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911.
Mingzhao Zhu Wayne D. Harshbarger Omar Robles Joanna Krysiak Kenneth G. Hull Sung Wook Cho Robyn D. Richardson Yanyan Yang Andres Garcia Lindsey Spiegelman Bianca Ramirez Christopher T. Wilson Ju Anne Yau James T. Moore Caitlen B. Walker James C. Sacchettini Wenshe R. Liu Stephan A. Sieber Daniel Romo 《Bioorganic & medicinal chemistry》2017,25(11):2901-2916
The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, β-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance. 相似文献
912.
An experimental demonstration that house finches add cigarette butts in response to ectoparasites 下载免费PDF全文
Monserrat Suárez‐Rodríguez Constantino Macías Garcia 《Journal of avian biology》2017,48(10):1316-1321
Urban species encounter resources that are uncommon in nature, such as materials found in city waste. Many studies have shown that these can be harmful to wildlife. In Mexico City, house finches bring cigarette butts to their nests, which reduces the amount of ectoparasites, but also induces genotoxic damage in chicks and parents. Yet, the reason for this behaviour is unknown. One possibility is that birds extract the cellulose fibres from discarded butts simply because they resemble feathers. Alternatively, disassembled cigarette butts may be brought to the nests because they repel ectoparasites. Here we tested the latter hypothesis by assessing whether house finches Carpodacus mexicanus increase the amount of cigarette butts in their nests in response to a raise in ectoparasite load. When present, fibres from butts are concentrated in the nest lining. By taking it away, we simultaneously removed most of the butt material and collected the bulk of the tick population infesting each nest, as these parasites cluster in the lining. We removed the bedding of nests when chicks had recently hatched, and randomly assigned each nests to one of the following treatments: 1) addition of live ticks, 2) addition of dead ticks and 3) simulation of tick addition. Females in the live ticks’ treatment added more butt fibres to their nests than parents in control treatments. Additionally, the amount of butt fibres in the original lining also predicted the amount of fibres added after the manipulation. It seems that the tendency to bring to the nest cigarette butts is at least partially a response to current, and perhaps also past, parasite load. 相似文献
913.
Lucas Borges-Pereira Kamila Anna Meissner Carsten Wrenger Célia R. S. Garcia 《Purinergic signalling》2017,13(3):267-277
Plasmodium falciparum is the causative agent of the most dangerous form of malaria in humans. It has been reported that the P. falciparum genome encodes for a single ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), an enzyme that hydrolyzes extracellular tri- and di-phosphate nucleotides. The E-NTPDases are known for participating in invasion and as a virulence factor in many pathogenic protozoa. Despite its presence in the parasite genome, currently, no information exists about the activity of this predicted protein. Here, we show for the first time that P. falciparum E-NTPDase is relevant for parasite lifecycle as inhibition of this enzyme impairs the development of P. falciparum within red blood cells (RBCs). ATPase activity could be detected in rings, trophozoites, and schizonts, as well as qRT-PCR, confirming that E-NTPDase is expressed throughout the intraerythrocytic cycle. In addition, transfection of a construct which expresses approximately the first 500 bp of an E-NTPDase-GFP chimera shows that E-NTPDase co-localizes with the endoplasmic reticulum (ER) in the early stages and with the digestive vacuole (DV) in the late stages of P. falciparum intraerythrocytic cycle. 相似文献
914.
Muscle spindle alterations precede onset of sensorimotor deficits in Charcot–Marie–Tooth type 2E 下载免费PDF全文
E. Villalón M. R. Jones C. Sibigtroth S. J. Zino J. M. Dale D. S. Landayan H. Shen D. D. W. Cornelison M. L. Garcia 《Genes, Brain & Behavior》2017,16(2):260-270
Charcot–Marie–Tooth (CMT) is the most common inherited peripheral neuropathy, affecting approximately 2.8 million people. The CMT leads to distal neuropathy that is characterized by reduced motor nerve conduction velocity, ataxia, muscle atrophy and sensory loss. We generated a mouse model of CMT type 2E (CMT2E) expressing human neurofilament light E396K (hNF‐LE396K), which develops decreased motor nerve conduction velocity, ataxia and muscle atrophy by 4 months of age. Symptomatic hNF‐LE396K mice developed phenotypes that were consistent with proprioceptive sensory defects as well as reduced sensitivity to mechanical stimulation, while thermal sensitivity and auditory brainstem responses were unaltered. Progression from presymptomatic to symptomatic included a 50% loss of large diameter sensory axons within the fifth lumbar dorsal root of hNF‐LE396K mice. Owing to proprioceptive deficits and loss of large diameter sensory axons, we analyzed muscle spindle morphology in presymptomatic and symptomatic hNF‐LE396K and hNF‐L control mice. Muscle spindle cross‐sectional area and volume were reduced in all hNF‐LE396K mice analyzed, suggesting that alterations in muscle spindle morphology occurred prior to the onset of typical CMT pathology. These data suggested that CMT2E pathology initiated in the muscle spindles altering the proprioceptive sensory system. Early sensory pathology in CMT2E could provide a unifying hypothesis for the convergence of pathology observed in CMT. 相似文献
915.
Reference values for TSH may be inadequate to define hypothyroidism in persons with morbid obesity: Di@bet.es study 下载免费PDF全文
Sergio Valdés Cristina Maldonado‐Araque Ana Lago‐Sampedro Juan Antonio Lillo‐Muñoz Eduardo Garcia‐Fuentes Vidal Perez‐Valero Carolina Gutiérrez‐Repiso Eva Garcia‐Escobar Albert Goday Inés Urrutia Laura Peláez Alfonso Calle‐Pascual Elena Bordiú Luis Castaño Conxa Castell Elias Delgado Edelmiro Menéndez Josep Franch‐Nadal Sonia Gaztambide Joan Girbés Emilio Ortega Joan Vendrell Matilde R. Chacón F. Javier Chaves Federico Soriguer Gemma Rojo‐Martínez 《Obesity (Silver Spring, Md.)》2017,25(4):788-793
916.
Stuart M. Cain Esperanza Garcia Zeina Waheed Karen L. Jones Trevor J. Bushell 《Channels (Austin, Tex.)》2017,11(6):574-586
Burst-firing in thalamic neurons is known to play a key role in mediating thalamocortical (TC) oscillations that are associated with non-REM sleep and some types of epileptic seizure. Within the TC system the primary output of GABAergic neurons in the reticular thalamic nucleus (RTN) is thought to induce the de-inactivation of T-type calcium channels in thalamic relay (TR) neurons, promoting burst-firing drive to the cortex and the propagation of TC network activity. However, RTN neurons also project back onto other neurons within the RTN. The role of this putative negative feedback upon the RTN itself is less well understood, although is hypothesized to induce de-synchronization of RTN neuron firing leading to the suppression of TC oscillations. Here we tested two hypotheses concerning possible mechanisms underlying TC oscillation modulation. Firstly, we assessed the burst-firing behavior of RTN neurons in response to GABAB receptor activation using acute brain slices. The selective GABAB receptor agonist baclofen was found to induce suppression of burst-firing concurrent with effects on membrane input resistance. Secondly, RTN neurons express CaV3.2 and CaV3.3 T-type calcium channel isoforms known to contribute toward TC burst-firing and we examined the modulation of these channels by GABAB receptor activation. Utilizing exogenously expressed T-type channels we assessed whether GABAB receptor activation could directly alter T-type calcium channel properties. Overall, GABAB receptor activation had only modest effects on CaV3.2 and CaV3.3 isoforms. The only effect that could be predicted to suppress burst-firing was a hyperpolarized shift in the voltage-dependence of inactivation, potentially causing lower channel availability at membrane potentials critical for burst-firing. Conversely, other effects observed such as a hyperpolarized shift in the voltage-dependence of activation of both CaV3.2 and CaV3.3 as well as increased time constant of activation of the CaV3.3 isoform would be expected to enhance burst-firing. Together, we hypothesize that GABAB receptor activation mediates multiple downstream effectors that combined act to suppress burst-firing within the RTN. It appears unlikely that direct GABAB receptor-mediated modulation of T-type calcium channels is the major mechanistic contributor to this suppression. 相似文献
917.
Asymmetric paternal effect on offspring size linked to parent‐of‐origin expression of an insulin‐like growth factor 下载免费PDF全文
Yolitzi Saldivar Lemus Jean‐Philippe Vielle‐Calzada Michael G. Ritchie Constantino Macías Garcia 《Ecology and evolution》2017,7(12):4465-4474
Sexual reproduction brings together reproductive partners whose long‐term interests often differ, raising the possibility of conflict over their reproductive investment. Males that enhance maternal investment in their offspring gain fitness benefits, even if this compromises future reproductive investment by iteroparous females. When the conflict occurs at a genomic level, it may be uncovered by crossing divergent populations, as a mismatch in the coevolved patterns of paternal manipulation and maternal resistance may generate asymmetric embryonic growth. We report such an asymmetry in reciprocal crosses between populations of the fish Girardinichthys multiradiatus. We also show that a fragment of a gene which can influence embryonic growth (Insulin‐Like Growth Factor 2; igf2) exhibits a parent‐of‐origin methylation pattern, where the maternally inherited igf2 allele has much more 5′ cytosine methylation than the paternally inherited allele. Our findings suggest that male manipulation of maternal investment may have evolved in fish, while the parent‐of‐origin methylation pattern appears to be a potential candidate mechanism modulating this antagonistic coevolution process. However, disruption of other coadaptive processes cannot be ruled out, as these can lead to similar effects as conflict. 相似文献
918.
Close and distant: Contrasting the metabolism of two closely related subspecies of Scots pine under the effects of folivory and summer drought 下载免费PDF全文
Albert Rivas‐Ubach Jordi Sardans José Antonio Hódar Joan Garcia‐Porta Alex Guenther Ljiljana Paša‐Tolić Michal Oravec Otmar Urban Josep Peñuelas 《Ecology and evolution》2017,7(21):8976-8988
Metabolomes, as chemical phenotypes of organisms, are likely not only shaped by the environment but also by common ancestry. If this is the case, we expect that closely related species of pines will tend to reach similar metabolomic solutions to the same environmental stressors. We examined the metabolomes of two sympatric subspecies of Pinus sylvestris in Sierra Nevada (southern Iberian Peninsula), in summer and winter and exposed to folivory by the pine processionary moth. The overall metabolomes differed between the subspecies but both tended to respond more similarly to folivory. The metabolomes of the subspecies were more dissimilar in summer than in winter, and iberica trees had higher concentrations of metabolites directly related to drought stress. Our results are consistent with the notion that certain plant metabolic responses associated with folivory have been phylogenetically conserved. The larger divergence between subspecies metabolomes in summer is likely due to the warmer and drier conditions that the northern iberica subspecies experience in Sierra Nevada. Our results provide crucial insights into how iberica populations would respond to the predicted conditions of climate change under an increased defoliation in the Mediterranean Basin. 相似文献
919.
Garcia MC Ma D Dicioccio AT Cali J 《In vitro cellular & developmental biology. Animal》2008,44(5-6):129-134
Assessment of a new chemical entity for cytochrome P450 (CYP) enzyme induction at an early stage in discovery is crucial to prevent potential drug-drug interactions. CYP3A, the most abundant CYP isoform in the liver, metabolizes approximately 50% of drugs currently on the market and is also a highly inducible enzyme. The use of both rat and human hepatocyte culture for the prediction of in vivo CYP3A induction has become refined and validated and is considered a standard in vitro model. The current evaluation of CYP3A enzyme induction involves the use of substrates requiring subsequent analysis of metabolites by high-performance liquid chromatography/mass spectrometry, which adds considerable time and cost. In the present study, we describe the use of a novel luminogenic substrate, luciferin-6'-pentafluoro-benzyl ether (PFBE), which allows for a fast and selective measurement of CYP3A enzyme induction in cultured rat hepatocytes. The extent of induction was evaluated using cells treated for 3 d with the prototypical inducers, dexamethasone, phenobarbital, and pregnenolone 16 alpha-carbonitrile (PCN). Enzyme activity was measured in the treated cells either by the depentafluorobenzylation of luciferin-PFBE or the testosterone 6-beta-hydroxylation. Using both methods, dexamethasone and PCN-treated cells exhibited strong CYP3A activity, whereas phenobarbital treatment resulted in a weak response. The fold induction varied between both methods, but this variability can be controlled by normalizing data from each treatment to a positive control. The results indicate that luciferin-PFBE is an attractive alternative to the use of conventional substrate, testosterone, providing a sensitive, robust, and rapid method compatible with the multiwell plate format for the assessment of CYP3A induction. 相似文献
920.
A miRacle in plant development: role of microRNAs in cell differentiation and patterning 总被引:1,自引:0,他引:1
Garcia D 《Seminars in cell & developmental biology》2008,19(6):586-595
MicroRNAs (miRNAs) are endogenous small regulatory RNAs, which control gene expression in eukaryotes. In plants they repress mRNA targets containing a highly complementary site, either by cleavage or translational repression. Studies of individual miRNA/target interactions highlight the involvement of the miRNA-based regulations in a broad range of developmental programs, throughout plant lifecycle. MicroRNAs can have distinct regulatory functions on their targets: some determine their spatial accumulation, some have a buffering role that ensures the robustness of their expression pattern, and finally others establish the temporal expression of targeted genes. 相似文献