bluuebunny/crossref_metadata_2025 huggingface dataset:
Remembering the Last Engagement
Authors: Adler Elizabeth M.
Published: December 2007

The experimental analysis of single-molecule biomechanical interactions frequently involves sequentially repeated measurements that are used to obtain a sufficiently large amount of data. The validity of this approach depends on the assumption that such sequential measurements are identical and independent of each other, an assumption Zarnitsyna
et al
. tested using a micropipette adhesion frequency assay. Cells expressing a particular ligand were held in a micropipette, and their adhesion (or lack thereof) to a second cell expressing the cognate receptor was repeatedly determined after an identical period of contact. Analyses of different receptor-ligand pairs revealed three distinct behaviors. The interaction between lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) was consistent with the assumption of independent and identical measurements. In contrast, interactions between the T cell receptor (TCR) and an antigen peptide bound to a major histocompatibility complex (pMHC) or between C-cadherins appeared to show molecular "memory." Thus, adhesion between a TCR-pMHC pair in one test increased the probability of adhesion in the next test, whereas adhesion between C-cadherins in one test decreased the likelihood that they would adhere in the next. Thus, the authors propose that receptor-ligand interactions involved in mediating cell adhesion show molecular memory, likely mediated through responses triggered by receptor engagement.

V. I. Zarnitsyna, J. Huang, F. Zhang, Y.-H. Chien, D. Leckband, C. Zhu, Memory in receptor-ligand-mediated cell adhesion.
Proc. Natl. Acad. Sci. U.S.A.
104
, 18037-18042 (2007).
[Abstract]
[Full Text]
The Yin-Yang of Inflammatory Responses
Authors: Simpson Stephen J.
Published: December 2007

Inflammatory responses in the nervous system are very tightly regulated. In particular, T helper 1 type T cell responses must be kept in check, and a potent negative regulator of these cells is the surface receptor TIM3, a member of the T cell immunoglobulin and mucin family. However, Anderson
et al
. report the unexpected finding that TIM3 also promotes inflammation through expression on cells of the innate immune system--namely, dendritic cells and microglia of the brain. The opposing roles for the same immune protein when expressed on different populations of immune cells raise intriguing questions about the balance between the promotion and inhibition of tissue inflammation.

A. C. Anderson, D. E. Anderson, L. Bregoli, W. D. Hastings, N. Kassam, C. Lei, R. Chandwaskar, J. Karman, E. W. Su, M. Hirashima, J. N. Bruce, L. P. Kane, V. K. Kuchroo, D. A. Hafler, Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells.
Science
318
, 1141-1143 (2007).
[Abstract]
[Full Text]
Cancer’s Mutational Landscape
Authors: Kiberstis Paula A.
Published: December 2007

The genomes of human tumors contain many sequence alterations, a subset of which help drive tumor growth. Wood
et al
. (see Perspective by Trent and Touchman) have now undertaken a systematic sequence analysis of >18,000 genes in human breast and colorectal tumors. Depiction of the mutational data on a topographic map indicates that each of these tumor types contains only a few gene "mountains" mutated at high frequency and a much larger number of gene "hills" mutated at low frequency. Importantly, while a large fraction of the mutations driving tumor growth reside in the gene hills rather than the mountains--a finding that underscores the heterogeneity of human cancer--it appears that many of the mutated genes function through cellular signaling pathways that are already well known.

L. D. Wood, D. W. Parsons, S. Jones, J. Lin, T. Sjöblom, R. J. Leary, D. Shen, S. M. Boca, T. Barber, J. Ptak, N. Silliman, S. Szabo, Z. Dezso, V. Ustyanksky, T. Nikolskaya, Y. Nikolsky, R. Karchin, P. A. Wilson, J. S. Kaminker, Z. Zhang, R. Croshaw, J. Willis, D. Dawson, M. Shipitsin, J. K. V. Willson, S. Sukumar, K. Polyak, B. H. Park, C. L. Pethiyagoda, P. V. Krishna Pant, D. G. Ballinger, A. B. Sparks, J. Hartigan, D. R. Smith, E. Suh, N. Papadopoulos, P. Buckhaults, S. D. Markowitz, G. Parmigiani, K. W. Kinzler, V. E. Velculescu, B. Vogelstein, The genomic landscapes of human breast and colorectal cancers.
Science
318
, 1108-1113 (2007).
[Abstract]
[Full Text]

J. M. Trent, J. W. Touchman, The gene topography of cancer.
Science
318
, 1079-1080 (2007).
[Summary]
[Full Text]
Entropy-Driven DNA Networks
Authors: Lavine Marc S.
Published: December 2007

A key aspect of electronic circuits is amplification or gain, so that low signals can be distinguished from any persistent background. Zhang
et al
. (see the Perspective by Bar-Ziv) show how gain can be achieved in biochemical circuits. They have designed complex catalytic networks based on DNA in which the output oligonucleotides that are released go on to act as catalysts for other reactions. The process is designed to be entropy-driven so that the pathways for reactions are well controlled and can be modified at will. Possible applications lie in the field of catalysis, sensor development, the development of an enzyme-free alternative for the polymerase chain reaction, and the construction of nanomachines.

D. Y. Zhang, A. J. Turberfield, B. Yurke, E. Winfree, Engineering entropy-driven reactions and networks catalyzed by DNA.
Science
318
, 1121-1125 (2007).
[Abstract]
[Full Text]

R. Bar-Ziv, DNA circuits get up to speed.
Science
318
, 1078-1079 (2007).
[Summary]
[Full Text]
Food for Thought?
Authors: Foley John F.
Published: December 2007

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the brain. The reduced production and function of neurotrophins (proteins that promote neuronal survival) in PD brains compared to that in normal brains may be a contributing factor in PD. Leptin is a hormone that functions in the hypothalamus to reduce appetite. Leptin receptors are also abundant in dopaminergic neurons in the SNc, leading Weng
et al
. to investigate whether leptin might play a role in neuronal survival. Immunohistochemical analyses showed that degeneration of mouse dopaminergic neurons in the SNc caused by injection into the brain of the neurotoxin 6-OHDA (a mouse model of PD) was less severe if the mice were pre-injected with leptin. Leptin was also protective against 6-OHDA-induced toxicity in mouse MN9D cells, a dopaminergic cell line. Western blotting assays and treatments with pharmacological inhibitors and short hairpin (sh) RNAs showed that the ability of leptin to block 6-OHDA-induced apoptosis was dependent on leptin receptor-mediated activation of Janus kinase 2 (JAK2), mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and the transcription factor cAMP response element-binding protein (CREB), a known neuronal survival factor. Leptin also stimulated the phosphorylation and nuclear localization of CREB in dopaminergic SNc neurons and increased the abundance of brain-derived neurotrophic factor (BDNF) in the brain compared with that in untreated animals. Together, these data suggest that treatment with leptin may be useful in therapies to combat PD.

Z. Weng, A. P. Signore, Y. Gao, S. Wang, F. Zhang, T. Hastings, X.-M. Yin, J. Chen, Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling.
J. Biol. Chem.
282
, 34479-34491 (2007).
[Abstract]
[Full Text]
Oxygen-Starved Worms
Authors: Foley John F.
Published: December 2007

Mammalian cardiac myocytes and neurons are conditioned by a period of hypoxia (low oxygen tension) to survive subsequent, more severe conditions of hypoxia. This adaptation process, known as hypoxic preconditioning (HP), has not been observed in invertebrates, leading Dasgupta
et al
. to investigate whether the nematode
Caenorhabditis elegans
exhibits features of HP. The authors exposed
C. elegans
to a 4-hour hypoxic episode, allowed the animals to recover, and then subjected them to a further 20 hours of hypoxia. This resulted in a much higher survival rate for these organisms than was observed in
C. elegans
that underwent 20-hour hypoxia without the earlier incubation. At least 8 hours of recovery time was needed after the initial hypoxic episode for protection to occur, which is consistent with late-phase HP in vertebrates. Microscopic analysis showed that the extent of hypoxia-induced pathology in the myocytes and neurons of
C. elegans
that had undergone HP was reduced compared with that in organisms without HP. Whereas
C. elegans
that had a loss-of-function mutation in
ced-4
(which encodes a component of the
C. elegans
apoptosis pathway) did not exhibit HP after early hypoxia,
C. elegans
with mutants of other components of this pathway exhibited normal HP. These included
C. elegans
with mutations in
ced-3
, which encodes CED-3, a protein that is known to multimerize with CED-4 to form an active caspase. This suggests a nonapoptotic role for CED-4 in the establishment of HP. Together, these data suggest that HP does indeed occur in invertebrates and that
C. elegans
might serve as a useful model organism for the study of HP.

N. Dasgupta, A. M. Patel, B. A. Scott, C. M. Crowder, Hypoxic preconditioning requires the apoptosis protein CED-4 in
C. elegans
.
Curr. Biol.
17
, 1954-1959 (2007).
[PubMed]
Ins
P
7
and Insulin Release
Authors: Ray L. Bryan
Published: December 2007

Inositol 1,4,5-trisphosphate (IP
3
) is a well-known second messenger in cellular signaling. More highly phosphorylated forms of this molecule, inositol pyrophosphates, may also function in cellular regulation. Illies
et al
. (see the Perspective by Nagamatsu and Ohara-Imaizumi) now show that Ins
P
7
(diphosphoinositol pentakisphosphate) is required for full exocytotic release of insulin from mouse pancreatic β cells. Depletion of the kinase that generates Ins
P
7
inhibited exocytosis, whereas overexpression of the enzyme stimulated exocytotic release of insulin. Pancreatic β cells may maintain high amounts of Ins
P
7
to help ensure ready release of insulin in response to metabolic demands.

C. Illies, J. Gromada, R. Fiume, B. Leibiger, J. Yu, K. Juhl, S.-N. Yang, D. K. Barma, J. R. Falck, A. Saiardi, C. J. Barker, P.-O. Berggren, Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic β cells.
Science
318
, 1299-1302 (2007).
[Abstract]
[Full Text]

S. Nagamatsu, M. Ohara-Imaizumi, IP
7
debut in insulin release.
Science
318
, 1249-1250 (2007).
[Abstract]
[Full Text]
Focus Issue: Mastering Nuclear Dynamics
Authors: Gough Nancy R.
Published: December 2007

Science
and
Science
's STKE delve into the complexity of the nucleus, a dynamic organelle. Along with a rich collection of articles about nuclear regulation, two Perspectives at
Science
's STKE highlight the nuclear transport of two very different transcriptional regulators.
Nuclear Localization of Growth Hormone Receptor: Another Age of Discovery for Cytokine Action?
Authors: Swanson Steven M. , Kopchick John J.
Published: December 2007

The conventional view of cytokine signaling is that receptors transmit information to the nucleus without leaving the plasma membrane. However, accumulating data suggest that some membrane receptors may signal by dissociating from the plasma membrane and translocating to the nucleus, where they direct the transcriptional machinery. One example is the growth hormone receptor (GHR), which has been observed in the nuclei of various normal and neoplastic tissues. Waters and colleagues now present new mechanistic data describing how GHR might localize to the nucleus and influence gene transcription. These findings may have implications for the way we think about cytokine signaling.
Losing RGS2 and a Taste for GHB
Authors: Adler Elizabeth M.
Published: December 2007

Depending on concentration, agonists of the γ-aminobutyric acid type B (GABA
B
) receptor can either potentiate or inhibit the activity of dopaminergic neurons arising in the ventral tegmentum (a pathway involved in addiction). Labouèbe
et al.--
researchers who provided a plausible mechanism for these opposing effects by showing that the coupling efficiency of GABA
B
receptors to G protein-activated inwardly rectifying potassium (GIRK) channels was greater in inhibitory GABAergic neurons than in dopaminergic neurons--explored regulation of GABA
B
-GIRK coupling. Immunoelectron microscopy of transgenic mice lacking different GIRK subunits showed that GIRK2 and GIRK3 were present in both ventral tegmental neurons in which they could detect tyrosine hydroxylase (TH, the rate-limiting enzyme for dopamine synthesis) and in neurons lacking TH, whereas GIRK1 was not found in TH-containing neurons. Both GIRK2 and GIRK3 contributed to currents evoked in dopaminergic neurons by the high-affinity GABA
B
agonist baclofen. Pharmacological analysis indicated that inhibition of regulator of G protein signaling proteins (RGS proteins, which act as GTPase-activating proteins) increased coupling efficiency (lowered EC
50
) of GABA
B
to GIRK. Furthermore, RGS2 was preferentially expressed in dopaminergic neurons and coupling efficiency was increased in mice lacking RGS2. Fluorescence resonance energy transfer (FRET) analysis, as well as electrophysiological analysis of knockout mice, indicated that RGS2 interacted directly with GIRK3 but not GIRK2. Repeated exposure of mice to γ-hydroxybutyrate (GHB, an addictive, low-affinity GABA
B
receptor agonist) or morphine over several days led to an increase in coupling efficiency between GABA
B
receptors and GIRK in dopaminergic neurons, as well as a decrease in RGS2 mRNA in the ventral tegmentum. Intriguingly, chronic exposure to GHB caused mice to lose their preference for solutions containing it and instead to avoid them. The authors suggest that these data may provide insight into new approaches to targeting dopaminergic activity in the ventral tegmentum to treat addiction.

G. Labouèbe, M. Lomazzi, H. G. Cruz, C. Creton, R. Luján, M. Li, Y. Yanagawa, K. Obata, M. Watanabe, K. Wickman, S. B. Boyer, P. A. Slesinger, C. Lüscher, RGS2 modulates coupling between GABA
B
receptors and GIRK channels in dopamine neurons of the ventral tegmental area.
Nat. Neurosci.
10
, 1559-1568 (2007).
[PubMed]
Sensing the End
Authors: Simpson Stephen J.
Published: December 2007

Cellular innate immune sensors detect foreign signals emanating from pathogens. Nallagatla
et al
. report that the pivotal sensing protein, double-stranded RNA-activated protein kinase (PKR), is finely tuned to recognize the 5′-triphosphate structures of single-stranded RNA molecules present in many bacteria and viruses. This recognition strategy is similar to the recently described detection of nucleic acid 5′-end signatures by another sensing protein, RIG-I. It remains unclear exactly how these key sensors go on to tailor the most appropriate cellular responses to intracellular pathogens.

S. R. Nallagatla, J. Hwang, R. Toroney, X. Zheng, C. E. Cameron, P. C. Bevilacqua, 5′-triphosphate-dependent activation of PKR by RNAs with short stem-loops.
Science
318
, 1455-1458 (2007).
[Abstract]
[Full Text]
A Discrete Signaling Function for an Inositol Pyrophosphate
Authors: Majerus Philip W.
Published: December 2007

Inositol pyrophosphates were, until recently, without clearly defined functions. Two recent papers in
Science
have now clearly defined a function for an IP
7
pyrophosphate (inositol hexaphosphate with one pyrophosphate) that is the product of the enzyme encoded by the
Vip1
gene in
Saccharomyces cerevisiae.
This IP
7
with a pyrophosphate tentatively assigned to be on either the 4 or 6 position is a cofactor that is required for inactivating the cyclin–cyclin-dependent kinase complex of Pho80, Pho81, and Pho85. Inhibition of the kinase results in the nuclear translocation of Pho4, which is a transcription factor that promotes expression of genes required for phosphate assimilation under conditions of low phosphate. When grown in low-phosphate media, IP
7
accumulates, which leads to the expression of genes involved in the acquisition of phosphate.
Follow the Leader
Authors: Foley John F.
Published: December 2007

The epithelial-mesenchymal transition allows cancer cells to remodel the extracellular matrix and invade tissues. However, invasive squamous cell carcinoma (SCC) cells do not lose their epithelial markers, which led Gaggioli
et al
. to investigate how these cells invaded tissues. The authors devised a three-dimensional culture system consisting of a matrix block, containing mainly collagen and laminin, placed in culture medium with its upper surface exposed. SCC cells placed on this surface did not invade the matrix when cultured alone but did so when cultured with fibroblasts from tumors, as determined by immunohistochemical staining. Invasion by SCC cells was blocked when a thin sheet of matrix was placed between the fibroblasts and the SCC cells. Differential fluorescent labeling of SCC cells and fibroblasts showed that a chain of invading SCC cells in the matrix was always preceded by a fibroblast. Electron and reflectance microscopy revealed that "tracks" in the matrix generated by fibroblasts contained deposits of fibronectin and evidence of matrix remodeling. Inhibitor studies showed that, whereas the invasion of the matrix by fibroblasts was dependent on the activities of matrix metalloproteinases, matrix remodeling was dependent on the small guanosine triphosphatase (GTPase) Rho and Rho-associated kinase (ROCK). Antibodies against the α3 and α5 integrins also inhibited matrix remodeling by fibroblasts. Inhibiting Rho or ROCK activity in SCC cells had no effect on their ability to follow fibroblasts; however, inhibition of the GTPase Cdc42 prevented invasion. Immunohistochemical analysis of sections from head and neck SCCs showed invading groups of SCC cells in close association with fibroblasts and fibronectin deposits. In commentary, Radisky discusses how the invasion process revealed in this study can help us in our understanding of metastasis.

C. Gaggioli, S. Hooper, C. Hidalgo-Carcedo, R. Grosse, J. F. Marshall, K. Harrington, E. Sahai, Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells.
Nat. Cell Biol.
9
, 1392-1400 (2007).
[PubMed]

D. C. Radisky, Leading the charge.
Nat. Cell Biol
.
9
, 1341-1342 (2007).
[PubMed]
Protecting the Liver from Death
Authors: Gough Nancy R.
Published: December 2007

The p53 protein plays key roles in regulating cell survival in response to stress, including roles in the nucleus as a transcriptional regulator, as well as transcription-independent roles outside the nucleus. One of these is activation of BAK oligomerization at the mitochondria, thereby promoting mitochondrial permeabilization and apoptosis. When p53 was stabilized by exposure of human HepG2 hepatoma cells to the MDM E3 ligase inhibitor nutlin-3, which does not cause DNA damage, an interaction between BAK and IGFBP1 was detected by affinity purification and coimmunoprecipitation and the two proteins colocalized at the mitochondria. Conditions that elevated p53, but did not inhibit RNA polymerase II (Pol II), also increased the abundance of IGFBP1 mRNA and protein, and protected cells from apoptosis. In HepG2 cells in which p53 was elevated and Pol II was inhibited, the abundance of IGFBP1 did not increase, p53 formed complexes with BAK, and the cells underwent apoptosis. Overexpression of IGFBP1 in osteosarcoma or breast carcinoma cell lines resulted in resistance to apoptosis caused by DNA damage. In isolated mitochondria from nutlin-3-treated HepG2 cells, conditions that promoted the accumulation of IGFBP1 at the mitochondria, the interaction of p53 with BAK and the formation of BAK oligomers was inhibited compared with that of mitochondria from untreated cells. The importance of IGFBP1 in vivo was confirmed with knockout mice, which were highly susceptible to liver damage caused by α-amanitin (inhibitor of Pol II) or cisplatin (DNA damage), and, in each case, mitochondrial accumulation of p53 correlated with apoptosis. As the expression of IGFBP1 is limited to liver, endometrium, and kidney, it appears that IGFBP1 may be a tissue-specific inhibitor of the mitochondrial p53 death pathway.

J. I.-J. Leu, D. L. George, Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at the mitochondria.
Genes Dev.
21
, 3095-3109 (2007).
[Abstract]
[Full Text]
Pain in the Brain
Authors: Ray L. Bryan
Published: December 2007

Delaney
et al.
provide new insights into signaling mechanisms that may help explain the integration of pain with stress reactions and with cognitive and emotional processing of pain signals in the brain. The discoveries come from an analysis of neurons in the central amygdala, a brain region where emotional responses to sensory stimuli are derived. Neurons carrying nociceptive information from a region known as the parabranchial nucleus make large synapses on cells of the central amygdala. Neurotransmission at these sites in rat brain slices was inhibited by noradrenaline, which is released by noradrenergic afferent neurons in the region. Electrophysiological experiments showed that noradrenaline acted presynaptically and appeared not to affect the probability of vesicle release but rather to limit the number of active release sites within the synapse. Experiments with inhibitors indicated that the noradrenaline acted at α2-adrenergic receptors coupled to G
i
- or G
o
-type heterotrimeric guanine nucleotide-binding proteins (G proteins). Loading of presynaptic terminals with a membrane-permeable peptide that binds to G protein βγ subunits inhibited the effects of noradrenaline, implicating Gβγ subunits in the process. Imaging of intracellular calcium concentrations with fluorescent dye showed that noradrenaline’s effects were independent of calcium concentrations. Thus, the Gβγ subunits appeared not to act by modulating channel activity but possibly by interacting with the vesicle release machinery. The actions of exogenous noradrenaline were also reproduced in experiments where release of noradrenaline from endogenous neurons was electrically stimulated. Tully
et al
. point out in commentary on the paper that this calcium-independent regulation might be particularly appropriate to reduce painful sensations during stressful situations that cause release of noradrenaline. Repetitive neuronal firing might gradually increase intracellular calcium concentrations sufficiently to overcome calcium-mediated inhibitory mechanisms, whereas the noradrenaline effect should be maintained even in the presence of rapid firing of presynaptic neurons.

A. J. Delaney, J. W. Crane, P. Sah, Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism.
Neuron
56
, 880-892 (2007).
[PubMed]

K. Tully, Y. Li, V. Y. Bolshakov, Keeping in check painful synapses in central amygdala.
Neuron
56
, 757-759 (2007).
[PubMed]
Learn from Your Mistakes
Authors: Stern Peter
Published: December 2007

Human experience is based on learning that our actions affect subsequent positive or negative outcomes. Rewards strengthen associations between contextual stimuli and actions, thereby reinforcing and maintaining successful behavior, whereas punishments induce avoidance of erroneous actions. While we usually learn from both positive and negative reinforcement, the relative amount of learning from success or errors varies between individuals. Klein
et al
. investigated a human genetic polymorphism associated with the density of brain dopamine D2 receptor. Reduced D2 receptor density was associated with less-efficient learning from errors. In people with lower D2 receptor density, the reduced capacity to learn from errors was accompanied by reduced feedback-related activity in the posterior medial frontal cortex, an area known to monitor for negative action outcomes.

T. A. Klein, J. Neumann, M. Reuter, J. Hennig, D. Y. von Cramon, M. Ullsperger, Genetically determined differences in learning from errors.
Science
318
, 1642-1645 (2007).
[Abstract]
[Full Text]
Identification of a Deubiquitinating Enzyme
Authors: Ray L. Bryan
Published: December 2007

Modification of proteins by the covalent attachment of ubiquitin chains has emerged as a major regulatory mechanism in cells. The enzymes that oppose this reaction, the deubiquitinating enzymes, are relatively poorly understood. Kayagaki
et al.
used an siRNA screen to search for deubiquitinating enzymes that influenced expression of the interferon I (IFN-I) gene in response to activation of Toll-like receptor 3 (TLR3), a central response by which the innate immune system detects viral RNAs and protects organisms from infection. They detected the deubiquitinase DUBA and went on to show that depletion of the enzyme enhanced the expression of IFN-1 and that overexpression of the protein inhibited the response. Other experiments identified the ubiquitin ligase TRAF3, which is required for induced expression of IFN-1, as a potential target of DUBA. Thus, DUBA restrains production of IFN-1, which, in excess, is associated with autoimmune disease.

N. Kayagaki, Q. Phung, S. Chan, R. Chaudhari, C. Quan, K. M. O'Rourke, M. Eby, E. Pietras, G. Cheng, J. F. Bazan, Z. Zhang, D. Arnott, V. M. Dixit, DUBA: A deubiquitinase that regulates type I interferon production.
Science
318
, 1628-1632 (2007).
[Abstract]
[Full Text]
Making the Right Cut
Authors: Vinson Valda
Published: December 2007

Regulated intramembrane proteolysis (RIP) represents an important signaling mechanism that is conserved from bacteria to humans. A notable example of RIP is the activation by cleavage of the transcription factor sterol regulatory element-binding protein by site-2 protease (S2P), a key event in regulating cellular cholesterol levels. Feng
et al
. now present the crystal structure of the transmembrane core of an archaebacterial S2P metalloprotease, which provides insight into how S2P functions. The structure shows the mechanism of cleavage at an active site, containing a catalytic zinc ion that is embedded deep in the membrane. Two conformations observed in the crystals suggest that a helical gating mechanism controls substrate access.

L. Feng, H. Yan, Z. Wu, N. Yan, Z. Wang, P. D. Jeffrey, Y. Shi, Structure of a site-2 protease family intramembrane metalloprotease.
Science
318
, 1608-1612 (2007).
[Abstract]
[Full Text]
Studies of SARM1 Uncover Similarities Between Immune and Neuronal Responses to Danger
Authors: Dalod Marc
Published: December 2007

Toll–interleukin-1 receptor (TIR) domain–containing proteins are best known as critical players in vertebrate immune defense against pathogens. Four of the five members of this family are required for the activation of immune cells downstream of the engagement of Toll-like receptors (TLRs) by microbial molecules. Mice deficient in any one of these four molecules show greatly enhanced susceptibility to specific classes of pathogens. However, the physiological function of the fifth mammalian protein, sterile alpha and TIR motif–containing 1 [SARM1, also known as myeloid differentiation marker 88-5 (MyD88-5)], has remained elusive. Now, the study of the SARM1 reporter and SARM1-deficient mice has uncovered an unanticipated function of this molecule in the regulation of neuronal survival in response to metabolic stress. Together with pioneering observations on the functions of TIR-1, the worm ortholog of SARM1, and other reports on the role of TLRs in neuronal development and responses to injury in mammals, these exciting results suggest that further studies of SARM1-deficient animals may uncover unexpected similarities between the ways in which neurons and immune cells sense and respond to danger.
Image Correlation Spectroscopy
Authors: Nohe Anja , Petersen Nils O.
Published: December 2007

Membrane domains, such as caveolae and clathrin-coated pits, regulate cell signaling and protein internalization in the plasma membrane. Fluorescence imaging and microscopy provide an opportunity to determine the receptor protein dynamics of membrane microdomains. The family of image correlation spectroscopy (ICS) techniques provides powerful tools with which to measure the aggregation, clustering, and dynamics of proteins in the plasma membrane. ICS is used to calculate the cluster density and the degree of aggregation of plasma membrane proteins, whereas image cross-correlation spectroscopy (ICCS) measures the fraction of colocalization of two proteins. Dynamic image correlation spectroscopy (DICS) can be used to analyze protein dynamics on the cell surface during live-cell imaging.
Identification of Redox-Active Cell-Surface Proteins by Mechanism-Based Kinetic Trapping
Authors: Schwertassek Ulla , Weingarten Lars , Dick Tobias P.
Published: December 2007

A number of thiol-dependent oxidoreductases are released from cells and act on the cell surface. Correspondingly, several cell-surface processes appear to depend on catalyzed thiol-disulfide exchange, including integrin activation and the fusion of viral particles with the host membrane. Tumor cells frequently increase the abundance of secreted and cell-surface forms of particular oxidoreductases, and evidence suggests that oxidoreductases released from tumor cells promote growth and contribute to the remodeling of the cellular microenvironment. Few cell-surface or membrane proteins that are targeted by extracellular redox enzymes have been identified. One major reason for this slow progress is the highly transient nature of thiol-disulfide exchange, making its detection by conventional techniques difficult or impossible. Here we describe the application of an activity-based proteomics approach, also known as "mechanism-based kinetic trapping," to identify individual cell-surface target proteins that engage in disulfide exchange with thiol-dependent oxidoreductases. Although we have applied this approach to thioredoxin-1, it should also be applicable to other members of the thioredoxin superfamily whose activity is based on the CXXC active-site motif.
Bringing It All Together
Authors: Adler Elizabeth M.
Published: December 2007

Polarization of various cell types depends on a complex containing the PDZ domain-containing scaffolding proteins Par-3 and Par-6 and atypical protein kinase C. Noting that phosphoinositides (PIPs) have also been implicated in cell polarization and that PDZ domains--although better known for mediating protein-protein interactions--can bind phosphatidylinositol (PI) lipids, Wu
et al
. investigated interactions between Par protein PDZ domains and PI lipids. The second Par-3 PDZ domain (PDZ2) bound to brain-derived liposomes with an affinity comparable to that of the PLCδ pleckstrin homology (PH) domain (a PI lipid-binding domain); strip-based assays and experiments with defined liposomes indicated that it bound directly to PIPs. Lipid-binding assays of 74 human PDZ domains and 14 PDZ tandems revealed that a subset bound PI lipids. Structural and biochemical analysis indicated that lipid binding by the Par-3 PDZ2 depended on a cluster of positively charged residues and that PDZ2 contained a PIP head group-binding pocket that overlapped its peptide ligand-binding site. In MDCK epithelial cells, Par-3 primarily localized to the cell membrane; mutational analysis indicated that membrane localization depended on PI lipid binding by PDZ2. Par-3 knockdown disrupted tight junction formation and reestablishment of polarization in MDCK cells. Epithelial repolarization was rescued by wild-type Par-3 or by a mutant in which the PLCδ PH domain replaced PDZ2 but not by mutants defective in lipid binding. The Par-3 PDZ3 domain bound to the lipid phosphatase PTEN. The authors conclude that lipid binding by the Par-3 PDZ2 domain is critical to its role in epithelial polarization and that the combination of PIP-binding by PDZ2 and PTEN-binding by PDZ3 could enable Par-3 to integrate PIP signaling.

H. Wu, W. Feng, J. Chen, L.-N. Chan, S. Huang, M. Zhang, PDZ domains of Par-3 as potential phosphoinositide signaling integrators.
Mol. Cell
28
, 886-898 (2007).
[PubMed]
TAMping Down Innate Immune Responses
Authors: Gough Nancy R.
Published: December 2007

Previous studies with knockout mice implicated the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases in regulation of innate immune responses. Rothlin
et al
. characterized the function of the receptor family in dendritic cells and showed that they stimulate the production of SOCS (suppressor of cytokine signaling) proteins, which are inhibitors of Toll-like receptor (TLR) signaling, thereby contributing to termination of the innate immune response. Splenic dendritic cells from single-, double-, or triple-knockout mice showed progressively severe hyperresponsiveness to stimuli that activate TLR3, TLR4, or TLR9, suggesting that the TAM family members are important inhibitors of multiple TLR pathways. In isolated mouse dendritic cells, only Mer and Axl were detected, and overnight activation of these cells with the TAM ligands Gas6 or ProS inhibited cytokine production stimulated by activation of TLR3, TLR4, or TLR9. The inhibition of TLR signaling by activation of the TAM proteins required new gene expression and protein synthesis, and screening for likely TLR inhibitors revealed that both the genes encoding SOCS1 and SOCS3 were stimulated in response to exposure of dendritic cells to Gas6. Gas6 stimulated the phosphorylation of the transcription factor STAT1, and STAT1 was required for TAM-mediated activation of
SOCS1
and
SOCS3
gene expression. TAM-mediated activation of STAT1 required the type I interferon (IFN) receptor subunit INFAR1, because Gas6 failed to stimulate SOCS1 expression in dendritic cells from
infar1
knockout mice. A TAM ligand-dependent interaction was detected between Axl and INFAR1 (by coimmunoprecipitation assay). Abundance of Axl mRNA was increased after TLR activation through a mechanism requiring STAT1 and INFAR1. IFN-mediated induction of
SOCS1
expression was substantially lost in TAM knockout dendritic cells. Coapplication of IFNα and Gas6 to dendritic cells increased SOCS1 mRNA production more than either ligand alone; however, expression of cytokine signaling stimulators by IFNα was inhibited by coapplication of Gas6. The authors suggest that there is a three-step inflammatory cycle: (i) activation of TLR signaling by a pathogen, (ii) amplification of the signal through production of IFN, and (iii) increased synthesis of the TAM proteins and production of SOCS proteins to inhibit TLR signaling. See O'Neill for commentary.

C. V. Rothlin, S. Ghosh, E. I. Zuniga, M. B. A. Oldstone, G. Lemke, TAM receptors are pleiotropic inhibitors of the innate immune response.
Cell
131
, 1124-1136 (2007).
[PubMed]

L. A. J. O'Neill, TAMpering with Toll-like receptor signaling.
Cell
131
, 1039-1041 (2007).
[PubMed]
HAMILTONIAN STRUCTURES OF TWO INTEGRABLE COUPLINGS OF THE MODIFIED AKNS HIERARCHY
Authors: ZHANG YUFENG , HON Y. C.
Published: December 2007

The extension of a three-dimensional Lie algebra into two higher-dimensional ones is used to deduce two new integrable couplings of the m-AKNS hierarchy. The Hamiltonian structures of the two integrable couplings are obtained, respectively. Specially, the complex Hamiltonian structure of the second integrable couplings is given.
STUDY ON THE OPTICAL PROPERTIES OF Mg, In CO-DOPED LITHIUM NIOBATE CRYSTALS
Authors: XU ZHAOPENG , JIAO BINLIANG , XU YUHENG , XU SHIWEN
Published: December 2007

Mg : In : LiNbO 3 crystals co-doped with 3 mol% MgO and 0.5 mol%, 1 mol% and 1.5 mol% In 2 O 3 were grown by the Czochralski method. The crystal composition and defect structure were analyzed by the infrared (IR) spectroscopy. The photo-damage resistance ability of the Mg : In : LiNbO 3 crystals was observed by straightly observing the transmission facula distortion method. The second harmonic generation (SHG) property of the Mg : In : LiNbO 3 crystals was measured. The results show that the photo-damage resistance ability of the Mg : In : LiNbO 3 crystals increases over one order of magnitude in comparison with that of the Mg : LiNbO 3 crystal. The phase-matching temperature of the Mg : In : LiNbO 3 crystals is near the room temperature. The SHG conversation efficiency of the Mg : In : LiNbO 3 crystals is higher than that of Mg -doped and In -doped LiNbO 3 crystals.
EFFECT OF L-METHIONINE ON THE OPTICAL PROPERTIES OF POTASSIUM ACID PHTHALATE
Authors: PAREY N. A. , SHAH M. A.
Published: December 2007

The effect of L-methionine doping on the optical properties of potassium acid phthalate have been studied. Bulk single crystals of L-methionine-doped potassium acid phthalate (LMDKAP) were grown by a slow cooling method using a constant temperature bath. X-ray powder diffraction study has revealed the significant variation in the cell parameter values and the shift in peak positions, which confirms the presence of dopant in the sample. The UV-VIS cut off wavelength of LMDKAP was found to be 300 nm and it is slightly less than KAP. The presence of functional groups present in LMDKAP were confirmed through FT-IR analysis.
THE STUDY OF COPPER-DOPED B2O3·Bi2O3 GLASS MATRIX BY SPECTROSCOPIC METHODS
Authors: ARDELEAN I. , LUCACEL RALUCA CICEO , CORA SIMONA
Published: December 2007

Glasses of x CuO · (100-x)[ B 2 O 3 · Bi 2 O 3] systems with 0≤x≤50 mol% were prepared and investigated by means of FT-IR, Raman and optical absorption spectroscopies. Complex network structures mainly built by BiO 3, BiO 6, BO 3 and BO 4 units were revealed for these glasses by means of FT-IR measurements. Similar structures were evidenced by means of Raman spectroscopy and additional new structural groups were detected in the glass structures, i.e. pyroborate, chain and ring type metaborate groups. The influence of copper-ion content (x) on the short-range order structure evolution was investigated. The optical absorption spectra for all glass samples present a single asymmetric band which corresponds to a 2 B 1g→2 B 2g transition of the of Cu 2+ ions in octahedral symmetry with an elongated tetragonal distortion.
EMERGENT FLUCTUATIONS IN THE TRAJECTORIES OF AGENT COLLECTIVES
Authors: MATHAI NEBU JOHN , ZOURNTOS TAKIS
Published: December 2007

Characteristics of the collective behavior of groups have been studied in diverse disciplines; in this work, we present an approach grounded in robotics. We first specify a model for collective behavior based on a formulation of a multi-agent robotic system. In contrast to some models found in the literature, we do not use stochastic mechanisms to introduce fluctuations. Rather, we present a fully deterministic model where fluctuations emerge due to the complex dynamics of a high-dimensional coupling of dynamical systems. We investigate the emergence of fluctuations in the trajectories of individual agents about the group average trajectory, and present an illustration of the onset of these fluctuations as inter-agent coupling is increased. A selection of behavioral modes are also provided, illustrating the nature of these fluctuations.
PROBABILITY DISTRIBUTIONS OF SCATTERED SIGNALS IN A RANDOM MULTILAYER
Authors: KIM J. -H.
Published: December 2007

This is a review paper on the study of the randomly scattered signals in a random multilayer based upon a stochastic and asymptotic formulation under strong mixing condition. This formulation generalizes the dominant Ito's formulation. The existence of a turning point of the random wave requires several type stochastic differential equations and the relevant limit theorems. The probability distributions of the randomly scattered signals have been obtained in the form of the Kolmogorov PDEs along the line of Khasminskii's limit theorem. This article demonstrates the step-by-step development of the relevant generators which contain the ultimate information for the probability distributions of the random signals.
Inhibitory and excitatory perigenital-to-bladder spinal reflexes in the cat
Authors: Tai Changfeng , Shen Bing , Wang Jicheng , Chancellor Michael B. , Roppolo James R. , de Groat William C.
Published: December 2007

This study revealed that in awake chronic spinal cord-injured (SCI) cats reflexes from perigenital skin area to the bladder can be either inhibitory or excitatory. Electrical perigenital stimulation at frequencies between 5 and 7 Hz significantly inhibited large-amplitude rhythmic reflex bladder activity, whereas frequencies between 20 and 40 Hz induced large-amplitude bladder contractions even at low bladder volumes when reflex bladder activity was absent. Both inhibitory and excitatory effects were enhanced as the stimulation intensity increased (5–30 V, 0.2-ms pulse width). During cystometrograms, the inhibitory stimulation (7 Hz) significantly increased the micturition volume threshold 35 ± 13% above the control volume, while the excitatory stimulation (30 Hz) significantly reduced the threshold 21 ± 3%. Mechanical perigenital stimulation applied by repeated light stroking of the perigenital skin with a cotton swab only induced an excitatory effect on the bladder. Both electrical and mechanical perigenital stimuli induced large-amplitude (>30 cmH2O) bladder contractions that were relatively consistent over a range of bladder volumes (10–90% of the capacity). However, the excitatory electrical stimulation only induced bladder contractions lasting on average 42.2 ± 3.9 s, but the mechanical stimulation induced bladder contractions that lasted as long as the stimulation continued (2–3 min). Excitatory electrical or mechanical perigenital stimulation also induced poststimulus voiding. The ability to either inhibit or excite the bladder by noninvasive methods could significantly transform the current clinical management of bladder function after SCI.
A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia
Authors: Raponi Mitch , Lancet Jeffrey E. , Fan Hongtao , Dossey Lesley , Lee Grace , Gojo Ivana , Feldman Eric J. , Gotlib Jason , Morris Lawrence E. , Greenberg Peter L. , Wright John J. , Harousseau Jean-Luc , Löwenberg Bob , Stone Richard M. , De Porre Peter , Wang Yixin , Karp Judith E.
Published: December 2007

At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a “leave one out” cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.
Controlled-source electromagnetic sounding in shallow water: Principles and applications
Authors: Andréis David , MacGregor Lucy
Published: December 2007

The marine controlled-source electromagnetic (CSEM) method is being applied to the problem of detecting and characterizing hydrocarbons in a variety of settings. Until recently, its use was confined to deepwater (water depths greater than approximately [Formula: see text]) because of the interaction of signals with the atmosphere in shallower water depths. The purpose of this study was to investigate, using a simple 1D analytical analysis, the physics of CSEM in shallow water. This approach demonstrates that it is difficult to simply decouple signals that have interacted with the earth from those that have interacted with the air using either frequency-domain or time-domain methods. Stepping away from wavelike approaches, which if applied without care can be misleading for the diffusive fields of CSEM, we demonstrate an effective way to mitigate the effect of the air in shallow water surveys by decomposing the EM signal into modes and using only the mode least affected by interaction with the atmosphere. Such decomposition is straightforward in a 1D earth, and we demonstrate that the approach remains valid in higher dimensional structures. We also show that the coupling between signals diffusing through the earth and those that have interacted with air can be used to our advantage in the interpretation of marine CSEM data.
GPR, TDR, and geochemistry measurements above an active gas vent to study near-surface gas-migration pathways
Authors: Pettinelli Elena , Beaubien Stan E. , Lombardi Salvatore , Annan A. Peter
Published: December 2007

The migration of deep gas to the atmosphere along faults and associated structures is important in many fields, from studying the natural contribution of atmospheric greenhouse gases leaking from geothermal areas to ensuring the safety of man-made natural gas and carbon dioxide [Formula: see text] geologic-storage sites. Near-surface geophysical and geochemical techniques were applied to a naturally occurring gas vent located along a deep terrestrial fault to better understand the structure and geophysical response of this gas-migration pathway. A number of ground-penetrating radar (GPR) profiles were first conducted across the vent. Spot samples were then measured along one of these profiles for in situ apparent permittivity (using time-domain reflectometry — TDR), complex permittivity on dried samples (using a capacitivecell), soil-gas composition, and clay and bulk mineralogy. Results show how the migrating gas induces secondary effects that modify the signature of the vent as seen in the GPR profiles. In particular, high flux rates across the vent core (i.e., the central portion of the vent) result in a total lack of vegetation, which in turn leads to high water content that is likely responsible, together with increased bulk conductivity, for GPR signal blanking. In the transition zone surrounding the core, a water-content minimum and other changes contribute to a deeper GPR signal penetration that highlights dipping events. Data show that the structure itself is slightly asymmetrical, which may indicate more fracturing to one side of the feature. This study shows that GPR surveys are capable of imaging secondary effects induced by gas migration in soils above a structural discontinuity, even if the structure itself cannot be imaged.
Constructing piecewise-constant models in multidimensional minimum-structure inversions
Authors: Farquharson Colin G.
Published: December 2007

A modification of the typical minimum-structure inver-sion algorithm is presented that generates blocky, piecewise-constant earth models. Such models are often more consistent with our real or perceived knowledge of the subsurface than the fuzzy, smeared-out models produced by current minimum-structure inversions. The modified algorithm uses [Formula: see text]-type measures in the measure of model structure instead of the traditional sum-of-squares, or [Formula: see text], measure. An iteratively reweighted least-squares procedure is used to deal with the nonlinearity introduced by the non-[Formula: see text] measure. Also, and of note here, diagonal finite differences are included in the measure of model structure. This enables dipping interfaces to be formed. The modified algorithm retains the benefits of the minimum-structure style of inversion — namely, reliability, robustness, and minimal artifacts in the constructed model. Two examples are given: the 2D inversion of synthetic magnetotelluric data and the 3D inversion of gravity data from the Ovoid deposit, Voisey’s Bay, Labrador.