Proceedings of the National Academy of Sciences of the United States of America
1091-6490
0027-8424
Mỹ
Cơ quản chủ quản: NATL ACAD SCIENCES , National Academy of Sciences
Lĩnh vực:
Multidisciplinary
Phân tích ảnh hưởng
Thông tin về tạp chí
PNAS publishes research reports, Brief Reports, Letters, Front Matter magazine content, Commentaries, Perspectives, and Colloquium Papers. In accordance with the guiding principles established by George Ellery Hale in 1914, PNAS also publishes brief first announcements of NAS members' and foreign associates' more important contributions to research and of work that appears to a member to be of particular importance. All submissions are evaluated by a member of the Editorial Board prior to acceptance. PNAS is a general science journal, and all papers should be intelligible to a broad scientific audience.
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Probing the timescale of the exchange interaction in a ferromagnetic alloy The underlying physics of all ferromagnetic behavior is the cooperative interaction between individual atomic magnetic moments that results in a macroscopic magnetization. In this work, we use extreme ultraviolet pulses from high-harmonic generation as an element-specific probe of ultrafast, optically driven, demagnetization in a ferromagnetic Fe-Ni alloy (permalloy). We show that for times shorter than the characteristic timescale for exchange coupling, the magnetization of Fe quenches more strongly than that of Ni. Then as the Fe moments start to randomize, the strong ferromagnetic exchange interaction induces further demagnetization in Ni, with a characteristic delay determined by the strength of the exchange interaction. We can further enhance this delay by lowering the exchange energy by diluting the permalloy with Cu. This measurement probes how the fundamental quantum mechanical exchange coupling between Fe and Ni in magnetic materials influences magnetic switching dynamics in ferromagnetic materials relevant to next-generation data storage technologies.
Tập 109 Số 13 - Trang 4792-4797 - 2012
Information-theoretic analysis of phenotype changes in early stages of carcinogenesis
Cancer is a multistep process characterized by altered signal transduction, cell growth, and metabolism. To identify such processes in early carcinogenesis we use an information theoretic approach to characterize gene expression quantified as mRNA levels in primary keratinocytes (
K
) and human papillomavirus 16 (HPV16)-transformed keratinocytes (HF1 cells) from early (
E
) and late (
L
) passages and from benzo(
a
)pyrene-treated (BP) L cells. Our starting point is that biological signaling processes are subjected to the same quantitative laws as inanimate, nonequilibrium chemical systems. Environmental and genomic constraints thereby limit the maximal thermodynamic entropy that the biological system can reach. The procedure uncovers the changes in gene expression patterns in different networks and defines the significance of each altered network in the establishment of a particular phenotype. The development of transformed HF1 cells is shown to be represented by one major transcription pattern that is important at all times. Two minor transcription patterns are also identified, one that contributes at early times and a distinguishably different pattern that contributes at later times. All three transcription patterns defined by our analysis were validated by gene expression values and biochemical means. The major transcription pattern includes reduced transcripts participating in the apoptotic network and enhanced transcripts participating in cell cycle, glycolysis, and oxidative phosphorylation. The two minor patterns identify genes that are mainly involved in lipid or carbohydrate metabolism.
Tập 107 Số 22 - Trang 10324-10329 - 2010
On a fundamental structure of gene networks in living cells Computers are organized into hardware and software. Using a theoretical approach to identify patterns in gene expression in a variety of species, organs, and cell types, we found that biological systems similarly are comprised of a relatively unchanging hardware-like gene pattern. Orthogonal patterns of software-like transcripts vary greatly, even among tumors of the same type from different individuals. Two distinguishable classes could be identified within the hardware-like component: those transcripts that are highly expressed and stable and an adaptable subset with lower expression that respond to external stimuli. Importantly, we demonstrate that this structure is conserved across organisms. Deletions of transcripts from the highly stable core are predicted to result in cell mortality. The approach provides a conceptual thermodynamic-like framework for the analysis of gene-expression levels and networks and their variations in diseased cells.
Tập 109 Số 12 - Trang 4702-4707 - 2012
An <i>Arabidopsis</i> mutation in translation elongation factor 2 causes superinduction of <i>CBF/DREB1</i> transcription factor genes but blocks the induction of their downstream targets under low temperatures
Low temperature regulates gene expression in bacteria, yeast, and animals as well as in plants. However, the signal transduction cascades mediating the low temperature responses are not well understood in any organism. To identify components in low temperature signaling genetically, we isolated
Arabidopsis thaliana
mutants in which cold-responsive genes are no longer induced by low temperatures. One of these mutations,
los1–1
, specifically blocks low temperature-induced transcription of cold-responsive genes. Surprisingly, cold-induced expression of the early response transcriptional activators, C-repeat/dehydration responsive element binding factors (CBF/DREB1s), is enhanced by the
los1–1
mutation. The
los1–1
mutation also reduces the capacity of plants to develop freezing tolerance but does not impair the vernalization response. Genetic analysis indicated that
los1–1
is a recessive mutation in a single nuclear gene. The
LOS1
gene encodes a translation elongation factor 2-like protein. Protein labeling studies show that new protein synthesis is blocked in
los1–1
mutant plants specifically in the cold. These results reveal a critical role of new protein synthesis in the proper transduction of low temperature signals. Our results also suggest that cold-induced transcription of
CBF/DREB1
s is feedback inhibited by their gene products or by products of their downstream target genes.
Tập 99 Số 11 - Trang 7786-7791 - 2002
Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy Solid tumors frequently contain large regions with low oxygen concentrations (hypoxia). The hypoxic microenvironment induces adaptive changes to tumor cell metabolism, and this alteration can further distort the local microenvironment. The net result of these tumor-specific changes is a microenvironment that inhibits many standard cytotoxic anticancer therapies and predicts for a poor clinical outcome. Pharmacologic targeting of the unique metabolism of solid tumors could alter the tumor microenvironment to provide more favorable conditions for anti-tumor therapy. Here, we describe a strategy in which the mitochondrial metabolism of tumor cells is increased by pharmacologic inhibition of hypoxia-inducible factor 1 (HIF1) or its target gene pyruvate dehydrogenase kinase 1 (PDK1). This acute increase in oxygen consumption leads to a corresponding decrease in tumor oxygenation. Whereas decreased oxygenation could reduce the effectiveness of some traditional therapies, we show that it dramatically increases the effectiveness of a hypoxia-specific cytotoxin. This treatment strategy should provide a high degree of tumor specificity for increasing the effectiveness of hypoxic cytotoxins, as it depends on the activation of HIF1 and the presence of hypoxia, conditions that are present only in the tumor, and not the normal tissue.
Tập 104 Số 22 - Trang 9445-9450 - 2007
Molecular evidence of cryptic speciation in planktonic foraminifers and their relation to oceanic provinces
The fossil record of planktonic foraminifers is a key source of data on the biodiversity and evolution of marine plankton. One of the most distinctive foraminiferal taxa,
Orbulina universa
, widely used as a stratigraphic and paleoclimatic index, has always been regarded as a single species. Here we present a phylogenetic analysis of
Orbulina
small subunit rDNA sequences from 25 pelagic stations covering 100° latitude in the Atlantic Ocean. The genetic data reveal the presence of three cryptic species, whose distribution is clearly correlated to hydrographic provinces, and particularly to sea-surface total chlorophyll a concentration. Our results, together with previous studies, suggest that a considerable part of the diversity among planktonic foraminifers has been overlooked in morphological taxonomies. Our data also support the idea that planktonic foraminifers, even if adapted to particular hydrographic conditions, are high-dispersal organisms whose speciation may be similar to that of other high-dispersal taxa in which reproductive mechanisms and behavior, rather than just geographic barriers to dispersal, play key roles in species formation and maintenance.
Tập 96 Số 6 - Trang 2864-2868 - 1999
Brain cholesterol turnover required for geranylgeraniol production and learning in mice The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning.
Tập 103 Số 10 - Trang 3869-3874 - 2006
Binding between the Niemann–Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain Niemann–Pick type C (NPC) 1 protein plays important roles in moving cholesterol and other lipids out of late endosomes by means of vesicular trafficking, but it is not known whether NPC1 directly interacts with cholesterol. We performed photoaffinity labeling of intact cells expressing fluorescent protein (FP)-tagged NPC1 by using [3 H]7,7-azocholestanol ([3 H]AC). After immunoprecipitation,3 H-labled NPC1-GFP appeared as a single band. Including excess unlabeled sterol to the labeling reaction significantly diminished the labeling. Altering the NPC1 sterol-sensing domain (SSD) with loss-of-function mutations (P692S and Y635C) severely reduced the extent of labeling. To further demonstrate the specificity of labeling, we show that NPC2, a late endosomal/lysosomal protein that binds to cholesterol with high affinity, is labeled, whereas mutant NPC2 proteins inactive in binding cholesterol are not. Vamp7, an abundant late endosomal membrane protein without an SSD but with one transmembrane domain, cannot be labeled. Binding between [3 H]AC and NPC1 does not require NPC2. Treating cells with either U-18666A, a compound that creates an NPC-like phenotype, or with bafilomycin A1, a compound that raises late endosomal pH, has no effect on labeling of NPC1-YFP, suggesting that both drugs affect processes other than NPC1 binding to cholesterol. We also developed a procedure to label the NPC1-YFP by [3 H]ACin vitro and showed that cholesterol is more effective in protection against labeling than its analogs epicholesterol or 5-α-cholestan. Overall, the results demonstrate that there is direct binding between NPC1 and azocholestanol; the binding does not require NPC2 but requires a functional SSD within NPC1.
Tập 101 Số 34 - Trang 12473-12478 - 2004
25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production 25-Hydroxycholesterol is produced in mammalian tissues. The function of this oxysterol is unknown. Here we describe a central role for 25-hydroxycholesterol in regulating the immune system. In initial experiments, we found that stimulation of macrophage Toll-like receptors (TLR) induced expression of cholesterol 25-hydroxylase and the synthesis of 25-hydroxycholesterol. Treatment of naïve B cells with nanomolar concentrations of 25-hydroxycholesterol suppressed IL-2-mediated stimulation of B cell proliferation, repressed activation-induced cytidine deaminase (AID) expression, and blocked class switch recombination, leading to markedly decreased IgA production. Consistent with these findings, deletion of the mouse cholesterol 25-hydroxylase gene caused an increase in serum IgA. Conversely, inactivation of the CYP7B1 oxysterol 7α-hydroxylase, which degrades 25-hydroxycholesterol, decreased serum IgA. The suppression of IgA class switching in B cells by a macrophage-derived sterol in response to TLR activation provides a mechanism for local and systemic negative regulation of the adaptive immune response by the innate immune system.
Tập 106 Số 39 - Trang 16764-16769 - 2009
Structure of a cholesterol-binding protein deficient in Niemann–Pick type C2 disease
Niemann–Pick disease type C2 (NP-C2) is a fatal hereditary disease characterized by accumulation of low-density lipoprotein-derived cholesterol in lysosomes. Here we report the 1.7-Å resolution crystal structure of the cholesterol-binding protein deficient in this disease, NPC2, and the characterization of its ligand binding properties. Human NPC2 binds the cholesterol analog dehydroergosterol with submicromolar affinity at both acidic and neutral pH. NPC2 has an Ig-like fold stabilized by three disulfide bonds. The structure of the bovine protein reveals a loosely packed region penetrating from the surface into the hydrophobic core that forms adjacent small cavities with a total volume of ≈160 Å
3
. We propose that this region represents the incipient cholesterol-binding site that dilates to accommodate an ≈740-Å
3
cholesterol molecule.
Tập 100 Số 5 - Trang 2512-2517 - 2003