral vasodilation in piglets. Piglets (1-2 wk old) were made hypoglycemic with insulin (200 U/kg i.v.) with and without an NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg i.v.). Electroencephalogram (EEG), cerebral O2 consumption (CMRO2), and cerebral blood flow (CBF) were measured before L-NAME and insulin and for 180 min after insulin. Hypoglycemia led to isoelectric EEG earlier after L-NAME (87 +/- 8 min) than without L-NAME pretreatment (132 +/- 13 min). CBF increased in all brain regions during hypoglycemia at the onset of isoelectric EEG and was associated with increased CMRO2.L-NAME prevented the increase in CMRO2 and attenuated vasodilation in forebrain (154 +/- 37 vs. 400 +/- 60%), cerebellum (251 +/- 52 vs. 386 +/- 52%), and cortical gray matter (183 +/- 47 vs. 524 +/- 93%) but had no effect on CBF responses in brain stem, thalamus, caudate, or hippocampus. We conclude that NO or a NO-containing compound mediates cerebral vasodilation induced by profound insulin-hypoglycemia in piglets and that this vasodilation plays an important role in the adaptation of immature brain to hypoglycemia.
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Franić, Ivana. "From metataxis to linguistic mediation: the forgotten structure?" Linguistica 54, no. 1 (December 31, 2014): 411–24. http://dx.doi.org/10.4312/linguistica.54.1.411-424.
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In his capital work Eléments de syntaxe structurale (1959) Lucien Tesnière introduces the concept of metataxis, structural change occurring during the transition from one language to another. While focusing on structural relationships that are built upon this passage, the author highlights the need to rethink the phrase in the target language. Departing from a purely mechanical perspective, Tesnière paves the way for contrastive analysis, but also for cognitive theories, referring to the concepts of traductions profondes and of the independence of structure and meaning.However, the action-oriented approach presupposes a dynamic process of learning / teaching that places the learner at the center and takes into account all the abilities of this “social actor”. In that way the CEFR opens the individual and social dimensions of mediation (Piccardo 2012), which is one of the key concepts of the action-oriented approach.In this paper we outline the conceptual foundations of metataxis and linguistic mediation and then examine the role of translation as the basic operation for the transition from one language to another, specifically in the learner-centred action-oriented approach. We rethink the concept of translation, taking into account its mechanical and structural aspects as well as its individual and social dimensions, which offers many opportunities for language and culture learning. The linguistic structure is considered as an essential component of linguistic mediation.
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Yadav, Meenakshi Sharma, Kahkasha Moin Quadri, and Manoj Kumar Yadav. "Semantic and Thematic Aspects in the Carrion Comfort by Gerard Manley Hopkins." International Journal of Linguistics and Translation Studies 3, no. 3 (September 12, 2022): 146–61. http://dx.doi.org/10.36892/ijlts.v3i3.264.
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Gerard Manley Hopkins sought a stronger rhetorical style in verse-sprung rhythm for the shape, sound, and sense of Carrion Comfort. The poet shows a sense of desolation produced partly by spiritual aridity and partly by a feeling of artistic frustration. The poem reveals strong tensions between his delight in the sensuous world, his urge to express it, and his equally powerful sense of religious vocation in the sonnet. This sonnet is enriched with the vivid use of echo figures of speech, alliteration, repetition, and a highly compressed syntax to project profound personal experiences, including his sense of God’s mystery, grandeur, and mercy in the energizing prosodic element of his verse sprung rhythm, in which each foot may consist of one stressed syllable and any number of unstressed syllables instead of the regular number of syllables used in the traditional meter. Despair and dejection play a prominent role in displaying the writer’s semantic point of view. The tone of the octave and sestet differ drastically in aspects. Initially, the tone is full of distress, while later, the technique is cheerful. This research attempt will seek answers to how the poem's mode and structure dramatize the speaker's exchange with his interiority and the exterior world? What is the effect of the variations in syntax reflecting a claustrophobic interior consciousness? Therefore, this paper explores the semantic and thematic aspects of the sonnet successfully, keeping in mind the poem's thematic aspects and perspectives.
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Ulianitckaia, Liubov. "The French Flemish dialect in the context of language situation of Belgium and France." Scandinavian Philology 19, no. 2 (2021): 336–46. http://dx.doi.org/10.21638/11701/spbu21.2021.207.
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This article addresses the historical language variants of Flanders, spoken both within and outside the region. The linguistic diversity of officially Dutch-speaking Flanders is represented by Limburgish, West Flemish, Brabantian, and East Flemish dialects, with Limburgish and West Flemish being entitled to the status of a distinct language. (Limburgish is recognized as a regional language in the Netherlands.) This paper reviews some sociolinguistic and political features of Flanders, acknowledging the area of West Flemish dialect group use. Special emphasis is placed on the French Flemish dialect, present in the territories of France and Belgium. This dialect is one of the most archaic West Flemish dialects that suffered a profound impact from French and other neighboring languages. The lexical and grammatical features of French Flemish are examined. It is noted that code switching is common for the French Flemish dialect. Some of the French Flemish syntax features related to the antecedent phenomena are explained via the binomiality idea, that states any verbal or substantive part of a sentence be composed of two parts, the first of which can be modified. Some syntax phenomena of French Flemish could be the result of grammatical interference between the West Flemish dialect and the French language. The paper also touches on the French Flemish support actions taken by France and Belgium, and discusses French Flemish seceding from West Flemish dialect group and acquiring a special status, that could be a status of a distinct language.
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Benonguil, John Achileeus, and Jerlyn Balones. "Cross-Linguistic Structural Priming on the Lexico-Syntactic Representations of Cebuano-English Bilinguals." Journal of English Language Teaching and Applied Linguistics 5, no. 1 (March 16, 2023): 68–90. http://dx.doi.org/10.32996/jeltal.2023.5.1.9.
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The effect of previously processed grammatical structure on its subsequent production is referred to as structural priming to explore syntax representations in bilingual brains. This psycholinguistic inquiry investigated the active-passive alternation syntactic category and whether bilingual representations of the first language (Cebuano) and second language (English) are more integrated considering the L2 proficiency. This study conducted two structural priming experiments on 60 Cebuano-English bilinguals from a randomized population exposed to a prime type with verb type manipulation. Research subjects formed their responses concerning the target response drawings. Responses were classified as active, passive, and other to assess priming effects. Additionally, this study followed the mixed between-and-within-subjects design. Priming effects were established in the two studies using the mixed-effects logistic regression analysis. Cross-linguistic priming was found in Study 1 (English to Cebuano) in both verb types with a p-value of (< .001). However, cross-linguistic priming was not found in Study 2 (Cebuano to English) in both verb types with a p-value of (0.242). Active utterances were profound in both studies rather than passive structures. The L2 proficiency of the research subjects was statistically significant in Study 1 and not significant in Study 2. This further means that second language proficiency affects Cebuano language production more than English. With the greater likelihood of active utterances, research subjects have not integrated the syntax of both languages, mainly attributed to different language experiences, constituent word order, and unbalanced bilingual proficiency capabilities.
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McAllister, R. M., I. Albarracin, E. M. Price, T. K. Smith, J. R. Turk, and K. D. Wyatt. "Thyroid status and nitric oxide in rat arterial vessels." Journal of Endocrinology 185, no. 1 (April 2005): 111–19. http://dx.doi.org/10.1677/joe.1.06022.
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Thyroid disease has profound effects on cardiovascular function. Hypo- and hyperthyroidism, for example, are associated with reduced and increased maximal endothelium-dependent vasodilation respectively. We therefore hypothesized that the capacity for vascular nitric oxide (NO) formation is decreased in hypothyroidism and increased in hyperthyroidism. To test this hypothesis, rats were made hypothyroid (HYPO) with propylthiouracil or hyperthyroid (HYPER) with triiodothyronine over 3–4 months. Compared with euthyroid control rats (EUT), HYPO exhibited blunted growth and lower citrate synthase activity in the soleus muscle; HYPER exhibited left ventricular hypertrophy and higher citrate synthase activity in the soleus muscle (P<0.05 for all effects). The capacity for NO formation was determined in aortic extracts by formation of [3H]l-citrulline from [3H]l-arginine, i.e. NO synthase (NOS) activity. Thyroid status modulated NOS activity (EUT, 36.8 ± 5.5 fmol/h per mg protein; HYPO, 26.0 ± 7.9; HYPER, 64.6 ± 12.7; P<0.05, HYPER vs HYPO). Expression of endothelial and neural isoforms of NOS was modulated by thyroid status in a parallel fashion. Capacity for responding to NO was also determined via measuring cGMP concentration in aortae incubated with sodium nitroprusside. Stimulated cGMP formation was also modulated by thyroid status (EUT, 73.0 ± 20.2 pmol/mg protein; HYPO, 152.4 ± 48.7; HYPER, 10.4 ± 2.6; P<0.05, HYPER vs HYPO). These data indicate that thyroid status alters capacities for both formation of and responding to NO. The former finding may contribute to previous findings concerning vascular function in thyroid disease states.
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Teycheney, Pierre-Yves, and Mark Tepfer. "Virus-specific spatial differences in the interference with silencing of the chs-A gene in non-transgenic petunia." Journal of General Virology 82, no. 5 (May 1, 2001): 1239–43. http://dx.doi.org/10.1099/0022-1317-82-5-1239.
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Potyviruses, such as potato virus Y and tobacco etch virus, as well as cucumber mosaic cucumovirus, interfere with post-transcriptional gene silencing (PTGS). When RedStar-type Petunia hybrida cultivars, whose flowers have alternating white and pigmented sectors, were infected with these viruses, each virus induced a different pattern of restoration of floral anthocyanin pigmentation. Local reversion to coloured phenotypes in the white sectors, which occurred through interference with PTGS of the chalcone synthase A (chs-A) gene, was correlated with locally increased levels of chs-A mRNA and virus concentration. Our results show that virus infection can interfere with PTGS of a native plant gene, and that this can have profound effects on symptom expression.
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Kang, Justin J., Liming Shu, James L. Park, James A. Shayman, and Peter F. Bodary. "Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A." American Journal of Physiology-Gastrointestinal and Liver Physiology 306, no. 2 (January 15, 2014): G140—G146. http://dx.doi.org/10.1152/ajpgi.00185.2013.
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A defect in the gene for the lysosomal enzyme α-galactosidase A (Gla) results in globotriaosylceramide (Gb3) accumulation in Fabry disease and leads to premature death from cardiac and cerebrovascular events. However, gastrointestinal symptoms are often first observed during childhood in these patients and are not well understood. In this study, we demonstrate an age-dependent microvasculopathy of the mesenteric artery (MA) in a murine model of Fabry disease (Gla-knockout mice) resulting from dysregulation of the vascular homeostatic enzyme endothelial nitric oxide synthase (eNOS). The progressive accumulation of Gb3 in the MA was confirmed by thin-layer chromatographic analysis. A total absence of endothelium-dependent dilation was observed in MAs from mice at 8 mo of age, while suppression of ACh-mediated vasodilation was evident from 2 mo of age. Endothelium-independent dilation with sodium nitroprusside was normal compared with age-matched wild-type mice. The microvascular defect in MAs from Fabry mice was endothelium-dependent and associated with suppression of the active homodimer of eNOS. Phosphorylation of eNOS at the major activation site (Ser1179) was significantly downregulated, while phosphorylation at the major inhibitory site (Thr495) was remarkably enhanced in MAs from aged Fabry mice. These profound alterations in eNOS bioavailability at 8 mo of age were observed in parallel with high levels of 3-nitrotyrosine, suggesting increased reactive oxygen species along with eNOS uncoupling in this vascular bed. Overall, the mesenteric microvessels in the setting of Fabry disease were observed to have an early and profound endothelial dysfunction associated with elevated reactive nitrogen species and decreased nitric oxide bioavailability.
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Cannon, Joanna E., Anita M. Hubley, Julia I. O’Loughlin, Lauren Phelan, Nancy Norman, and Alayna Finley. "A Technology-based Intervention to Increase Reading Comprehension of Morphosyntax Structures." Journal of Deaf Studies and Deaf Education 25, no. 1 (August 9, 2019): 126–39. http://dx.doi.org/10.1093/deafed/enz029.
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Abstract The purpose of this study was to examine the effectiveness of a technology-based intervention (LanguageLinks: Syntax Assessment and Intervention®; Laureate Learning Systems, Inc., 2013) to improve reading comprehension for d/Deaf and hard of hearing (DHH) elementary students. The intervention was a self-paced, interactive program designed to scaffold learning of morphosyntax structures. Participants included 37 DHH students with moderate to profound hearing levels, 7–12 years of age, in Grades 2–6. Assessment data were collected pre- and post- an 8-week intervention using a randomized control trial methodology. Findings indicate the intervention did not appear to be effective in improving performance, and 17 out of 36 morphosyntax structures were found difficult to comprehend for participants in the treatment group. These difficult structures included aspects of pronominalization, the verbal system, and number in nouns. Results are compared to previous research, with recommendations for future areas of research related to increasing knowledge of morphosyntax for learners who are DHH.
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Henry, Anne C. ""Explorations in Dot-and-Dashland": George Meredith's Aphasia." Nineteenth-Century Literature 61, no. 3 (December 1, 2006): 311–42. http://dx.doi.org/10.1525/ncl.2006.61.3.311.
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George Meredith's writing is notorious for its "obscurity." This essay examines that obscurity through the punctuation that Meredith employed, in particular his use of ellipsis marks. Throughout his novelistic career Meredith attempted to capture the nebulousness of both thought and speech by means of a difficult and elliptical syntax and by using the punctuation of ellipsis: dashes and suspension points (though the latter are more commonly associated with later,modernist writers). This essay addresses Meredith's fascination with the unarticulated and inarticulate, as well as his attitudes toward transcription. His 1881 novel The Tragic Comedians is of particular importance in this analysis, as there he traced explicitly one of his character's "explorations in Dot-and-Dashland."The revisions that Meredith made to the manuscript of The Tragic Comedians underline his profound commitment to scrutiny and criticism of that which is obscure in our experiences and interactions, however his detractors used this against him.
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Russell-Goldman, Eleanor, Jiayong Xu, Xiaobing Wang, John Chan, and JoAnn M. Tufariello. "A Mycobacterium tuberculosis Rpf Double-Knockout Strain Exhibits Profound Defects in Reactivation from Chronic Tuberculosis and Innate Immunity Phenotypes." Infection and Immunity 76, no. 9 (June 30, 2008): 4269–81. http://dx.doi.org/10.1128/iai.01735-07.
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ABSTRACT Resuscitation-promoting factors (Rpfs), apparent peptidoglycan hydrolases, have been implicated in the reactivation of dormant bacteria. We previously demonstrated that deletion of rpfB impaired reactivation of Mycobacterium tuberculosis in a mouse model. Because M. tuberculosis encodes five Rpf paralogues, redundant functions among the family members might obscure rpf single-knockout phenotypes. A series of rpf double knockouts were therefore generated. One double mutant, ΔrpfAB, exhibited several striking phenotypes. Consistent with the proposed cell wall-modifying function of Rpfs, ΔrpfAB exhibited an altered colony morphology. Although ΔrpfAB grew comparably to the parental strain in axenic culture, in vivo it exhibited deficiency in reactivation induced in C57BL/6 mice by the administration of nitric oxide synthase inhibitor (aminoguanidine) or by CD4+ T-cell depletion. Notably, the reactivation deficiency of ΔrpfAB was more severe than that of ΔrpfB in aminoguanidine-treated mice. A similar deficiency was observed in ΔrpfAB reactivation from a drug-induced apparently sterile state in infected NOS2−/− mice upon cessation of antimycobacterial therapy. Secondly, ΔrpfAB showed a persistence defect not seen with the ΔrpfB or ΔrpfA single mutants. Interestingly, ΔrpfAB exhibited impaired growth in primary mouse macrophages and induced higher levels of the proinflammatory cytokines tumor necrosis factor alpha and interleukin 6. Simultaneous reintroduction of rpfA and rpfB into the double-knockout strain complemented the colony morphology and macrophage cytokine secretion phenotypes. Phenotypes related to cell wall composition and macrophage responses suggest that M. tuberculosis Rpfs may influence the outcome of reactivation, in part, by modulating innate immune responses to the bacterium.
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Abdulkareem, Angham Abdulrhman, Bader H. Shirah, and Muhammad Imran Naseer. "Whole Exome Sequencing Reveals a Novel Homozygous Variant in the Ganglioside Biosynthetic Enzyme, ST3GAL5 Gene in a Saudi Family Causing Salt and Pepper Syndrome." Genes 14, no. 2 (January 30, 2023): 354. http://dx.doi.org/10.3390/genes14020354.
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Salt and pepper developmental regression syndrome (SPDRS) is an autosomal recessive disorder characterized by epilepsy, profound intellectual disability, choreoathetosis, scoliosis, and dermal pigmentation along with dysmorphic facial features. GM3 synthase deficiency is due to any pathogenic mutation in the ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 5 (ST3GAL5) gene, which encodes the sialyltransferase enzyme that synthesizes ganglioside GM3. In this study, the Whole Exome Sequencing (WES) results presented a novel homozygous pathogenic variant, NM_003896.3:c.221T>A (p.Val74Glu), in the exon 3 of the ST3GAL5 gene. causing SPDRS with epilepsy, short stature, speech delay, and developmental delay in all three affected members of the same Saudi family. The results of the WES sequencing were further validated using Sanger sequencing analysis. For the first time, we are reporting SPDRS in a Saudi family showing phenotypic features similar to other reported cases. This study further adds to the literature and explains the role of the ST3GAL5 gene, which plays an important role, and any pathogenic variants that may cause the GM3 synthase deficiency that leads to the disease. This study would finally enable the creation of a database of the disease that provides a base for understanding the important and critical genomic regions that will help control intellectual disability and epilepsy in Saudi patients.
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Pardee, Timothy, Jamie Jennings-Gee, Peter Alexander, and William Gmeiner. "Thymidylate Synthase Inhibition with the Novel Fluoropyrimidine FdUMP[10] Is Highly Effective Against Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 1505. http://dx.doi.org/10.1182/blood.v120.21.1505.1505.
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Abstract Abstract 1505 Despite significant improvements in cure rates in pediatric patients, outcomes in adults with acute lymphoblastic leukemia (ALL) remain dismal with an estimated 5-year survival of less than 10% for patients over the age of 60. Compared to children, ALL in adults is characterized by an increased incidence of poor prognostic cytogenetics, lower complete remission rates, and higher relapse rates. Once relapse occurs in adults, the outcome is truly dismal, with a 6% salvage rate with current therapies. Initial treatment of ALL combines essentially all currently used agents, leaving very few therapies once relapse occurs. There is a clear need for better therapeutic options for these patients. 5-Fluorouracil (5-FU) is a fluoropyrimidine (FP) prodrug that must first be converted to 5-fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP) in order to inhibit thymidylate synthase (TS) and shut down tumor thymidine synthesis. It can also be metabolized to a ribose metabolite that interferes with RNA processing and leads to toxicity in any transcriptionally active cell. The profound GI toxicities of 5-FU and lack of potency against ALL has lead to the abandonment of TS inhibition in the treatment of ALL. In contrast, FdUMP[10] is a oligodeoxynucleotide containing 10 FdUMP moieties linked by phosphodiester bonds. FdUMP[10] has profound activity against preclinical models of acute myeloid leukemia (AML), with minimal toxicities. The human T cell ALL cell line, Jurkat, was extremely sensitive to FdUMP[10], with an IC50of 5.4nM (95% CI 4.609–6.417). We sought to determine the activity of FdUMP[10] against additional preclinical ALL models. In vitro, FdUMP[10] exhibited remarkable activity against the human T and B Cell ALL cell lines, DG75, Molt-4, CCRF-CEM, and SUP-B15 with an average IC50 value of 1.83nM (Range 0.21–4.1nM). In two murine ALL cell lines driven by expression of BCR-ABL, FdUMP[10] exhibited even greater activity, with an average IC50 value of 0.662nM (range 0.125–1.2nM). For comparison we also tested 5-FU and cytarabine in the same assay against DG75, MOLT-4 and a BCR-ABL driven murine line. In all cases FdUMP[10] was the most potent agent and was more than 1000 times more potent than 5-FU despite having only 10 times the FP content. In vivo, FdUMP[10] treatment provided a statistically significant increase in survival in a BCR-ABL driven, syngeneic ALL mouse model (p=0.0002 by log rank test). In a separately derived syngeneic model expressing the T315I variant of BCR-ABL, treatment with FdUMP[10] significantly prolonged survival (p=0.0013). In AML models exposure to FdUMP[10] resulted in apoptosis. To assess if ALL cells undergo a similar apoptotic response we exposed human and mouse ALL cells to FdUMP[10] and assessed for apoptosis induction via propidium iodide (PI) and Annexin V staining. As we found previously in AML models, FdUMP[10] exposure resulted in a robust induction of Annexin V and PI staining consistent with an apoptotic response. The level of apoptosis with FdUMP[10] could not be reproduced by 5-FU even when used at 100 times higher concentration. To determine the effect of FdUMP[10] on thymidylate synthase (TS) activity in ALL, Jurkat cells were exposed to 10nM FdUMP[10] or 100nM 5- FU and TS activity was assayed. We found a profound and prolonged inhibition with FdUMP[10] compared to 5-FU, despite the identical amount of fluoropyrimidine. FdUMP[10] is synergistic with doxorubicin and cytarabine in AML models. To assess whether FdUMP[10] could synergize with targeted therapy in ALL, Baf-3 cells expressing BCR-ABL were exposed to the tyrosine kinase inhibitor nilotinib plus FdUMP[10]. The combination was synergistic, with combinatory index values of 0.7113 to 0.4803. In preliminary data in vivo, the combination of FdUMP[10] and nilotinib resulted in a greater reduction in leukemic burden then nilotinib alone. In summary, FdUMP[10] exhibited remarkable activity against human and murine ALL cells in vitro and in vivo by inducing apoptosis and profound TS inhibition, and showing a synergistic benefit when combined with nilotinib. These data demonstrate that TS is a valid target in ALL cells. This fact combined with previous studies demonstrating a favorable toxicity profile, make FdUMP[10] a promising candidate for treatment of ALL. Disclosures: Pardee: Salzburg Therapuetics: Membership on an entity's Board of Directors or advisory committees. Gmeiner:Salzburg Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Upmacis, Rita K., Mark J. Crabtree, Ruba S. Deeb, Hao Shen, Paul B. Lane, Lea Esther S. Benguigui, Nobuyo Maeda, David P. Hajjar, and Steven S. Gross. "Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 5 (November 2007): H2878—H2887. http://dx.doi.org/10.1152/ajpheart.01144.2006.
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Diminished nitric oxide (NO) bioactivity and enhanced peroxynitrite formation have been implicated as major contributors to atherosclerotic vascular dysfunctions. Hallmark reactions of peroxynitrite include the accumulation of 3-nitrotyrosine (3-NT) in proteins and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH4). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH4 becomes oxidized in organs of apolipoprotein E-deficient (ApoE−/−) atherosclerotic mice and 2) determine the specific contribution of inducible NOS (iNOS) to these processes. Whereas protein 3-NT and oxidized BH4 were undetected or near the detection limit in heart, lung, and kidney of 3-wk-old ApoE−/− mice or ApoE−/− mice fed a regular chow diet for 24 wk, robust accumulation was evident after 24 wk on a Western (atherogenic) diet. Since 3-NT accumulation was diminished 3- to 20-fold in heart, lung, and liver in ApoE−/− mice missing iNOS, iNOS-derived species are involved in this reaction. In contrast, iNOS-derived species did not contribute to elevated protein 3-NT formation in kidney or brain. iNOS deletion also afforded marked protection against BH4 oxidation in heart, lung, and kidney of atherogenic ApoE−/− mice but not in brain or liver. These findings demonstrate that iNOS-derived species are increased during atherogenesis in ApoE−/− mice and that these species differentially contribute to protein 3-NT accumulation and BH4 oxidation in a tissue-selective manner. Since BH4 oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions.
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Suzuki, Hideyuki, Hiroyuki Ikezaki, Rinku Chandiwala, Dennis Hong, and Israel Rubinstein. "Effects ofPseudomonas aeruginosaendotoxin on vasodilation in the intact spinotrapezius muscle." Journal of Applied Physiology 91, no. 1 (July 1, 2001): 351–56. http://dx.doi.org/10.1152/jappl.2001.91.1.351.
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The purpose of this study was to determine whether short-term exposure to clinically relevant concentrations of Pseudomonas aeruginosa lipopolysaccharide (LPS) impairs vasoreactivity of resistance arterioles in the intact spinotrapezius muscle microcirculation and, if so, to determine the mechanisms mediating this response. Using intravital microscopy, we found that 60-min suffusion of P. aeruginosa LPS (0.03–3.0 μg/ml) on the in situ hamster spinotrapezius muscle elicited an immediate, profound, and prolonged concentration-dependent vasodilation ( P < 0.05). This response was reversible once suffusion of P. aeruginosa LPS was stopped. Pretreatment with NG-nitro-l-arginine methyl ester (10.0 μM), a nonselective nitric oxide (NO) synthase inhibitor, but not NG-nitro-d-arginine methyl ester, abrogated P. aeruginosa LPS-induced vasodilation and elicited a small, albeit significant, vasoconstriction. Indomethacin had no significant effects on P. aeruginosa LPS-induced responses. P. aeruginosa LPS had no significant effects on acetylcholine- and nitroglycerin-induced vasodilation in the spinotrapezius muscle. Collectively, these data indicate that short-term exposure to clinically relevant concentrations of P. aeruginosa LPS evokes an immediate, potent, prolonged, and reversible NO-dependent, prostaglandin-independent vasodilation in skeletal muscles in vivo. We suggest this response could play an important role in the pathophysiology of the profound vasomotor dysfunction observed in the peripheral circulation of patients with P. aeruginosa sepsis syndrome.
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Md Amin, Mohamed Eusuff. "Locating Logic Faculty in the Mental System." Journal of Cognitive Sciences and Human Development 8, no. 2 (September 29, 2022): 157–69. http://dx.doi.org/10.33736/jcshd.4533.2022.
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Taken from Chomsky’s Knowledge of Language (1986), it is noted that logical form (LF) is not a direct reflection of deep structure (D-structure). It has induced a question, where is then 'logic' located in the human psychology (in the sense of the mind-system) if it is not in the D-structure. To answer this question, we will try to see how different languages (in this paper, English, Malay and Turkish) are structured differently on the surface (S-structure) yet can have the same internal syntax (D-structure). However, when there is a change in semantics (in the sense of intended meaning), a change in LF is noted, although the D-structure might remain the same. Making sense of this, we argue that D-structure is not the innermost faculty of the human innate system (mind) but rather, how S-structure is to D-structure, that is how D-structure is to the human logic faculty. In other words, with D-structure, logic faculty is more profound.
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Esteban, Avelino Corral. "A Study of DOM in Asturian (‘Dialectu Vaqueiru’)." Journal of Language Contact 13, no. 1 (June 25, 2020): 96–140. http://dx.doi.org/10.1163/19552629-bja10004.
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The present paper explores Differential Object Marking in a variety of Asturian (Western Iberian Romance) spoken in western Asturias (northwestern Spain). This ancestral form of speech stands out from Central Asturian and especially from Standard Spanish. For a number of reasons, ranging from profound changes in pronunciation, vocabulary, morphology and information structure to slight but very relevant effects on syntax. The main goal of this study is to examine the special marking of direct objects in order to find out what triggers the distribution of Differential Object Marking in this variety. To this aim, this paper will examine, from a variationist perspective, the influence of a number of semantic and discourse-pragmatic parameters on the marking of direct objects in this Western Asturian language as well as in Standard Spanish 1 and Central Asturian (which is generally considered the normative variety of Asturian). The results obtained from this comparison will allow us to outline the differences between these three varieties in terms of object marking, shedding more light on the origin and function of Differential Object Marking in Spanish.
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CHEN, ZHENGXIN. "DATABASE KEYWORD SEARCH: BEYOND ITS CURRENT LANDSCAPE." International Journal of Information Technology & Decision Making 11, no. 02 (March 2012): 491–500. http://dx.doi.org/10.1142/s0219622012400123.
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As an active research field, database keyword search (KWS) has put much emphasis on the performance issues, due to its high computational cost. However, a closer examination on KWS reveals that there are some other interesting aspects worth noting. In this paper, we examine KWS from a broader perspective, analyzing its profound implications. Freed from syntax-related considerations, KWS users now have better opportunities to explore the data in the way as they wish, and such exploration may reveal useful hindsight for understanding the hidden nature of the data, thus benefiting the exploitation on the use of the data. In particular, we examine the potential of KWS to data mining from the behavior mining perspective. This examination also leads us to a discussion of viewing KWS in the "web of life" context. We further discuss connections of KWS with other related concepts, including dataspace. Based on our findings and critical examination, we also provide a brief overview of an integrated environment which facilitates the interplay of KWS and data mining.
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Mys, L. A., N. A. Strutynska, Y. V. Goshovska, and V. F. Sagach. "Stimulation of the endogenous hydrogen sulfide synthesis suppresses oxidative–nitrosative stress and restores endothelial-dependent vasorelaxation in old rats." Canadian Journal of Physiology and Pharmacology 98, no. 5 (May 2020): 275–81. http://dx.doi.org/10.1139/cjpp-2019-0411.
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Hydrogen sulfide (H2S) is an endogenous gas transmitter with profound effects on the cardiovascular system. We hypothesized that stimulation of H2S synthesis might alleviate age-associated changes in vascular reactivity. Pyridoxal-5-phosphate (PLP), the coenzyme of H2S-synthesizing enzymes, was administrated to old male Wistar rats per os at a dose of 0.7 mg/kg body mass once a day for 2 weeks. H2S content in the aortic tissue, markers of oxidative stress, inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS), arginase activities, and endothelium-dependent vasorelaxation of the aortic rings were studied. Our results showed that PLP restored endogenous H2S and low molecular weight S-nitrosothiol levels in old rat aorta to the levels detected in adults. PLP significantly reduced diene conjugate content, hydrogen peroxide and peroxynitrite generation rates, and iNOS and arginase activity in the aortic tissue of old rats. PLP also greatly improved acetylcholine-induced relaxation of old rat aorta (47.7% ± 4.8% versus 18.4% ± 4.1% in old rats, P < 0.05) that was abolished by NO inhibition with N-nitro-l-arginine methyl ester hydrochloride (L-NAME) or H2S inhibition with O-carboxymethylhydroxylamine (O-CMH). Thus, PLP might be used for stimulation of endogenous H2S synthesis and correction of oxidative and nitrosative stress and vessel tone dysfunction in aging and age-associated diseases.
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Candiracci, Julie, Valerie Migeot, Yok-Hian Chionh, Fanelie Bauer, Thomas Brochier, Brandon Russell, Kazuhiro Shiozaki, Peter Dedon, and Damien Hermand. "Reciprocal regulation of TORC signaling and tRNA modifications by Elongator enforces nutrient-dependent cell fate." Science Advances 5, no. 6 (June 2019): eaav0184. http://dx.doi.org/10.1126/sciadv.aav0184.
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Nutrient availability has a profound impact on cell fate. Upon nitrogen starvation, wild-type fission yeast cells uncouple cell growth from cell division to generate small, round-shaped cells that are competent for sexual differentiation. The TORC1 (TOR complex 1) and TORC2 complexes exert opposite controls on cell growth and cell differentiation, but little is known about how their activity is coordinated. We show that transfer RNA (tRNA) modifications by Elongator are critical for this regulation by promoting the translation of both key components of TORC2 and repressors of TORC1. We further identified the TORC2 pathway as an activator of Elongator by down-regulating a Gsk3 (glycogen synthase kinase 3)–dependent inhibitory phosphorylation of Elongator. Therefore, a feedback control is operating between TOR complex (TORC) signaling and tRNA modification by Elongator to enforce the advancement of mitosis that precedes cell differentiation.
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Everts, Bart, Eyal Amiel, Gerritje J. W. van der Windt, Tori C. Freitas, Robert Chott, Kevin E. Yarasheski, Erika L. Pearce, and Edward J. Pearce. "Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells." Blood 120, no. 7 (August 16, 2012): 1422–31. http://dx.doi.org/10.1182/blood-2012-03-419747.
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Abstract TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte–derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte–derived DCs.
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Ross, Sarah E., Robin L. Erickson, Nahid Hemati, and Ormond A. MacDougald. "Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBPα Kinase." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 8433–41. http://dx.doi.org/10.1128/mcb.19.12.8433.
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ABSTRACT CCAAT/enhancer binding protein α (C/EBPα) is a transcription factor involved in creating and maintaining the adipocyte phenotype. We have shown previously that insulin stimulates dephosphorylation of C/EBPα in 3T3-L1 adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation reveal that a C/EBPα peptide (amino acids H215 to K250) is phosphorylated on T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. Accordingly, GSK3 phosphorylates the predicted region of C/EBPα on threonine in vitro, and GSK3 uses C/EBPα as a substrate in vivo. In addition, the effect of pharmacological agents on GSK3 activity correlates with regulation of C/EBPα phosphorylation. Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPα, whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPα. Collectively, these data indicate that insulin stimulates dephosphorylation of C/EBPα on T222 and T226 through inactivation of GSK3. Since dephosphorylation of C/EBPα in response to lithium is blocked by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease accessibility of widespread sites within the N terminus of C/EBPα, consistent with phosphorylation causing profound conformational changes. Finally, phosphorylation of C/EBPα and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.
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Breland, Luke, Joanna H. Lowenstein, and Susan Nittrouer. "Disparate Oral and Written Language Abilities in Adolescents With Cochlear Implants: Evidence From Narrative Samples." Language, Speech, and Hearing Services in Schools 53, no. 1 (January 5, 2022): 193–212. http://dx.doi.org/10.1044/2021_lshss-21-00062.
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Purpose: In spite of improvements in language outcomes for children with hearing loss (HL) arising from cochlear implants (CIs), these children can falter when it comes to academic achievement, especially in higher grades. Given that writing becomes increasingly relevant to educational pursuits as children progress through school, this study explored the hypothesis that one challenge facing students with CIs may be written language. Method: Participants were 98 eighth graders: 52 with normal hearing (NH) and 46 with severe-to-profound HL who used CIs. Oral and written narratives were elicited and analyzed for morphosyntactic complexity and global narrative features. Five additional measures were collected and analyzed as possible predictors of morphosyntactic complexity: Sentence Comprehension of Syntax, Grammaticality Judgment, Expressive Vocabulary, Forward Digit Span, and Phonological Awareness. Results: For oral narratives, groups performed similarly on both morphosyntactic complexity and global narrative features; for written narratives, critical differences were observed. Compared with adolescents with NH, adolescents with CIs used fewer markers of morphosyntactic complexity and scored lower on several global narrative features in their written narratives. Adolescents with NH outperformed those with CIs on all potential predictor measures, except for Sentence Comprehension of Syntax. Moderately strong relationships were found between predictor variables and individual measures of morphosyntactic complexity, but no comprehensive pattern explained the results. Measures of morphosyntactic complexity and global narrative features were not well correlated, suggesting these measures are assessing separate underlying constructs. Conclusions: Adolescents with CIs fail to show writing proficiency at high school entry equivalent to that of their peers with NH, which could constrain their academic achievement. Interventions for children with CIs need to target writing skills, and writing assessments should be incorporated into diagnostic assessments. Supplemental Material: https://doi.org/10.23641/asha.17139059
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Steinbrecher, Kris A., Willie Wilson, Patricia C. Cogswell, and Albert S. Baldwin. "Glycogen Synthase Kinase 3β Functions To Specify Gene-Specific, NF-κB-Dependent Transcription." Molecular and Cellular Biology 25, no. 19 (October 1, 2005): 8444–55. http://dx.doi.org/10.1128/mcb.25.19.8444-8455.2005.
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ABSTRACT Loss of glycogen synthase kinase 3β (GSK-3β) in mice results in embryonic lethality via hepatocyte apoptosis. Consistent with this result, cells from these mice have diminished nuclear factor κB (NF-κB) activity, implying a functional role for GSK-3β in regulating NF-κB. Here, we have explored mechanisms by which GSK-3β may control NF-κB function. We show that cytokine-induced IκB kinase activity and subsequent phosphorylation of IκBα, p105, and p65 are not affected by the absence of GSK-3β activity. Furthermore, nuclear accumulation of p65 following tumor necrosis factor treatment is unaffected by the loss of GSK-3β. However, NF-κB DNA binding activity is reduced in GSK-3β null cells and in cells treated with a pharmacological inhibitor of GSK-3. Expression of certain NF-κB-regulated genes, such as IκBα and macrophage inflammatory protein 2, is minimally affected by the absence of GSK-3β. Conversely, we have identified a subset of NF-κB-regulated genes, including those for interleukin-6 and monocyte chemoattractant protein 1, that require GSK-3β for efficient expression. We show that efficient localization of p65 to the promoter regions of the interleukin-6 and monocyte chemoattractant protein 1 genes following tumor necrosis factor alpha treatment requires GSK-3β. Therefore, GSK-3β has profound effects on transcription in a gene-specific manner through a mechanism involving control of promoter-specific recruitment of NF-κB.