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91.
We reconstruct essential features of Lagrange’s theory of analytical functions by exhibiting its structure and basic assumptions,
as well as its main shortcomings. We explain Lagrange’s notions of function and algebraic quantity, and we concentrate on
power-series expansions, on the algorithm for derivative functions, and the remainder theorem—especially on the role this
theorem has in solving geometric and mechanical problems. We thus aim to provide a better understanding of Enlightenment mathematics
and to show that the foundations of mathematics did not, for Lagrange, concern the solidity of its ultimate bases, but rather
purity of method—the generality and internal organization of the discipline. 相似文献
92.
Sarno S Mazzorana M Traynor R Ruzzene M Cozza G Pagano MA Meggio F Zagotto G Battistutta R Pinna LA 《Cellular and molecular life sciences : CMLS》2012,69(3):449-460
8-hydroxy-4-methyl-9-nitrobenzo(g)chromen-2-one (NBC) has been found to be a fairly potent ATP site-directed inhibitor of
protein kinase CK2 (Ki = 0.22 μM). Here, we show that NBC also inhibits PIM kinases, especially PIM1 and PIM3, the latter
as potently as CK2. Upon removal of the nitro group, to give 8-hydroxy-4-methyl-benzo(g)chromen-2-one (here referred to as
“denitro NBC”, dNBC), the inhibitory power toward CK2 is almost entirely lost (IC50 > 30 μM) whereas that toward PIM1 and PIM3 is maintained; in addition, dNBC is a potent inhibitor of a number of other kinases
that are weakly inhibited or unaffected by NBC, with special reference to DYRK1A whose IC50 values with NBC and dNBC are 15 and 0.60 μM, respectively. Therefore, the observation that NBC, unlike dNBC, is a potent
inducer of apoptosis is consistent with the notion that this effect is mediated by inhibition of endogenous CK2. The structural
features underlying NBC selectivity have been revealed by inspecting its 3D structure in complex with the catalytic subunit
of Z. mays CK2. The crucial role of the nitro group is exerted both through a direct electrostatic interaction with the side chain of Lys68
and, indirectly, by enhancing the acidic dissociation constant of the adjacent hydroxyl group which interacts with a conserved
water molecule in the deepest part of the cavity. By contrast, the very same nitro group is deleterious for the binding to
the active site of DYRK1A, as disclosed by molecular docking. This provides the rationale for preferential inhibition of DYRK1A
by dNBC. 相似文献
93.
Elisa Bisicchia Valerio Chiurchiù Maria Teresa Viscomi Laura Latini Filomena Fezza Luca Battistini Mauro Maccarrone Marco Molinari 《Cellular and molecular life sciences : CMLS》2013,70(12):2191-2204
Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB2) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB2 and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB2 and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB2, but not GRα. Overall, our study demonstrates for the first time the existence of a CB2-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB2 as a new target for chronic inflammatory and neurodegenerative diseases. 相似文献
94.
A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures 总被引:1,自引:0,他引:1
Sharp AJ Mefford HC Li K Baker C Skinner C Stevenson RE Schroer RJ Novara F De Gregori M Ciccone R Broomer A Casuga I Wang Y Xiao C Barbacioru C Gimelli G Bernardina BD Torniero C Giorda R Regan R Murday V Mansour S Fichera M Castiglia L Failla P Ventura M Jiang Z Cooper GM Knight SJ Romano C Zuffardi O Chen C Schwartz CE Eichler EE 《Nature genetics》2008,40(3):322-328
We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes. 相似文献
95.
96.
Kassmann CM Lappe-Siefke C Baes M Brügger B Mildner A Werner HB Natt O Michaelis T Prinz M Frahm J Nave KA 《Nature genetics》2007,39(8):969-976
Oligodendrocytes myelinate axons for rapid impulse conduction and contribute to normal axonal functions in the central nervous system. In multiple sclerosis, demyelination is caused by autoimmune attacks, but the role of oligodendroglial cells in disease progression and axon degeneration is unclear. Here we show that oligodendrocytes harbor peroxisomes whose function is essential for maintaining white matter tracts throughout adult life. By selectively inactivating the import factor PEX5 in myelinating glia, we generated mutant mice that developed normally, but within several months showed ataxia, tremor and premature death. Absence of functional peroxisomes from oligodendrocytes caused widespread axonal degeneration and progressive subcortical demyelination, but did not interfere with glial survival. Moreover, it caused a strong proinflammatory milieu and, unexpectedly, the infiltration of B and activated CD8+ T cells into brain lesions. We conclude that peroxisomes provide oligodendrocytes with an essential neuroprotective function against axon degeneration and neuroinflammation, which is relevant for human demyelinating diseases. 相似文献
97.
Tartaglia M Pennacchio LA Zhao C Yadav KK Fodale V Sarkozy A Pandit B Oishi K Martinelli S Schackwitz W Ustaszewska A Martin J Bristow J Carta C Lepri F Neri C Vasta I Gibson K Curry CJ Siguero JP Digilio MC Zampino G Dallapiccola B Bar-Sagi D Gelb BD 《Nature genetics》2007,39(1):75-79
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development. 相似文献
98.
Chen YH Hu L Punta M Bruni R Hillerich B Kloss B Rost B Love J Siegelbaum SA Hendrickson WA 《Nature》2010,467(7319):1074-1080
The plant SLAC1 anion channel controls turgor pressure in the aperture-defining guard cells of plant stomata, thereby regulating the exchange of water vapour and photosynthetic gases in response to environmental signals such as drought or high levels of carbon dioxide. Here we determine the crystal structure of a bacterial homologue (Haemophilus influenzae) of SLAC1 at 1.20 ? resolution, and use structure-inspired mutagenesis to analyse the conductance properties of SLAC1 channels. SLAC1 is a symmetrical trimer composed from quasi-symmetrical subunits, each having ten transmembrane helices arranged from helical hairpin pairs to form a central five-helix transmembrane pore that is gated by an extremely conserved phenylalanine residue. Conformational features indicate a mechanism for control of gating by kinase activation, and electrostatic features of the pore coupled with electrophysiological characteristics indicate that selectivity among different anions is largely a function of the energetic cost of ion dehydration. 相似文献
99.
100.