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991.
Lu Z Napolitano JB Theberge A Ali A Hammond ML Tan E Tong X Xu SS Latham MJ Peterson LB Anderson MS Eveland SS Guo Q Hyland SA Milot DP Chen Y Sparrow CP Wright SD Sinclair PJ 《Bioorganic & medicinal chemistry letters》2010,20(24):7469-7472
A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model. 相似文献
992.
The 37/67 kDa laminin receptor (LAMR) is a multifunctional protein, acting as an extracellular receptor, localizing to the nucleus, and playing roles in rRNA processing and ribosome assembly. LAMR is important for cell viability; however, it is unclear which of its functions are essential. We developed a silent mutant LAMR construct, resistant to siRNA, to rescue the phenotypic effects of knocking down endogenous LAMR, which include inhibition of protein synthesis, cell cycle arrest, and apoptosis. In addition, we generated a C-terminal-truncated silent mutant LAMR construct structurally homologous to the Archaeoglobus fulgidus S2 ribosomal protein and missing the C-terminal 75 residues of LAMR, which displays more sequence divergence. We found that HT1080 cells stably expressing either silent mutant LAMR construct still undergo arrest in the G1 phase of the cell cycle when treated with siRNA. However, the expression of full-length silent mutant LAMR rescues cell viability, whereas the expression of the C-terminal-truncated LAMR does not. Interestingly, we also found that both silent mutant constructs restore protein translation and localize to the nucleus. Our findings indicate that the ability of LAMR to regulate viability is associated with its C-terminal 75 residues. Furthermore, this function is distinct from its role in cell proliferation, independent of its ribosomal functions, and may be regulated by a nonnuclear localization. 相似文献
993.
994.
Jamieson M 《Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences》2010,41(4):356-366
An allergy is commonly understood to be an overreaction of the immune system to harmless substances that are misrecognised as foreign. This concept of allergy as an abnormal, misdirected immune response-a biological fault-stems from the idea that the immune system is an inherently defensive operation designed to protect the individual through an innate capacity to discriminate between the benign and toxic, or self and nonself. However, this definition of allergy represents a radical departure from its original formulation. Literally meaning 'altered reactivity', the term was coined in 1906 by Austrian paediatrician Clemens von Pirquet, to describe the fundamentally mutable nature of the immune response. This paper argues that the conventional interpretation of allergy-as-pathology derives from specific concepts of 'organism', 'response', and 'normal' immune function that have-for over a century-governed the perception and study of immune phenomena within immunology. Through an examination of Louis Pasteur's conceptualisation of the host body/microorganism relationship, I argue that immunology is founded on a view of the organism as a discrete, autonomous entity, and on a concomitant notion of the immune response as essentially reactive. Revisiting the concept of 'altered reactivity', this paper points to the fact that allergy was initially posited as a general theory of immune responsiveness and, importantly, one that poses a significant challenge to orthodox notions of immunopathology. It suggests that Pirquet's unique view of immune responsiveness presents an account of organismic or biological identity that encapsulates, rather than reduces, its ecological complexity. 相似文献
995.
Jeffrey A Markert Denise M Champlin Ruth Gutjahr-Gobell Jason S Grear Anne Kuhn Thomas J McGreevyJr Annette Roth Mark J Bagley Diane E Nacci 《BMC evolutionary biology》2010,10(1):205
Background
When a large number of alleles are lost from a population, increases in individual homozygosity may reduce individual fitness through inbreeding depression. Modest losses of allelic diversity may also negatively impact long-term population viability by reducing the capacity of populations to adapt to altered environments. However, it is not clear how much genetic diversity within populations may be lost before populations are put at significant risk. Development of tools to evaluate this relationship would be a valuable contribution to conservation biology. To address these issues, we have created an experimental system that uses laboratory populations of an estuarine crustacean, Americamysis bahia with experimentally manipulated levels of genetic diversity. We created replicate cultures with five distinct levels of genetic diversity and monitored them for 16 weeks in both permissive (ambient seawater) and stressful conditions (diluted seawater). The relationship between molecular genetic diversity at presumptive neutral loci and population vulnerability was assessed by AFLP analysis. 相似文献996.
Alexandre Charlet Arnaud H Muller Alexis Laux Véronique Kemmel Annie Schweitzer Jean-Christophe Deloulme Denise Stuber François Delalande Enrica Bianchi Alain Van Dorsselaer Dominique Aunis Annie Andrieux Pierrick Poisbeau Yannick Goumon 《Molecular pain》2010,6(1):1-14
Calcitonin gene-related peptide (CGRP) plays an important role in peripheral and central sensitization. CGRP also is a key molecule in the spino-parabrachial-amygdaloid pain pathway. Blockade of CGRP1 receptors in the spinal cord or in the amygdala has antinociceptive effects in different pain models. Here we studied the electrophysiological mechanisms of behavioral effects of CGRP in the amygdala in normal animals without tissue injury. Whole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in rat brain slices showed that CGRP (100 nM) increased excitatory postsynaptic currents (EPSCs) at the parabrachio-amygdaloid (PB-CeLC) synapse, the exclusive source of CGRP in the amygdala. Consistent with a postsynaptic mechanism of action, CGRP increased amplitude, but not frequency, of miniature EPSCs and did not affect paired-pulse facilitation. CGRP also increased neuronal excitability. CGRP-induced synaptic facilitation was reversed by an NMDA receptor antagonist (AP5, 50 μM) or a PKA inhibitor (KT5720, 1 μM), but not by a PKC inhibitor (GF109203X, 1 μM). Stereotaxic administration of CGRP (10 μM, concentration in microdialysis probe) into the CeLC by microdialysis in awake rats increased audible and ultrasonic vocalizations and decreased hindlimb withdrawal thresholds. Behavioral effects of CGRP were largely blocked by KT5720 (100 μM) but not by GF109203X (100 μM). The results show that CGRP in the amygdala exacerbates nocifensive and affective behavioral responses in normal animals through PKA- and NMDA receptor-dependent postsynaptic facilitation. Thus, increased CGRP levels in the amygdala might trigger pain in the absence of tissue injury. 相似文献
997.
Carrie L Tatar Sunita Appikatla Denise A Bessert Ajaib S Paintlia Inderjit Singh Robert P Skoff 《ASN neuro》2010,2(4)
PMD (Pelizaeus–Merzbacher disease) is a rare neurodegenerative disorder that impairs motor and cognitive functions and is associated with a shortened lifespan. The cause of PMD is mutations of the PLP1 [proteolipid protein 1 gene (human)] gene. Transgenic mice with increased Plp1 [proteolipid protein 1 gene (non-human)] copy number model most aspects of PMD patients with duplications. Hypomyelination and demyelination are believed to cause the neurological abnormalities in mammals with PLP1 duplications. We show, for the first time, intense microglial reactivity throughout the grey and white matter of a transgenic mouse line with increased copy number of the native Plp1 gene. Activated microglia in the white and grey matter of transgenic mice are found as early as postnatal day 7, before myelin commences in normal cerebra. This finding indicates that degeneration of myelin does not cause the microglial response. Microglial numbers are doubled due to in situ proliferation. Compared with the jp (jimpy) mouse, which has much more oligodendrocyte death and hardly any myelin, microglia in the overexpressors show a more dramatic microglial reactivity than jp, especially in the grey matter. Predictably, many classical markers of an inflammatory response, including TNF-α (tumour necrosis factor-α) and IL-6, are significantly up-regulated manyfold. Because inflammation is believed to contribute to axonal degeneration in multiple sclerosis and other neurodegenerative diseases, inflammation in mammals with increased Plp1 gene dosage may also contribute to axonal degeneration described in patients and rodents with PLP1 increased gene dosage. 相似文献
998.
Fabio Richlan Denise Sturm Matthias Schurz Martin Kronbichler Gunther Ladurner Heinz Wimmer 《PloS one》2010,5(8)
Background
We used fMRI to examine functional brain abnormalities of German-speaking dyslexics who suffer from slow effortful reading but not from a reading accuracy problem. Similar to acquired cases of letter-by-letter reading, the developmental cases exhibited an abnormal strong effect of length (i.e., number of letters) on response time for words and pseudowords.Results
Corresponding to lesions of left occipito-temporal (OT) regions in acquired cases, we found a dysfunction of this region in our developmental cases who failed to exhibit responsiveness of left OT regions to the length of words and pseudowords. This abnormality in the left OT cortex was accompanied by absent responsiveness to increased sublexical reading demands in phonological inferior frontal gyrus (IFG) regions. Interestingly, there was no abnormality in the left superior temporal cortex which—corresponding to the onological deficit explanation—is considered to be the prime locus of the reading difficulties of developmental dyslexia cases.Conclusions
The present functional imaging results suggest that developmental dyslexia similar to acquired letter-by-letter reading is due to a primary dysfunction of left OT regions. 相似文献999.
1000.
David G. Addiss Jacky Louis-Charles Jacquelin Roberts Frederic LeConte Joyanna M. Wendt Marie Denise Milord Patrick J. Lammie Gerusa Dreyer 《PLoS neglected tropical diseases》2010,4(4)