bluuebunny/crossref_metadata_2025 huggingface dataset:
Raman scattering of longitudinal-optical-phonon-plasmon coupling in Cl-doped ZnSe under high pressure
Authors: Lin Y. C. , Chiu C. H. , Fan W. C. , Chia C. H. , Yang S. L. , Chuu D. S. , Lee M. C. , Chen W. K. , Chang W. H. , Chou W. C.
Published: December 2007

The vibrational, electronic, and crystalline properties of n-type chlorine-doped ZnSe (ZnSe:Cl) layers with a carrier concentration from 8.2×1015 to 1.8×1018 cm−3 are studied by Raman spectroscopy. The spectral line shapes of the longitudinal-optical-phonon and plasmon coupling mode are analyzed using the Raman scattering efficiency and the dielectric function to obtain the electron densities and mobility. The splitting of the transverse-optical (TO) phonon and the redshift of the chlorine-related impurity vibration mode are clearly observed when pressure is applied. The semiconductor-to-metal phase transition pressure of ZnSe:Cl layers declines as the carrier concentration increases, indicating that n-type doping reduces crystal stability. Additionally, the pressure-induced weakening of the longitudinal-optical-phonon-plasmon coupling efficiency suggests that pressure tends to degrade the n-type characteristic of ZnSe:Cl because of the emergence of the new deep donorlike state.
Electrically driven light emission from hot single-walled carbon nanotubes at various temperatures and ambient pressures
Authors: Wang Xinran , Zhang Li , Lu Yuerui , Dai Hongjie , Kato Y. K. , Pop Eric
Published: December 2007

Electroluminescence of individual single-walled carbon nanotubes down to ∼15K is measured. We observe electrically driven light emission from suspended quasimetallic nanotubes in vacuum down to ∼15K and under different gas pressures at room temperature. Light emission is found to originate from hot electrons in the presence of electrically driven nonequilibrium optical phonons. Reduced light emission is observed in exponential manner as electron and optical phonon temperatures in the nanotube are lowered by lower ambient temperature or higher gas pressure. The results reveal over wide ambient conditions, light emission in a suspended tube is from thermally excited electron-hole recombination.
Precise measurements of electron and hole g factors of single quantum dots by using nuclear field
Authors: Kaji R. , Adachi S. , Sasakura H. , Muto S.
Published: December 2007

We demonstrated the cancellation of the external magnetic field by the nuclear field at one edge of the nuclear polarization bistability in single InAlAs quantum dots. The cancellation for the electron Zeeman splitting gives the precise value of the hole g factor. In combination with the exciton g factor that is obtained from the Zeeman splitting for linearly polarized excitation, the magnitude and the sign of the electron and hole g factors in the growth direction are evaluated.
Optical investigation of type II GaSb∕GaAs self-assembled quantum dots
Authors: Alonso-Álvarez Diego , Alén Benito , García Jorge M. , Ripalda José M.
Published: December 2007

We have studied the emission and absorption properties of type II GaSb∕GaAs quantum dots embedded in a p-i-n photodiode. The excitation power evolution provides clear signatures of the spatially separated confinement of electrons and holes in these nanostructures. We have estimated the confinement potential for the holes to be ∼500meV, leading to an intense room temperature emission assisted by recapture processes from the wetting layer. Photocurrent measurements show strong absorption in the wetting layer and in the quantum dots at room temperature which are important for photodetection applications based in this system.
Electrical spin injection into the InAs∕GaAs wetting layer
Authors: Li C. H. , Kioseoglou G. , Hanbicki A. T. , Goswami R. , Hellberg C. S. , Jonker B. T. , Yasar M. , Petrou A.
Published: December 2007

We have used transport measurements, transmission electron microscopy, and polarization dependent photo- and electroluminescence to characterize the InAs∕GaAs(001) wetting layer (WL) system. Transport data confirm formation of a two-dimensional electron gas in modulation-doped structures. The optical pumping of the WL in an undoped structure provides a ratio of radiative to spin lifetime (τr∕τs)∼1, which is constant over the measurement range of 10–100K. We demonstrate efficient spin injection from an Fe Schottky tunnel contact into the WL, and achieve an electron spin polarization of ∼55% from 5to50K, which decreases monotonically with increasing temperature.
Strong excitonic transition of Zn1−xMgxO alloy
Authors: Tampo H. , Shibata H. , Maejima K. , Yamada A. , Matsubara K. , Fons P. , Niki S. , Tainaka T. , Chiba Y. , Kanie H.
Published: December 2007

A strong excitonic optical transition in a Zn1−xMgxO alloy grown by radical source molecular beam epitaxy was observed using both optical reflectivity measurements and photoluminescence (PL) measurements. Clear and strong reflectance peaks at room temperature (RT) were observed from 3.42eV (x=0.05)to4.62eV (x=0.61) from ZnMgO layers at RT. Distinct clear PL spectra at RT were also observed for energies up to 4.06eV (x=0.44). The peak intensity of the reflected signal increased for x values up to x∼0.2 simultaneously with an increase in PL intensity; however, a Stokes shift between the reflectance peak and the PL peak was not observed for x values below 0.2. These facts suggest that the oscillator strength of ZnMgO is enhanced by alloying, and the underlying mechanism is discussed. Furthermore, we demonstrate that the strong reflectance properties even at RT provide an easy method to determine the Mg composition of a thin ZnMgO layer in a ZnMgO∕ZnO heterostructure.
Low resistance as-deposited Cr∕Au contacts on p-type GaN
Authors: Kalaitzakis F. G. , Pelekanos N. T. , Prystawko P. , Leszczynski M. , Konstantinidis G.
Published: December 2007

The influence of several predeposition surface treatments and different contact metals to the electrical properties of metal/p-GaN contacts was studied. A low resistance as-deposited Cr∕Au Ohmic contact was achieved, using boiling aqua regia as surface treatment. The Ohmic resistance of Cr∕Au contacts with 50μm interspacing was found to be 50Ω, while the specific contact resistivity value was measured 2.6×10−3Ωcm2. Direct comparison with the standard oxidized Ni∕Au contacts confirmed the superior characteristics of the Cr∕Au contact scheme. Violet emission was readily obtained when the as-deposited Cr∕Au contacts were used as the p electrode of a light emitting diode emitting at 385nm.
Crack-free GaN grown on AlGaN∕(111)Si micropillar array fabricated by polystyrene microsphere lithography
Authors: Chen Guan-Ting , Chyi Jen-Inn , Chan Chia-Hua , Hou Chia-Hung , Chen Chii-Chang , Chang Mao-Nan
Published: December 2007

The authors report on the growth of GaN on AlGaN∕(111)Si micropillar array by metal-organic chemical vapor deposition. Using the substrates with micropillar array, 2-μm-thick GaN films without cracks can be achieved. Transmission electron microscopy, atomic force microscopy, and micro-Raman studies indicate that the dislocation density and residual stress of the GaN grown on micropillar array are also reduced. The results reveal the potential of this type of substrates for growing GaN-based devices as well as preparing GaN freestanding substrates.
Amygdala depotentiation and fear extinction
Authors: Kim Jeongyeon , Lee Sukwon , Park Kyungjoon , Hong Ingie , Song Beomjong , Son Gihoon , Park Heewoo , Kim Woon Ryoung , Park Eunjin , Choe Han Kyung , Kim Hyun , Lee Changjoong , Sun Woong , Kim Kyungjin , Shin Ki Soon , Choi Sukwoo
Published: December 2007

Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy, which involves enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a cellular mechanism for fear extinction; however, a direct link between depotentiation and extinction has not yet been tested. To address this issue, we applied both
ex vivo
and
in vivo
approaches to rats in which fear memory had been consolidated. A unique form of depotentiation reversed conditioning-induced potentiation at thalamic input synapses onto the LA (T-LA synapses)
ex vivo
. Extinction returned the enhanced T-LA synaptic efficacy observed in conditioned rats to baseline and occluded the depotentiation. Consistently, extinction reversed conditioning-induced enhancement of surface expression of AMPAR subunits in LA synaptosomal preparations. A GluR2-derived peptide that blocks regulated AMPAR endocytosis inhibited depotentiation, and microinjection of a cell-permeable form of the peptide into the LA attenuated extinction. Our results are consistent with the use of depotentiation to weaken potentiated synaptic inputs onto the LA during extinction and provide strong evidence that AMPAR removal at excitatory synapses in the LA underlies extinction.
Solution Interactions via Interferometry
Authors: Szuromi Phil
Published: December 2007

Interferometry is one of several techniques that can be used to probe the concentration and binding interactions of biomolecules, provided that the molecule’s binding partner is immobilized on a surface. Bornhop
et al
. now show that a fairly simple realization of back-scattering interferometry, which makes use of microfluidic channels for sample mixing and as the multipath cell for the laser light, can be used to determine dissociation constants for several pairs, apparently through changes in refractive index upon binding. Dissociation constants were determined for several binding pairs, including protein A with immunoglobulin G and activated calmodulin (CaM) with a small-molecule inhibitor or with calcineurin. Unlike microcalorimetric methods, these assays can be performed with very low amounts of samples; for example, the several CaM assays required only 200 picomoles of this protein.

D. J. Bornhop, J. C. Latham, A. Kussrow, D. A. Markov, R. D. Jones, H. S. Sørensen, Free-solution, label-free molecular interactions studied by back-scattering interferometry.
Science
317
, 1732-1736 (2007).
[Abstract]
[Full Text]
Competing for PH Domains
Authors: Gough Nancy R.
Published: December 2007

The inositol phospholipid PtdIns(3,4,5)P
3
is an important signaling lipid, the effects of which are predominantly mediated by its interaction with proteins containing pleckstrin homology (PH) domains. In neutrophils and the model organism
Dictyostelium discoideum
, PtdIns(3,4,5)P
3
plays an important role in chemotaxis. In
D. discoideum
, a soluble inositol polyphosphate diphosphoinositol pentakisphosphate (InsP
7
) was found to inhibit chemotaxis by competing for PH domains. Now Jia
et al
. show that in neutrophils, Ins(1,3,4,5)P
4
appears to serve as the soluble competitor for PH domains and consequently negatively influences neutrophil response to the chemoattractant fMLP. Stimulation of HL60 cells, a human cell line with characteristics of neutrophils, with fMLP rapidly and transiently increased the concentration of Ins(1,3,4,5)P
4
, increased the activity of the enzyme that produces this inositol polyphosphate, InsP3K, and increased the association of Ins(1,3,4,5)P
4
with a PH domain (using a PH domain linked to green fluorescent protein PH
Akt
-GFP). Application of a membrane-permeant derivative of Ins(1,3,4,5)P
4
was used to artificially increase Ins(1,3,4,5)P
4
concentration and, in HL60 cells, this inhibited chemoattractant-induced membrane translocation of PH
Akt
-GFP and phosphorylation of endogenous Akt, which is dependent on membrane association. In mouse neutrophils, artificial elevation of Ins(1,3,4,5)P
4
inhibited fMLP-stimulated chemotaxis (both directed movement and speed of migration). InsP3KB was the only isoform of InsP3K detected in mouse or human neutrophils. Analysis of neutrophils from mice deficient in InsP3KB showed that responses to fMLP were augmented (higher proportion of the kinase Akt was phosphorylated, abundance of filamentous actin was increased, and superoxide production was enhanced) compared with those in wild-type cells. Furthermore, the InsP3KB-deficient cells showed enhanced chemotaxis and increased sensitivity to chemoattractant stimulation. InsP3KB-deficient mice (in a mouse peritoneal inflammation assay) or InsP3KB-deficient neutrophils (in an adoptive transfer assay) showed enhanced recruitment to the site of bacterial or inflammatory agent injection compared with that of wild-type mice or cells from the host animal. Thus, Ins(1,3,4,5)P
4
appears to serve as a negative regulator of neutrophil stimulation, which may help keep the inflammatory response in check.

Y. Jia, K. K. Subramanian, C. Erneux, V. Pouillon, H. Hattori, H. Jo, J. You, D. Zhu, S. Schurmans, H. R. Luo, Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5-trisphophate signaling in neutrophils.
Immunity
27
, 453-467 (2007).
[PubMed]
Priming Protein Pyrophosphorylation
Authors: Gough Nancy R.
Published: December 2007

Inositol pyrophosphates are emerging players in the cell regulation arena. Although it was previously reported that diphosphoinositol pentakisphosphate [5-PP-Ins(1,2,3,4,6)P
5
, also abbreviated IP
7
] phosphorylates proteins in yeast and mammals, Bhandari
et al
. now provide biochemical evidence that this phosphorylation is a pyrophosphorylation event with different chemical characteristics than phosphorylation mediated by ATP. The authors found that although yeast proteins were readily phosphorylated by IP
7
, when the same targets were expressed in bacteria, these proteins were not phosphorylated by IP
7
. The addition of yeast extract and ATP or GTP to the bacterially produced proteins restored IP
7
-mediated phosphorylation. Casein kinase 2 (CK2) is an enzyme that can use either GTP or ATP to phosphorylate target proteins. Phosphorylation of an IP
7
target expressed in bacteria (a fragment of protein NSR1) by CK2 or isolation of the NSR1 fragment from bacteria also expressing CK2 made the peptide a target for IP
7
-mediated phosphorylation, suggesting that there is a priming phosphorylation required for IP
7
-mediated phosphorylation. A synthetic peptide from another IP
7
and CK2 target, Nopp140, was phosphorylated by IP
7
, but only when the peptide was synthesized with the serine residues prephosphorylated. The number of sites phosphorylated by IP7 always correlated with the number of preexisting phosphates on the peptide, and methylation of phosphates prevented IP
7
-mediated phosphorylation of prephosphorylated peptides. A peptide in which the sites were pyrophosphorylated during synthesis was not a target for IP
7
-mediated phosphorylation. Together these data suggest that IP
7
mediates a pyrophosphorylation modification after priming by an enzymatic ATP-mediated phosphorylation event. Consistent with a different type of bond, the phosphorylation by IP
7
was more labile under acid conditions than was phosphorylation through an ATP-mediated process. In contrast, IP
7
-mediated phosphorylation was resistant to the action of phosphatases (λ-phosphatase, alkaline phosphatase, calcineurin, or protein phosphatase 1). Whether this type of pyrophosphorylation event influences protein activity and function and how this process might be regulated are interesting questions.

R. Bhandari, A. Saiardi, Y. Ahmadibeni, A. M. Snowman, A. C. Resnick, T. Z. Kristiansen, H. Molina, A. Pandey, J. K. Werner Jr., K. R. Juluri, Y. Xu, G. D. Prestwich, K. Parang, S. H. Snyder, Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event.
Proc. Natl. Acad. Sci. U.S.A.
104
, 15305-15310 (2007).
[Abstract]
[Full Text]
What Awful Smell?
Authors: Adler Elizabeth M.
Published: December 2007

Although a rose by any other name might smell as sweet, two people smelling it might not experience that "sweetness" the same way. Different people differ markedly in their perceptions of particular odors: For example, some people think the testosterone derivative androstenone smells pleasantly floral, others think it smells like sweat or urine, and others don’t perceive its scent at all. Keller
et al
. expressed 335 putative human odorant receptors in a line of human cells that stably expresses accessory factors for odorant receptor expression and identified
OR7D4
--which is expressed in nasal epithelium--as encoding the receptor most responsive to androstenone. Searching a SNP database for
OR7D4
polymorphisms and sequencing the
OR7D4
coding region of 391 individuals enabled the identification of the most common
OR7D4
allele and a variant with two amino acid substitutions (R88W and T133M, leading to their respective designation as RT and WM). OR7D4 RT responded to androstenone and the related androstadienone (but not to 64 other odorants), whereas OR7D4 WM failed to respond to any odorants (including androstenone and androstadienone). People who were heterozygous for RT and WM or homozygous for WM were in general less sensitive to these two compounds than people who were homozygous for RT--and tended to have more positive perceptions of these odors. Statistical analysis implicated genetic polymorphisms in OR7D4 in differences in androstenone and androstadienone perception, although they did not fully account for such differences, indicating that odorant receptor function per se contributes to the subjective perception of odor.

A. Keller, H. Zhuang, Q. Chi, L. B. Vosshall, H. Matsunami, Genetic variation in a human odorant receptor alters odour perception.
Nature
449
, 468-472 (2007).
[PubMed]
Serpins Save Cells
Authors: Ray L. Bryan
Published: December 2007

Biologically active proteases are held in check in part by a family of peptidase inhibitors known as serpins. Most serpins are secreted proteins, but some are intracellular proteins implicated in regulating lysosomal proteases. Knockout mice have failed to reveal the biological roles of these inhibitors, though--possibly because mice have some 28 members of the intracellular variety. Therefore, Luke
et al
. turned to the worm
Caenorhabditis elegans
, which has about a third as many intracellular serpins. Loss of one of these, SRP-6, caused animals to become highly sensitive to hypo-osmotic stress and to die as a result of necrotic cell death. This effect appeared to require inhibition of cysteine peptidases because survival of the knockout worms was improved in mutant animals engineered to express wild-type SRP-6 but not in animals that expressed a mutant serpin that lacked inhibitory activity. Calcium mobilization appeared to be required for cell death as SRP-6 knockout animals lacking the ryanodine receptor, the inositol-1,4,5-trisphosphate receptor, or the Ca
2+
-binding protein calreticulin showed suppression of cell death. Lysosome-like gut granules also appeared to be required, because death was suppressed in animals lacking the Rab-like guanosine triphosphatase Glo-1, which is required for formation of these acidic granules. Animals lacking SRP-6 were also more susceptible than wild-type animals to heat shock, hypoxia, or hyperoxia. The authors argue that the common effects of serpins on these stimuli, which cause distinct biochemical alterations to initiate cell death, indicate that there may be a central necrotic death mechanism that can be regulated by serpins. If so, serpins could act as an antidote to cells undergoing damage by such stresses, which occur, for example, during heart attacks. Such a prosurvival function of intracellular serpins may help explain why increased expression of some serpin family members is associated with a poor prognosis in various human cancers.

C. J. Luke, S. C. Pak, Y. S. Askew, T. L. Naviglia, D. J. Askew, S. M. Nobar, A. C. Vetica, O. S. Long, S. C. Watkins, D. B. Stolz, R. J. Barstead, G. L. Moulder, D. Brömme, G. A. Silvermann, An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury.
Cell
,
130
, 1108-1119 (2007).
[PubMed]
Modeling Developmental Segmentation
Authors: Purnell Beverly A.
Published: December 2007

One of the classic problems in embryology is the segmentation of the body plan. In vertebrates, this process is underpinned by a multicellular oscillatory genetic network. Riedel-Kruse
et al
. modeled this complex "segmentation clock" as a population of simple, coupled oscillators in the presence of noise and compared their modeling with experimentally induced segment defects after quantitative inhibition of Notch signaling in the zebrafish embryo. The model predicts the position of posterior defects, a synchronized transition, and the existence of resynchronization and allows the estimation of coupling strength, noise, and robustness to perturbation.

I. H. Riedel-Kruse, C. Müller, A. C. Oates, Synchrony dynamics during initiation, failure, and rescue of the segmentation clock.
Science
317
, 1911-1915 (2007).
[Abstract]
[Full Text]
Neuronal Pathfinding
Authors: Hines Pamela J.
Published: December 2007

During development, the growing tips of neurons must locate and identify their preferred targets. Neurons follow attractive and repulsive guidance signals to build a network to connect muscle activity to brain signals, sensory inputs to behavioral responses, and so on. Fujisawa
et al
. have now discovered another component, EVA-1, in the guidance system for neurons that fine-tunes the guidance signals sent and received by different neurons in the model organism
Caenorhabditis elegans
.

K. Fujisawa, J. L. Wrana, J. G. Culotti, The Slit receptor EVA-1 coactivates a SAX-3/Robo–mediated guidance signal in
C. elegans
.
Science
317
, 1934-1938 (2007).
[Abstract]
[Full Text]
Sulfated Tyrosine and HIV Entry
Authors: Vinson Valda J.
Published: December 2007

In order for human immunodeficiency virus type 1 (HIV-1) to enter host cells, its envelope glycoprotein gp120 must bind to the host-cell surface receptor CD4 and to a co-receptor. An unusual posttranslational modification, tyrosine sulfation, is important to the co-receptor interaction. Huang
et al
. have investigated HIV-1 gp120 interactions with a sulfated N-terminal peptide from the co-receptor CCR5 and determined the crystal structure of a tyrosine-sulfated antibody in complex with gp120 and CD4. A conserved site in gp120 recognizes sulfo-tyrosine and might be a target for design of therapeutics.

C.-c. Huang, S. N. Lam, P. Acharya, M. Tang, S.-H. Xiang, S. Shahzad-ul Hussan, R. L. Stanfield, J. Robinson, J. Sodroski, I. A. Wilson, R. Wyatt, C. A. Bewley, P. D. Kwong, Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4.
Science
317
, 1930-1934 (2007).
[Abstract]
[Full Text]
PI3K Class IB Pathway in Neutrophils
Authors: Andrews Simon , Stephens Len R. , Hawkins Phillip T.
Published: December 2007

Activation of G
i
-coupled receptors in neutrophils stimulates class IB phosphoinositide 3-kinase (PI3K) (also known as PI3Kγ) through the combined actions of Gβγ subunits and the small guanosine triphosphatase (GTPase) Ras, resulting in the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P
3
] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P
2
] in the plasma membrane. In most cases, the effectors of this pathway possess a pleckstrin homology (PH) domain that mediates the interaction with and regulation by these two lipid messengers. These direct effectors sit within a complex regulatory network that includes several other signaling pathways and that is responsible for the control of important neutrophil functions, including adhesion, chemotaxis, secretion, and the "respiratory burst" [activation of the nicotinamide adenosine diphosphate (NADPH) oxidase]. Although the molecular details that link the direct effectors of class IB PI3K to these complex cell responses are still largely unknown, these responses involve complex regulation of small GTPases of the Rac, Rho, and Arf families.
Hypoxia-Inducible Factor 1 (HIF-1) Pathway
Authors: Semenza Gregg L.
Published: December 2007

Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix-PAS domain transcription factor that is expressed in all metazoan organisms and is composed of HIF-1α and HIF-1β subunits. Under hypoxic conditions, HIF-1 regulates the transcription of hundreds of genes in a cell type–specific manner. The HIF-1α subunit is regulated by O
2
-dependent hydroxylation of proline residue 402, 564, or both, by prolyl hydroxylase domain protein 2 (PHD2), which promotes binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation; and O
2
-dependent hydroxylation of asparagine residue 803 by factor inhibiting HIF-1 (FIH-1), which blocks the binding of the 300-kilodalton coactivator protein (p300) and CREB binding protein (CBP). The hydroxylation reactions, which utilize O
2
and α-ketoglutarate as substrates and generate CO
2
and succinate as by-products, provide a mechanism by which changes in cellular oxygenation are transduced to the nucleus as changes in HIF-1 activity. Hydroxylase activity is inhibited in the presence of low concentrations of O
2
, high concentrations of tricarboxylic acid cycle intermediates (isocitrate, oxaloacetate, succinate, or fumarate), or chelators of Fe(II). Receptor for activated C kinase 1 (RACK1) competes with heat shock protein 90 (HSP90) for binding to HIF-1α and mediates O
2
-independent ubiquitination and proteasomal degradation. A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1α.
Cell Signaling: Details, Details, Details
Authors: Gough Nancy R. , Adler Elizabeth M. , Foley John F.
Published: December 2007

From plants to flies to animals, new pathways and updates to the Database of Cell Signaling highlight pathways that regulate diverse functions—from cell motility and survival to development in mammals, plants, and insects.
A Long, Deprived Life or a Short, Sweet One?
Authors: Adler Elizabeth M.
Published: December 2007

In many multicellular eukaryotes--including mammals--reduced caloric intake is associated with increased life span. It has been postulated that this might result from a decrease in the metabolically dependent production of reactive oxygen species (ROS). However, whether reduced ROS production translates into increased life span has been a subject of debate. Schulz
et al
. exposed the nematode
Caenorhabditis elegans
to 2-deoxy-D-glucose (DOG)--which isn’t metabolized beyond the initial phosphorylation by hexokinase--to create a metabolic state similar to that elicited by glucose deprivation. Although glucose metabolism was decreased, mitochondrial respiration was increased, as was life span. Knockdown of a glycolytic enzyme also increased respiration and extended life span, whereas increased glucose availability led to a decrease in both parameters. DOG failed to increase oxygen consumption or life span in worms lacking AAK-2 (the
C. elegans
homolog of AMP-dependent kinase). DOG elicited an increase in ROS production after 48 hours and an increase in catalase activity after 6 days. Moreover, worms treated with DOG for 6 days were resistant to paraquat and sodium azide, stressors that can increase mitochondrial ROS production. Pretreatment with the ROS scavenger N-acetylcysteine reduced the DOG-dependent increases in ROS and life span, and in resistance to azide and paraquat, as did treatment with ascorbic acid (vitamin C) and trolox (a vitamin E derivative). The authors propose that glucose restriction may increase life span through a mechanism that depends on an AAK-dependent increase in ROS production--and thereby stress resistance--and raise questions about the desirability of antioxidant supplements.

T. J. Schulz, K. Zarse, A. Voigt, N. Urban, M. Birringer, M. Ristow, Glucose restriction extends
Caenorhabditis elegans
life span by inducing mitochondrial respiration and increasing oxidative stress.
Cell. Metab.
6
, 280-293 (2007).
[PubMed]
Released from the Nucleolus
Authors: Gough Nancy R.
Published: December 2007

Hand1 is a basic helix-loop-helix transcription factor involved in cell fate determination. One of its roles is in the differentiation of trophoblast stem cells to trophoblast giant cells (TGs), a process critical for the formation of the placenta. Martindill
et al.
show that Hand1 is localized in the nucleolus in a proliferating trophoblast-like cell line and is released from the nucleolus to spread throughout the nucleus at the onset and during differentiation into TGs. This process appears to involve phosphorylation of Hand1 by the polo-like kinase Plk4, the abundance of which increases at the onset of differentiation, which is localized to the nucleolus during the G2-to-mitosis transition. (Plk4 is also involved in exit from the mitotic cycle and the onset of endoreplication, which are involved in TG specification.) In addition, the regulatory subunit (B56δ) of protein phosphatase 2A was present in the nucleus, including the nucleolus in proliferating cells, and redistributes to the cytoplasm during TG differentiation. Overexpression of B56δ prevented nucleolar release of Hand1 and TG differentiation. The sequestration of Hand1 in the nucleolus appeared to involve a protein of the HIC family of transcriptional repressors, HICp40, because knockdown of this protein promoted release of Hand1 from the nucleolus and promoted TG differentiation, whereas overexpression prevented these events. Thus, it appears that dynamic subnuclear movement of Hand1, controlled by phosphorylation by Plk4, couples Hand1 to TG differentiation (see Tanenbaum and Medema for commentary).

D. M. J. Martindill, C. A. Risebro, N. Smart, M. Del Mar Franco-Viseras, C. O. Rosario, C. J. Swallow, J. W. Dennis, P. R. Riley, Nucleolar release of Hand1 acts as a molecular switch to determine cell fate.
Nat. Cell Biol.
9
, 1131-1141 (2007).
[PubMed]

M. E. Tanenbaum, R. H. Medema, Cell fate in the hand of Plk4.
Nat. Cell Biol.
9
, 1127-1129 (2007).
[PubMed]
Too Close for Molecular Comfort
Authors: Adler Elizabeth M.
Published: December 2007

Release of Ca
2+
from intracellular stores leads to the rapid translocation of the endoplasmic reticulum (ER)-resident protein STIM1 (stromal interacting molecule 1) to a region of the ER near the plasma membrane. This enables the interaction of STIM1 with the Orai1 channel and the subsequent entry of Ca
2+
across the plasma membrane. Várnai
et al
. investigated this process in living COS-7 cells in which they created molecular bridges between the plasma membrane and the adjacent ER. They targeted fluorescently labeled constructs containing the FRB fragment of mTOR (mammalian target of rapamycin) to the cytoplasmic face of the ER, and constructs containing the FKBP-12 protein to the inner face of the plasma membrane, and induced their heterodimerization with rapamycin. This allowed visualization of stable contact zones between the ER and the plasma membrane in conjunction with visualization of fluorescently labeled STIM1 and Orai1 (or both) before and after treatment with thapsigargin (to deplete Ca
2+
stores in the ER) or stimulation of P2Y receptors with ATP. These regions of juxtaposition coincided with the regions in which STIM1 and Orai1 interacted after store depletion; however, Orai1, and the STIM1-Orai1 complex, were excluded from cross-linked contact regions in which the gap between the ER and the plasma membrane was too narrow. The authors used linkers to create bridges of different length, which indicated that STIM1 could be accommodated when the gap between the two membranes was 4 to 6 nm, whereas Orai1 required a gap of 11 to 14 nm, suggesting that it exists as part of a large macromolecular complex.

P. Várnai, B. Tóth, D. J. Tóth, L. Hunyady, T. Balla, Visualization and manipulation of plasma membrane-endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1-Orai1 complex.
J. Biol. Chem.
282
, 29678-29690 (2007).
[Abstract]
[Full Text]
Neuronal Road Map
Authors: Hines Pamela J.
Published: December 2007

As the neural system develops, a distinctive network of interneuron connections is created. Colón-Ramos
et al
. now find that, in the nematode worm
Caenorhabditis elegans
, the supporting glial cells provide the requisite road map for making these connections. Particular glial cells express netrin, a signaling molecule, which tells the postsynaptic neuron where to find its connection and tells the presynaptic neuron where to build the substructures required for the connection. Localization of netrin expression in the glial cells serves to focus the neuronal synapse-building capacity in the right spot.

D. A. Colón-Ramos, M. A. Margeta, K. Shen, Glia promote local synaptogenesis through UNC-6 (netrin) signaling in
C. elegans.
Science
318
, 103-106 (2007).
[Abstract]
[Full Text]
Plant Protector Identified
Authors: Zahn Laura M.
Published: December 2007

Plants that survive an initial pathogen attack often develop enhanced resistance to subsequent infections. For example, previous infection of tobacco plants by tobacco mosaic virus (TMV) enhances resistance elsewhere in the plant to subsequent challenge by TMV or other pathogens, which is termed systemic acquired resistance (SAR). The development of SAR requires the movement of a signal made in the primary infected tissue through the phloem to the distal systemic tissue. Park
et al
. show that the mobile signal for SAR is a biologically inactive form of salicylic acid, methyl salicylate (MeSA), a key hormone for activating host defenses to many plant pathogens.

S.-W. Park, E. Kaimoyo, D. Kumar, S. Mosher, D. F. Klessig, Methyl salicylate is a critical mobile signal for plant systemic acquired resistance.
Science
318
, 113-116 (2007).
[Abstract]
[Full Text]
The Silence of the Flowering Genes
Authors: Hines Pamela J.
Published: December 2007

Transcription of genes is controlled by specific factors at each promoter and by a general state of activation or silencing in the surrounding chromatin. In the course of studying chromatin silencing in the plant
Arabidopsis
, Bäurle
et al
. noticed a defect in flowering. It seems that some of the genes already known to control flowering time, including
FCA
and
FPA
, also function to modify chromatin involved in other processes outside of flowering regulation. Haploid female gametophytic development and embryonic development seem to be particularly susceptible to failure of the chromatin-modification functions of FCA and FPA. Hence, FCA and FPA proteins are localized in the nucleus and are required for efficient silencing of a number of loci by mechanisms that seem to vary with different loci.

I. Bäurle, L. Smith, D. C. Baulcombe, C. Dean, Widespread role for the flowering-time regulators FCA and FPA in RNA-mediated chromatin silencing.
Science
318
, 109-112 (2007).
[Abstract]
[Full Text]
Phosphorylated Cofilin Not Inactive After All
Authors: Gough Nancy R.
Published: December 2007

Cofilin is an actin-depolymerizing factor, and this activity is inhibited when the protein is phosphorylated by LIM-kinase or TES-kinase. In an attempt to identify the mechanism by which the muscarinic acetylcholine receptor activated phospholipase D (PLD) downstream of the Rho effector Rho-kinase, Han
et al
. found that in the fibroblast cell line HEK293 and the neuroblastoma cell line N1E-115, PLD1 was not directly phosphorylated by Rho-kinase, but instead carbachol-stimulated PLD1 activation was inhibited by expression of a kinase-deficient LIM-kinase 1, which is a target for Rho-kinase. However, PLD1 was not a substrate for LIM-kinase 1 either, suggesting another step in the path from the receptor to PLD1. As cofilin is a known substrate for LIM-kinase 1, the authors overexpressed cofilin or a nonphosphorylatable mutant S3A cofilin and showed that carbachol-mediated stimulation of PLD1 was enhanced in the presence of excess wild-type cofilin and inhibited by S3A cofilin. RNAi-mediated depletion of cofilin also reduced carbachol-mediated activation of PLD1, consistent with a role for endogenous cofilin. Expression of a phosphorylation-mimic mutant of cofilin S3D also enhanced carbachol-stimulated PLD1 activation, whereas overexpression of the cofilin phosphatase slingshot inhibited PLD activation. Pull-down assays, as well as colocalization assays and coimmunoprecipitation assays with transfected cells, showed a direct interaction between PLD1 and phosphorylated, but not unphosphorylated, cofilin. If the interaction between cofilin and PLD1 was disrupted by expressing a fragment of PLD1 (F-3 fragment) responsible for mediating the interaction, then carbachol-mediated PLD1 activation was inhibited. Carbachol stimulation of stress fiber formation was also inhibited by the F-3 fragment. Carbachol stimulated the transient phosphorylation of cofilin and increased the interaction between the cofilin and PLD1 in coimmunoprecipitation assays. Phosphorylated cofilin stimulated PLD1 activity in vitro. Thus, phosphorylated cofilin is not an inactive entity but rather interacts with partners other than actin, such as PLD1.

L. Han, M. B. Stope, M. López de Jesús, P. A. Oude Weernink, M. Urban, T. Wieland, D. Rosskopf, K. Mizuno, K. H. Jakobs, M. Schmidt, Direct stimulation of receptor-controlled phospholipase D1 by phospho-cofilin.
EMBO J.
26
, 4189-4202 (2007).
[PubMed]
Endothelial Cells as Salt Sensors
Authors: Ray L. Bryan
Published: December 2007

Ingestion of large amounts of salt in the diet has been associated with increased blood pressure and harmful cardiovascular effects, but precisely how salt influences blood pressure is not clear. Oberleithner
et al
. describe experiments showing a direct effect of sodium on the physical stiffness of endothelial cells. The authors tested the effects on endothelial cells of small changes in sodium concentration (from about 130 to 150 mm) within a range that corresponds to that observed in humans ingesting a high-salt diet. They monitored changes in stiffness of cultured human endothelial cells by atomic force microscopy. Increases in the concentration of sodium increased stiffness of the endothelial cells within minutes, provided that the cells also were exposed to physiological concentrations of the hormone aldosterone. The increase in stiffness was inhibited in cells exposed to amilioride, an inhibitor of epithelial sodium channels. The authors applied simulated shear stress to the cells by shaking the culture flasks, a treatment expected to enhance accumulation of nitric oxide. Under these conditions, increased sodium concentration decreased the nitrite concentration in the culture medium. It remains unclear how the cells are sensing the extracellular concentration of sodium (a change in osmolality was prevented in the experiments by addition of mannitol). The authors propose that swelling of endothelial cells in response to relatively small increases in sodium concentration in the blood might have important effects on blood pressure. Endothelial cells sense mechanical stress, and their normal response of activating nitric oxide synthase appears to be blunted when the cells swell and stiffen after exposure to higher sodium concentrations. This could lead to increases in total vascular resistance and contributed to the deleterious effects of hypertension.

H. Oberleithner, C. Riethmüller, H. Schillers, G. A. MacGregor, H. E. de Wardener, M. Hausberg, Plasma sodium stiffens vascular endothelium and reduces nitric oxide release.
Proc. Natl. Acad. Sci. U.S.A.
104
, 16281-16286 (2007).
[Abstract]
[Full Text]
An Endogenous SERM?
Authors: Adler Elizabeth M.
Published: December 2007

Although estrogens have long been thought to be protective against cardiovascular disease, this assumption has been challenged by clinical trials that failed to corroborate such protective effects of hormone replacement therapy in postmenopausal women. Umetani
et al
. found that the cholesterol metabolite 27-hydroxycholesterol (27HC, which is found in atherosclerotic lesions) competed with estradiol for binding to estrogen receptor α and β (ERα and ERβ), inhibited estradiol-dependent activation of transcriptional activity of the receptors, and inhibited the estradiol-dependent association of ERβ with the transcriptional coactivator SRC-1. In mice fed diets rich in cholesterol and fat, hypercholesterolemia was associated with increased vascular concentrations of 27HC, so that it reached concentrations comparable to those affecting ER function. 27HC inhibited the estradiol-dependent increase in mRNA encoding inducible and endothelial nitric oxide synthase (iNOS and eNOS) in mouse aortic cultures, as well as estradiol-dependent NOS activity in rat aortic rings and lysates of a vascular smooth muscle cell line. Furthermore, 27HC reversed the estradiol-dependent inhibition of phenylephrine-mediated constriction of rat aortic rings. 27HC administration also decreased aortic expression of the mRNA encoding iNOS and eNOS in vivo, and dietary hypercholesterolemia was associated with a decrease in iNOS mRNA and protein in male mice. 27HC inhibited the rapid (nontranscriptional) estradiol-dependent stimulation of eNOS activity in bovine aortic endothelial cells, as well as estradiol-dependent endothelial cell migration in vitro and re-endothelialization in vivo. The pro- or anti-estrogenic effects of 27HC depended on tissue type, leading the authors to propose that it acted as an endogenous selective estrogen receptor modulator (SERM). The anti-estrogenic effects of 27HC in the vasculature led them to suggest that it might contribute to a lack of cardioprotective effects of estrogen in postmenopausal women.

M. Umetani, H. Domoto, A. K. Gormley, I. S. Yuhanna, C. L. Cummins, N. B. Javitt, K. S. Korach, P. W. Shaul, D. J. Mangelsdorf, 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen.
Nat. Med.
13
, 1185-1192 (2007).
[PubMed]
Uncovering a Mitochondrial Unfolded Protein Response
Authors: Gough Nancy R.
Published: December 2007

Proteins are synthesized and folded and assembled in the cytosol, endoplasmic reticulum (ER), and mitochondria. For the cytosol and ER, pathways associated with excess unfolded or misfolded proteins have been characterized and are called the heat shock response and the ER unfolded protein response (UPR
er
). Haynes
et al
. applied a genome-wide RNAi screen to identify four genes involved in the mitochondrial UPR (UPR
mt
) in
Caenorhabditis elegans
. Three of the genes were characterized in detail:
dve-1
, which encodes a homolog of the
Drosophila
homeobox transcription factor defective proventriculus and mammalian SatB2;
ubl
-
5
, which encodes a ubiquitin-like protein; and
clpp-1
, which encodes a protein homologous to the bacterial protease ClpP. (The fourth encoded guanosine triphosphatase homologous to mammalian Rheb.) Reduction in the expression of any of these genes compromised the expression of the chaperone Hsp60 in response to mitochondrial unfolded protein stress without interfering with UPR
er
and caused perturbed mitochondrial morphology, consistent with persistent UPR
mt
. DVE-1 showed a nuclear localization and redistributed to nuclear puncta in response to conditions of mitochondrial unfolded protein stress. In worms deficient in, but not completely lacking, DVE-1 (the latter was lethal), mitochondrial mass was decreased (as detected by MitoTracker staining and ligand blot assay). In an affinity purification assay, a tagged form of DVE-1 and a tagged form of UBL-5 were found to form a complex when the worms were subjected to conditions causing mitochondrial unfolded protein stress. A similar interaction was observed for the mammalian homologs. RNAi experiments suggested that CLPP-1 acted upstream of UBL-5 (the expression of which is stimulated in response to conditions of mitochondrial unfolded protein stress) and of DVE-1 in the UPR
mt
. CLPP-1 was localized to the matrix of the mitochondria, where it appeared to be part of a large multisubunit complex. When CLPP-1 activity was decreased by RNAi, increased expression of the
ubl-5
and
hsp60
genes in response to conditions that cause mitochondrial unfolded protein stress was compromised, and the redistribution of DVE-1 to nuclear puncta was also blocked. Protease inhibitors also prevented the stimulation of
ubl-5
expression in response to mitochondrial unfolded protein stress, suggesting that the protease activity of CLPP-1 is important for its function in the UPR
mt
.

C. M. Haynes, K. Petrova, C. Benedetti, Y. Yang, D. Ron, ClpP mediates activation of a mitochondrial unfolded protein response in
C. elegans
.
Dev. Cell
13
, 467-480 (2007).
[PubMed]
Cholesterol and Alzheimer’s Disease
Authors: Foley John F.
Published: December 2007

The relationship between the abundance of cholesterol in the brain and Alzheimer’s disease (AD) progression is a controversial one, although cholesterol is necessary for neuronal function. Because the
ε4
allele of the gene encoding apolipoprotein E (apoE), a lipoprotein that transports cholesterol, is a genetic risk factor for late-onset AD, Liu
et al
. investigated a link between amyloid precursor protein (APP), apoE, and cholesterol metabolism. Sequential cleavage of APP, a transmembrane protein, by β-secretase and γ-secretase releases amyloid β-peptide (Aβ) and the APP intracellular domain (AICD) into the extracellular space, where the former forms plaques. The authors found that the abundance of apoE (as measured by enzyme-linked immunosorbent assay) was lower in the brains of
APP
-deficient mice (APP-KO) and mice deficient in both
APP
and the related
APLP2
(DKO) than in wild-type mice. Real-time polymerase chain reaction and Western blotting analyses showed that the abundance of the apoE receptor LRP1 was higher in APP-KO and DKO mice than in wild-type controls. Brain-specific deletion of
LRP1
resulted in the higher abundance of apoE in the brains of these mice than in the brains of wild-type mice. Deletion of the gene encoding β-secretase, which is required for Aβ production, had no effect on LRP1 abundance or function. However, deletion of both
presenilin 1
(
PS1
) and
PS2
(PS DKO), which encode proteins critical to the function of γ-secretase, resulted in the higher abundance of LRP1 in PS DKO mice compared with that of wild-type mice. Further analysis showed that the AICD, released through γ-secretase activity, combined with the adaptor protein Fe65 and bound to the
LRP1
promoter, inhibiting its expression. Thus, APP processing by γ-secretase results in the decreased abundance of LRP1, which results in the reduced uptake of apoE-complexed cholesterol. Together, these data suggest a role for APP in regulating apoE and cholesterol metabolism, through the lipoprotein receptor LRP1, which provides new therapeutic targets for treating AD.

Q. Liu, C. V. Zerbinatti, J. Zhang, H.-S. Hoe, B. Wang, S. L. Cole, J. Herz, L. Muglia, G. Bu, Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1.
Neuron
56
, 66-78 (2007).
[PubMed]
Unraveling PKA Isoform Specificity
Authors: Vinson Valda J.
Published: December 2007

Cyclic adenosine monophosphate (cAMP) is a signal for cellular stress that, in mammalian cells, binds to cAMP-dependent protein kinase (PKA) to activate diverse signaling pathways. Functional diversity is achieved partly by isoform diversity in the catalytic and regulatory (R) subunits of PKA. In particular, there are two main classes of regulatory subunit, type I and type II, that inhibit C in the absence of cAMP. To gain insight into the molecular basis for isoform diversity, Wu
et al
. have determined the structure of an RIIα holoenzyme and compared it to the previously determined structure of an RIα holoenzyme. The structure shows that the C subunit uses different docking motifs to interact with different inhibitors and shows how ATP differentially regulates the two holoenzymes. The insights may guide design of isoform-specific activators or antagonists for PKA.

J. Wu, S. H. J. Brown, S. von Daake, S. S. Taylor, PKA type IIα holoenzyme reveals a combinatorial strategy for isoform diversity.
Science
318
, 274-279 (2007).
[Abstract]
[Full Text]