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91.
Macromolecular drugs hold great promise as novel therapeutics of several major disorders, such as cancer and cardiovascular
disease. However, their use is limited by lack of efficient, safe, and specific delivery strategies. Successful development
of such strategies requires interdisciplinary collaborations involving researchers with expertise on e.g., polymer chemistry,
cell biology, nano technology, systems biology, advanced imaging methods, and clinical medicine. This poses obvious challenges
to the scientific community, but also provides opportunities for the unexpected at the interface between different disciplines.
This review summarizes recent studies of macromolecular delivery that should be of interest to researchers involved in macromolecular
drug synthesis as well as in vitro and in vivo drug delivery studies. 相似文献
92.
Differential expression analysis for sequence count data 总被引:22,自引:0,他引:22
High-throughput sequencing assays such as RNA-Seq, ChIP-Seq or barcode counting provide quantitative readouts in the form
of count data. To infer differential signal in such data correctly and with good statistical power, estimation of data variability
throughout the dynamic range and a suitable error model are required. We propose a method based on the negative binomial distribution,
with variance and mean linked by local regression and present an implementation, DESeq, as an R/Bioconductor package. 相似文献
93.
Björkbom A Róg T Kankaanpää P Lindroos D Kaszuba K Kurita M Yamaguchi S Yamamoto T Jaikishan S Paavolainen L Päivärinne J Nyholm TK Katsumura S Vattulainen I Slotte JP 《Biochimica et biophysica acta》2011,1808(4):1179-1186
We have prepared palmitoyl sphingomyelin (PSM) analogs in which either the 2-NH was methylated to NMe, the 3-OH was methylated to OMe, or both were methylated simultaneously. The aim of the study was to determine how such modifications in the membrane interfacial region of the molecules affected interlipid interactions in bilayer membranes. Measuring DPH anisotropy in vesicle membranes prepared from the SM analogs, we observed that methylation decreased gel-phase stability and increased fluid phase disorder, when compared to PSM. Methylation of the 2-NH had the largest effect on gel-phase instability (T(m) was lowered by ~7°C). Atomistic molecular dynamics simulations showed that fluid phase bilayers with methylated SM analogs were more expanded but thinner compared to PSM bilayers. It was further revealed that 3-OH methylation dramatically attenuated hydrogen bonding also via the amide nitrogen, whereas 2-NH methylation did not similarly affect hydrogen bonding via the 3-OH. The interactions of sterols with the methylated SM analogs were markedly affected. 3-OH methylation almost completely eliminated the capacity of the SM analog to form sterol-enriched ordered domains, whereas the 2-NH methylated SM analog formed sterol-enriched domains but these were less thermostable (and thus less ordered) than the domains formed by PSM. Cholestatrienol affinity to bilayers containing methylated SM analogs was also markedly reduced as compared to its affinity for bilayers containing PSM. Molecular dynamics simulations revealed further that cholesterol's bilayer location was deeper in PSM bilayers as compared to the location in bilayers made from methylated SM analogs. This study shows that the interfacial properties of SMs are very important for interlipid interactions and the formation of laterally ordered domains in complex bilayers. 相似文献
94.
Peter Hammershøj Mikkel Jessing Anders Ø. Madsen Knud J. Jensen Jørn B. Christensen Ulrik Boas 《International journal of peptide research and therapeutics》2007,13(1-2):209-212
The development of new linkers (handles) for solid-phase synthesis provides new chemical opportunities for peptide synthesis.
To understand the chemical properties of a recently developed backbone amide linker from a structural perspective, the crystal
structure of S-((5-formyl-3,4-ethylenedioxy)thiophene-2-yl)-3-thiopropionic acid (T-BAL2) was studied. Specifically, we wished
to address whether this highly substituted thiophene retained planarity in the aromatic ring as well as between the aromatic
ring and the aldehyde carbonyl. Furthermore, we sought an explanation for the relatively low reactivity in reductive aminations
of the thienylaldehyde with amines in solution and on solid phase. Based on the crystal structure of T-BAL2, the thienyl-C
(aldehyde) and C–O (aldehyde) bond lengths were applied as measures for the electron-deficiency (electrophilicity) of the
aldehyde and compared to similar bond lengths found in previously reported formylated homo- and hetero-aromatic systems, which
show significantly higher reactivity towards imine formation. The bond lengths found in the present structure are in accordance
with normal C–C single bond and C–O double bond lengths. The high similarity in aldehyde bond lengths in the present system
and in the reported systems indicates similar electron distribution in these systems. The lower reactivity of the present
system may therefore not be attributed to electronic factors. 相似文献
95.
Christoph Scherber David J. Gladbach Karen Stevnbak Rune Juelsborg Karsten Inger Kappel Schmidt Anders Michelsen Kristian Rost Albert Klaus Steenberg Larsen Teis Nørgaard Mikkelsen Claus Beier Søren Christensen 《Ecology and evolution》2013,3(6):1449-1460
The impact of climate change on herbivorous insects can have far‐reaching consequences for ecosystem processes. However, experiments investigating the combined effects of multiple climate change drivers on herbivorous insects are scarce. We independently manipulated three climate change drivers (CO2, warming, drought) in a Danish heathland ecosystem. The experiment was established in 2005 as a full factorial split‐plot with 6 blocks × 2 levels of CO2 × 2 levels of warming × 2 levels of drought = 48 plots. In 2008, we exposed 432 larvae (n = 9 per plot) of the heather beetle (Lochmaea suturalis Thomson ), an important herbivore on heather, to ambient versus elevated drought, temperature, and CO2 (plus all combinations) for 5 weeks. Larval weight and survival were highest under ambient conditions and decreased significantly with the number of climate change drivers. Weight was lowest under the drought treatment, and there was a three‐way interaction between time, CO2, and drought. Survival was lowest when drought, warming, and elevated CO2 were combined. Effects of climate change drivers depended on other co‐acting factors and were mediated by changes in plant secondary compounds, nitrogen, and water content. Overall, drought was the most important factor for this insect herbivore. Our study shows that weight and survival of insect herbivores may decline under future climate. The complexity of insect herbivore responses increases with the number of combined climate change drivers. 相似文献
96.
Long-distance migration: evolution and determinants 总被引:15,自引:0,他引:15
Long‐distance migration has evolved in many organisms moving through different media and using various modes of locomotion and transport. Migration continues to evolve or become suppressed as shown by ongoing dynamic and rapid changes of migration patterns. This great evolutionary flexibility may seem surprising for such a complex attribute as migration. Even if migration in most cases has evolved basically as a strategy to maximise fitness in a seasonal environment, its occurrence and extent depend on a multitude of factors. We give a brief overview of different factors (e.g. physical, geographical, historical, ecological) likely to facilitate and/or constrain the evolution of long‐distance migration and discuss how they are likely to affect migration. The basic driving forces for migration are ecological and biogeographic factors like seasonality, spatiotemporal distributions of resources, habitats, predation and competition. The benefit of increased resource availability will be balanced by costs associated with the migratory process in terms of time (incl. losses of prior occupancy advantages), energy and mortality (incl. increased exposure to parasites). Furthermore, migration requires genetic instructions (allowing substantial room for learning in some of the traits) about timing, duration and distance of migration as well as about behavioural and physiological adaptations (fuelling, organ flexibility, locomotion, use of environmental transport etc) and control of orientation and navigation. To what degree these costs and requirements put constraints on migration often depends on body size according to different scaling relationships. From this exposé it is clear that research on migration warrants a multitude of techniques and approaches for a complete as possible understanding of a very complex evolutionary syndrome. In addition, we also present examples of migratory distances in a variety of taxons. In recent years new techniques, especially satellite radio telemetry, provide new information of unprecedented accuracy about journeys of individual animals, allowing re‐evaluation of migration, locomotion and navigation theories. 相似文献
97.
Jia X Gharibyan AL Öhman A Liu Y Olofsson A Morozova-Roche LA 《Journal of molecular biology》2011,(5):699-712
Parkinson's disease is a common neurodegenerative disorder characterized by α-synuclein (α-Syn)-containing Lewy body formation and selective loss of dopaminergic neurons in the substantia nigra. We have demonstrated the modulating effect of noopept, a novel proline-containing dipeptide drug with nootropic and neuroprotective properties, on α-Syn oligomerization and fibrillation by using thioflavin T fluorescence, far-UV CD, and atomic force microscopy techniques. Noopept does not bind to a sterically specific site in the α-Syn molecule as revealed by heteronuclear two-dimensional NMR analysis, but due to hydrophobic interactions with toxic amyloid oligomers, it prompts their rapid sequestration into larger fibrillar amyloid aggregates. Consequently, this process rescues the cytotoxic effect of amyloid oligomers on neuroblastoma SH-SY5Y cells as demonstrated by using cell viability assays and fluorescent staining of apoptotic and necrotic cells and by assessing the level of intracellular oxidative stress. The mitigating effect of noopept against amyloid oligomeric cytotoxicity may offer additional benefits to the already well-established therapeutic functions of this new pharmaceutical. 相似文献
98.
Can spatial sorting associated with spawning migration explain evolution of body size and vertebral number in Anguilla eels? 下载免费PDF全文
Spatial sorting is a process that can contribute to microevolutionary change by assembling phenotypes through space, owing to nonrandom dispersal. Here we first build upon and develop the “neutral” version of the spatial sorting hypothesis by arguing that in systems that are not characterized by repeated range expansions, the evolutionary effects of variation in dispersal capacity and assortative mating might not be independent of but interact with natural selection. In addition to generating assortative mating, variation in dispersal capacity together with spatial and temporal variation in quality of spawning area is likely to influence both reproductive success and survival of spawning migrating individuals, and this will contribute to the evolution of dispersal‐enhancing traits. Next, we use a comparative approach to examine whether differences in spawning migration distance among 18 species of freshwater Anguilla eels have evolved in tandem with two dispersal‐favoring traits. In our analyses, we use information on spawning migration distance, body length, and vertebral number that was obtained from the literature, and a published whole mitochondrial DNA‐based phylogeny. Results from comparative analysis of independent contrasts showed that macroevolutionary shifts in body length throughout the phylogeny have been associated with concomitant shifts in spawning migration. Shifts in migration distance were not associated with shifts in number of vertebrae. These findings are consistent with the hypothesis that spatial sorting has contributed to the evolution of more elongated bodies in species with longer spawning migration distances, or resulted in evolution of longer migration distances in species with larger body size. This novel demonstration is important in that it expands the list of ecological settings and hierarchical levels of biological organization for which the spatial sorting hypothesis seems to have predictive power. 相似文献
99.
The effects of bioaugmentation with a pentachlorophenol (PCP)-adapted consortium and biostimulation with glucose as a carbon source on anaerobic bioremediation of PCP-contaminated soil were investigated in terms of the initial PCP removal rate and the extent of PCP dechlorination and mineralization. Samples from two PCP-contaminated sites were prepared, put into a series of Hungate tubes, inoculated, and fed under different conditions. Chlorophenols in the tubes were monitored over a 4-month period to measure PCP transformation in the soil. In less contaminated soil (10 mg PCP/kg soil), it was found that biostimulation with glucose at 1 g/kg soil or bioaugmentation at 0.14 g volatile suspended solids (VSS)/kg soil could greatly improve PCP degradation. The best PCP degradation was obtained when both bioaugmentation and biostimulation were applied, but higher levels of glucose (2 g/kg soil) or inoculum (0.56 g VSS/kg soil) had little additional effect. The highest initial PCP-removal rate reached 8.1 μmol/kg soil-d, which is almost 20 times greater than in the unamended controls. PCP was dechlorinated to lesser chlorinated phenols with 0.6 chlorine remaining on average, and the extent of mineralization approached 70% in 4 months. In highly PCP-contaminated soil (90 mg PCP/kg soil), PCP degradation was partially inhibited, but the relative effects of augmentation, stimulation, and combined treatments were the same as in the less contaminated soil. 相似文献
100.
Angot E Steiner JA Lema Tomé CM Ekström P Mattsson B Björklund A Brundin P 《PloS one》2012,7(6):e39465
Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology. 相似文献