bluuebunny/crossref_metadata_2025 huggingface dataset:
Second‐class doctors? The impact of a professional career structure on the employment conditions of overseas‐ and UK‐qualified doctors
Authors: Oikelome Franklin , Healy Geraldine
Published: March 2007

Career structures and their associated boundaries both offer and restrict career opportunities and provide the potential to be sites of unfair discrimination. Yet the impact of such structures is rarely explored. This article investigates the impact of a career structure on the employment conditions of a medical career grade in which some three‐quarters of the doctors qualified overseas. The comparison of UK and overseas qualified doctors in the Staff and Associate Specialist Group provides an underexplored perspective on a professional career structure with a particular reference to reward, workload, autonomy and morale. The article draws on a quantitative study of 1,715 Staff and Associate Specialist doctors undertaken in 2004. The findings demonstrate a complex comparative picture with overseas‐qualified doctors earning more, working for longer hours, having less autonomy and a lower morale than their UK‐qualified comparators. We conclude by pointing to the potential for certain career structures to structurally and systematically disadvantage some groups.
Muscle metabolism during graded quadriceps exercise in man
Authors: Helge Jørn W. , Stallknecht Bente , Richter Erik A. , Galbo Henrik , Kiens Bente
Published: March 2007

The aim of the study was to examine local muscle metabolism in response to graded exercise when the involved muscle mass is too small to elicit marked hormonal changes and local blood flow restriction. Nine healthy overnight fasted male subjects performed knee extension exercise with both thighs kicking at 25% of maximal power (Wmax) for 45 min (23 ± 1% of pulmonary ) followed by 35 min of kicking with one thigh at 65% and the other at 85%Wmax (40 ± 1%). Primed constant infusion of [U‐13C] palmitate and [2H5]glycerol was carried out. Blood was sampled from a femoral artery and both femoral veins, and thigh blood flow was determined by thermodilution. Muscle biopsies were obtained from m. vastus lateralis of both thighs. From rest through exercise at 25, 65 and 85%Wmax the thigh blood flow (0.3 ± 0.1, 2.5 ± 0.2, 3.5 ± 0.2, 4.1 ± 0.3 l min−1) and oxygen uptake (0.02 ± 0.01, 0.27 ± 0.03, 0.48 ± 0.04, 0.55 ± 0.05 l min−1) increased (P < 0.05). The plasma fatty acids oxidized in the thigh (5 ± 1, 114 ± 15, 162 ± 30, 180 ± 31 μmol min−1) increased (P < 0.05) with exercise intensity, whereas the total thigh fat oxidation (19 ± 6, 312 ± 64, 356 ± 93, 323 ± 120 μmol min−1) increased (P < 0.05) from rest, but remained unchanged through exercise. The thigh glycerol uptake (1 ± 1, 16 ± 4, 24 ± 10, 39 ± 8 μmol min−1) increased significantly from rest through exercise at 25–65 and 85%Wmax, respectively. Glucose uptake and glycogen breakdown always increased with exercise intensity. In conclusion, in the presence of a high blood flow and oxygen supply and only small hormonal changes, total fat oxidation in muscle increases from rest to light exercise, but then remains constant with exercise intensity up to heavy exercise. However, with increasing exercise intensity, oxidation of plasma free fatty acids increases and accordingly oxidation of other fat sources decreases. These findings are in contrast to whole body measurements performed during graded exercise involving a large muscle mass during which fat oxidation peaks at around 60% of .
Inhibition of KATPchannels in the rat tail artery by neurally released noradrenaline acting on postjunctional α2‐adrenoceptors
Authors: Tan Joy H. , Al Abed Amr , Brock James A.
Published: March 2007

In rat tail artery, activation of postjunctional α2‐adrenoceptors by noradrenaline (NA) released from sympathetic axons produces a slow depolarization (NAD) of the smooth muscle through a decrease in K+conductance. In this study we used intracellular recording to investigate whether the K+channel involved is the ATP‐sensitive K+(KATP) channel. Changes in membrane resistance were monitored by measuring the time constant of decay of excitatory junction potentials. The KATPchannel blockers, glibenclamide (10 μm) and PNU 37883A (5 μm), depolarized the smooth muscle and increased membrane resistance. Conversely, the KATPchannel openers, pinacidil (0.1 and 0.5 μm) and levcromakalim (0.1 μm), hyperpolarized the smooth muscle and decreased membrane resistance. Activation of KATPchannels with calcitonin gene‐related peptide (CGRP; 10 nm) also hyperpolarized the smooth muscle and decreased membrane resistance. The NAD was abolished by both glibenclamide and PNU 37883A but was potentiated by CGRP. However, unlike CGRP, the directly acting KATPchannel openers, pinacidil and levcromakalim, inhibited the NAD. The effects of other K+channel blockers were also determined. A high concentration of Ba2+(1 mm), which would be expected to block KATPchannels, abolished the NAD, whereas teteraethylammonium (1 mm) and 4‐aminopyridine (1 mm) increased its amplitude. Apamin (0.5 μm) and a lower concentration of Ba2+(0.1 mm) did not affect the NAD. These findings indicate that activation of α2‐adrenoceptors by neurally released NA depolarizes the membrane of vascular smooth muscle by inhibiting KATPchannels open in the resting membrane.
The Variable Rotation Period of the Inner Region of Saturn's Plasma Disk
Authors: Gurnett D. A. , Persoon A. M. , Kurth W. S. , Groene J. B. , Averkamp T. F. , Dougherty M. K. , Southwood D. J.
Published: March 2007

We show that the plasma and magnetic fields in the inner region of Saturn's plasma disk rotate in synchronism with the time-variable modulation period of Saturn's kilometric radio emission. This relation suggests that the radio modulation has its origins in the inner region of the plasma disk, most likely from a centrifugally driven convective instability and an associated plasma outflow that slowly slips in phase relative to Saturn's internal rotation. The slippage rate is determined by the electrodynamic coupling of the plasma disk to Saturn and by the drag force exerted by its interaction with the Enceladus neutral gas torus.
How Do MicroRNAs Regulate Gene Expression?
Authors: Jackson Richard J. , Standart Nancy
Published: March 2007

Several thousand human genes, amounting to about one-third of the whole genome, are potential targets for regulation by the several hundred microRNAs (miRNAs) encoded in the genome. The regulation occurs posttranscriptionally and involves the ~21-nucleotide miRNA interacting with a target site in the mRNA that generally has imperfect complementarity to the miRNA. The target sites are almost invariably in the 3′-untranslated region of the messenger RNA (mRNA), often in multiple copies. Metazoan miRNAs were previously thought to down-regulate protein expression by inhibiting target mRNA translation at some stage after the translation initiation step, without much effect on mRNA abundance. However, recent studies have questioned these suppositions. With some targets, an increase in the rate of mRNA degradation by the normal decay pathway contributes to the decrease in protein expression. miRNAs can also inhibit translation initiation, specifically the function of the cap-binding initiation factor, eIF4E. Repressed target mRNAs as well as miRNAs themselves accumulate in cytoplasmic foci known as P-bodies, where many enzymes involved in mRNA degradation are concentrated. However, P-bodies may also serve as repositories for the temporary and reversible storage of untranslated mRNA, and reducing the expression (knockdown) of several distinct P-body protein components can alleviate miRNA-mediated repression of gene expression.
RGS Proteins: Swiss Army Knives in Seven-Transmembrane Domain Receptor Signaling Networks
Authors: Heximer Scott P. , Blumer Kendall J.
Published: March 2007

Coordinated regulation of heterotrimeric guanine nucleotide–binding protein (G protein) activity is critical for the integration of information from multiple intracellular signaling networks. The human regulator of G protein signaling (RGS) protein family contains more than 35 members that are well suited for this purpose. Although all RGS proteins contain a core ~120–amino acid Gα-interacting domain (called the RGS domain), they differ widely in size and organization of other functional domains. Architecturally complex RGS proteins contain multiple modular protein-protein interaction domains that mediate their interaction with diverse signaling effectors. Architecturally simple RGS proteins contain small amino-terminal domains; however, they show surprising versatility in the number of intracellular partners with which they interact. This Perspective focuses on RGS2, a simple RGS protein with the potential to integrate multiple signaling networks. In three recent studies, the amino-terminal domain of RGS2 was shown to interact with and regulate three different effector proteins: adenylyl cyclase, tubulin, and the cation channel TRPV6. To explain this growing list of RGS2-interacting partners, we propose two models: (i) The amino-terminal domain of RGS2 comprises several short effector protein interaction motifs; (ii) the amino-terminal domain of RGS2 adopts distinct structures to bind various targets. Whatever the precise mechanism controlling its target interactions, these studies suggest that RGS2 is a key point of integration for multiple intracellular signaling pathways, and they highlight the role of RGS proteins as dynamic, multifunctional signaling centers that coordinate a diverse range of cellular functions.
Bcl-xL Deamidation a Trigger for Apoptosis
Authors: Gough Nancy R.
Published: March 2007

Using a transgenic mouse as a model for T cell lymphoma, Zhao
et al
. provide evidence that defective deamidation of Bcl-xL contributes to the apoptosis resistance and oncogenesis of thymocytes in these animals. These mice (
CD45
−/−

lck
F505

) are deficient in the phosphatase CD45 and have a mutant form of the kinase Lck. DNA damage does not cause apoptosis in the thymocytes of these mice despite a normal p53 response. Bcl-xL sequesters the proapoptotic BH3 domain proteins, such as Bim and Puma, and deamidation, which converts Asn
52
and Asn
66
to isoaspartate (Iso-Asp), has been suggested to prevent this interaction, allowing apoptosis to proceed. Zhao
et al
. show that Bcl-xL deamidation (monitored by retardation on native gel electrophoresis) was not prevented by a pan-caspase inhibitor or by knockdown of Bax and Bak (two proteins required for mitochondrial-mediated apoptosis). Thus, Bcl-xL deamidation appears to occur before caspase activation and not as a consequence of caspase activation. Coimmunoprecipitation experiments confirmed that Bcl-xL did not bind Bim or Puma and that the interaction between Bcl-xL and these two proteins was not lost in response to DNA damage in the cells from the
CD45
−/−

lck
F505

mice. Anion-exchange chromatography was used to separate native from deamidated Bcl-xL, and the lack of interaction between Bim and the deamidated forms was confirmed. The authors noted that deamidation occurs more readily at higher pH and found that DNA damage raises the intracellular pH of wild-type thymocytes. When the pH of wild-type cells was artificially elevated, Bcl-xL deamidation occurred to a greater extent than at neutral pH, and when DNA damage was induced under conditions that prevented the elevation in pH, Bcl-xL deamidation was prevented, and the number of apoptotic cells was reduced. The resistance to apoptosis in response to DNA damage was overcome in the
CD45
−/−

lck
F505

thymocytes when the pH was increased to 7.55 or above. DNA damage triggers an increase in the abundance of the Na
+
/H
+
exchanger 1 (NHE-1) through increased gene expression in wild-type cells, and this is not observed in the
CD45
−/−

lck
F505

cells. Overexpression of NHE-1 in the
CD45
−/−

lck
F505

and wild-type cells caused Bcl-xL deamidation and triggered apoptosis; whereas pharmacological inhibition of NHE-1 activity blocked alkalinization, Bcl-xL deamidation, and apoptosis. Using cells from patients with chronic lymphocytic leukemia, the authors showed that enforced alkalinization caused an increase in Bcl-xL deamidation and apoptosis.

R. Zhao, D. Oxley, T. S. Smith, G. A. Follows, A. R. Green, D. R. Alexander, DNA damage-induced Bcl-x
L
deamidation is mediated by NHE-1 antiport regulated intracellular pH.
PLoS Biol.
5
, e1 (2007).
[PubMed]
EGFR Signaling Inhibits E2F1-Induced Apoptosis in Vivo: Implications for Cancer Therapy
Authors: Ginsberg Doron
Published: March 2007

The retinoblastoma tumor suppressor (RB) restricts cell proliferation by regulating members of the E2F family of transcription factors. In human tumors RB is often inactivated, resulting in aberrant E2F-dependent transcription and uncontrolled proliferation. One of the E2F proteins, E2F1, can also induce apoptosis. The extent of E2F1-induced apoptosis is known to be tissue- and cell-specific, but until now, it has been unclear what variables determine cellular sensitivity to E2F1-induced apoptosis in vivo. A recent study reveals epidermal growth factor receptor (EGFR) signaling to be one such variable, as EGFR signaling cooperates with RB in inhibiting E2F1-induced apoptosis. This finding raises the possibility that therapeutic manipulation of EGFR signaling may specifically trigger the death of cancer cells with inactive RB, thereby enabling "targeted" cancer treatments.
Making the Gradient
Authors: Hurtley Stella M.
Published: March 2007

The role of gradients of morphogens in developmental biology is well established, but the mechanisms involved in the establishment and maintenance of these gradients are controversial. Kicheva
et al
. present a quantitative study of the kinetics of morphogen transport and the formation of morphogen gradients in the wing disc of
Drosophila
. The steady-state gradients of two morphogens can be described by a simple exponential decay defined by four key kinetic parameters.

A. Kicheva, P. Pantazis, T. Bollenbach, Y. Kalaidzidis, T. Bittig, F. Jülicher, M. González-Gaitán, Kinetics of morphogen gradient formation.
Science
315
, 521-525 (2007).
[Abstract]
[Full Text]
Exploiting Your Niche
Authors: Purnell Beverly
Published: March 2007

In
Drosophila
, male germ line stem cells orient the mitotic spindle to generate a daughter stem cell and a cell destined for germ cell differentiation after asymmetric cell division. Using gene mutation and ultrastructural studies, Yamashita
et al
. (see also the Perspective by Spradling and Zheng) now identify the mechanism by which the oriented spindle is established. The mother and daughter centrosomes are differentially oriented, with the mother centrosome anchored close to the niche-stem cell junction by microtubules, whereas the daughter centrosome migrates to the other side of the cell. This differential centrosome identity and migration may provide a mechanism for asymmetric cell division in the generation of daughter cells with different developmental fates.

Y. M. Yamashita, A. P. Mahowald, J. R. Perlin, M. T. Fuller, Asymmetric inheritance of mother versus daughter centrosome in stem cell division.
Science
315
, 518-521 (2007).
[Abstract]
[Full Text]

A. C. Spradling, Y. Zheng, The mother of all stem cells?
Science
315
, 469-470 (2007).
[Summary]
[Full Text]
Why the Taste of Some Spicy Foods Lingers
Authors: Gough Nancy R.
Published: March 2007

TRPA1 is a member of the transient receptor potential (TRP) family of ion channels and is involved in the sensation of noxious stimuli, including chemicals in food that are perceived as pungent or spicy. Macpherson
et al
. report that structurally diverse chemicals that can covalently interact with cysteine residues activate mouse TRPA1 channels. Using alkyne-modified agonists, they detected the alkyne-tagged residues on the channels using a fluorophore that reacted with the alkyne. Preincubation of the channel with cysteine-modifying agonists lacking the alkyne tag decreased the fluorescent signal (prevented access to the cysteines for the alkyne-tagged agonist). However, agonists, such as icilin, that cannot modify cysteines did not alter the labeling of the TRPA1 by the alkyne-tagged cysteine-modifying agonist. Thus, there is more than one way to activate TRPA1. Mass spectrometry analysis showed that 14 cysteines in the N-terminal cytosolic region were sites of modification. However, only three cysteines (Cys
415
, Cys
422
, Cys
622
) appeared to have an effect on channel activity based on mutagenesis analysis. Although mutation of any of these three cysteines reduced channel activity, normalized current analysis showed that channels with any of these mutations were selectively defective in response to cysteine-reactive agonists and not to icilin, with Cys
622
showing the strongest decrease in responsiveness. The persistent stimulation predicted to occur in response to a covalent modification was validated by experiments in which an increase in calcium concentrations or single-channel activity was observed following washout of cysteine-modifying agonists. Caterina discusses this work and that of Hinman
et al
., who previously reported this mechanism of action.

L. J. Macpherson, A. E. Dubin, M. J. Evans, F. Marr, P. G. Schultz, B. F. Cravatt, A. Patapoutian, Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines.
Nature
445
, 541-545 (2007).
[PubMed]

M. J. Caterina, Sticky spices.
Nature
445
, 491-492 (2007).
[PubMed]

A. Hinman, H.-h. Chuang, D. M. Bautista, D. Julius, TRP channel activation by reversible covalent modification.
Proc. Natl. Acad. Sci. U.S.A.
103
, 19564-19568 (2006).
[Abstract]
[Full Text]
Maintaining a Barrier
Authors: Adler Elizabeth M.
Published: March 2007

Airway epithelial cells require effective mechanisms to repair damage after injuries and maintain a barrier against airborne pathogens and toxins. Wesley
et al
. used confluent monolayers of normal human bronchial epithelial (NHBE) cells or immortalized human tracheobronchial epithelial cells (HBE1) to investigate mechanisms of airway epithelial repair. Wounded monolayers released adenosine triphosphate (ATP) into the medium, and 1 to 10 μM exogenous ATP enhanced wound closure and promoted HBE1 cell migration. Pharmacological blockade of P2 purinergic receptors (with suramin or Cibracon blue) or hydrolysis of ATP and adenosine diphosphate (ADP) (with apyrase) inhibited wound closure and migration. ATP stimulated H
2
O
2
production, and fluorescence microscopy of indicator-loaded cells revealed a localized increase in H
2
O
2
near wounds. Wound-induced H
2
O
2
production was inhibited by suramin and apyrase; further, basal, ATP-stimulated, and wound-induced H
2
O
2
production were all inhibited in HBE1 cells by siRNA directed against dual oxidase 1 (Duox1, an NADPH oxidase homolog expressed in tracheobronchial epithelial cells). Expression in HBE1 cells of siRNA directed against Duox1 inhibited wound closure and cell migration; a pharmacological inhibitor of NADPH oxidase had effects similar to those of Duox1 knockdown and was also effective in NHBE cells. Wounding also stimulated extracellular signal-regulated kinase (ERK) activation, matrix metalloproteinase-9 expression, and gelatinase activity, all of which were inhibited by suramin and Duox1 knockdown. Thus, the authors conclude that Duox1 is activated by an ATP-dependent mechanism to play a key role in the repair of airway epithelium.

U. V. Wesley, P. F. Bove, M. Hristova, S. McCarthy, A. van der Vliet, Airway epithelial cell migration and wound repair by ATP-mediated activation of dual oxidase 1.
J. Biol. Chem.
282
, 3213-3220 (2007).
[Abstract]
[Full Text]
An Unkind Cut Leading to a Broken Heart
Authors: Adler Elizabeth M.
Published: March 2007

Postpartum (or peripartum) cardiomyopathy (PPCM), which occurs late in pregnancy--or up to a few months after delivery--is associated with acute onset of heart failure in women with no history of heart disease (see Leinwand). Hilfiker-Kleiner
et al
. found that female mice lacking cardiomyocyte STAT3 (signal transducer and activator of transcription 3) developed PPCM. Pregnancy is associated with cardiac hypertrophy and increased capillary density, physiological changes that occurred in mice lacking cardiac STAT3. However, unlike mice that expressed cardiac STAT3, postpartum mice lacking cardiac STAT3 (CKO-PP mice) lost the increased capillary density. CKO-PP mice also had an attenuated increase in cardiac manganese superoxide dismutase and excessive cardiac production of reactive oxygen species, leading to increased abundance and activity of the proteolytic enzyme cathepsin D. Further, cardiac tissue from CK-PP mice stimulated cleavage of prolactin (a cathepsin D substrate) into an antiangiogenic 16-kD form. Increasing circulating prolactin stimulated cardiac damage in mice overexpressing cardiac cathepsin D, and persistent cardiac expression of 16-kD prolactin led to a pregnancy-independent decrease in capillary density and cardiac function. In contrast, pharmacological inhibition of prolactin secretion prevented PPCM. Analysis of left-ventricular tissue from women with PPCM revealed decreased STAT3 abundance; moreover, cathepsin D activity and 16-kD prolactin were increased in their serum. A preliminary study suggested that inhibiting prolactin release was protective of cardiac function in women at high risk of PPCM. Thus, the authors suggest that cardiac STAT3 is critical to postpartum cardiac function and propose that inhibiting prolactin release may represent a viable approach to PPCM treatment.

D. Hilfiker-Kleiner, K. Kaminski, E. Podewski, T. Bonda, A. Schaefer, K. Sliwa, O. Forster, A. Quint, U. Landmesser, C. Doerries, M. Luchtefeld, V. Poli, M. D. Schneider, J.-L. Balligand, F. Desjardins, A. Ansari, I. Struman, N. Q. N. Nguyen, N. H. Zschemisch, G. Klein, G. Heusch, R. Schulz, A. Hilfiker, H. Drexler, A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy.
Cell
128
, 589-600 (2007).
[Online Journal]

L. A. Leinwand, Molecular events underlying pregnancy-induced cardiomyopathy.
Cell
128
, 437-438 (2007).
[Online Journal]
A Receptor for Vitamin A Uptake
Authors: Hurtley Stella M.
Published: March 2007

Vitamin A has a large number of biological functions, including roles in vision, reproduction, immunity, tissue regeneration, and neuronal signaling. The existence of a cell surface receptor for the vitamin A carrier retinol binding protein (RBP) was proposed more than 30 years ago. Kawaguchi
et al
. now report the identification and characterization of the long-sought RBP receptor. The RBP receptor is a multipass-transmembrane domain protein with robust RBP binding and vitamin A uptake activity and is localized to the expected cellular locations for vitamin A uptake.

R. Kawaguchi, J. Yu, J. Honda, J. Hu, J. Whitelegge, P. Ping, P. Wiita, D. Bok, H. Sun, A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A.
Science
315
, 820-825 (2007).
[Abstract]
[Full Text]
Meeting Report: Targeting the Kinome—20 Years of Tyrosine Kinase Inhibitor Research in BaselA report on the "Targeting the Kinome" meeting, Basel, Switzerland, 4 to 6 December 2006.
Authors: Bozulic Lana , Morin Pier , Hunter Tony , Hemmings Brian A.
Published: March 2007

With basic and pharmaceutical researchers, chemists, pharmacologists, and clinicians, the Targeting the Kinome meeting brought together a tremendous group of scientists to discuss the past, present, and future of protein kinase research, with a special emphasis on cancer therapy development. The topics ranged from the kinases themselves as drug targets through the interactions that the actions of these enzymes promote, to the physiological and pathological processes they regulate. Attendees gained insight into drug development, as well as increased understanding of how normal cellular processes are subverted during oncogenesis, which may lead to new targets for intervention.
Sugar-Coating the Road to Atherosclerosis
Authors: Adler Elizabeth M.
Published: March 2007

Diabetes promotes the development of atherosclerosis, increasing the risk of such serious complications as myocardial infarctions, stroke, and amputation. Indeed, most people with diabetes die of conditions associated with atherosclerosis. Hyperglycemia leads to an increase in the abundance of thrombospondin-1 (TSP-1), which has pro-atherogenic effects, providing one potential link between diabetes and the enhanced development of atherosclerotic lesions. Raman
et al
. exposed cultured human aortic smooth muscle cells (HASMC) to glucose, glucose analogs that participate in distinct segments of glucose metabolism, and other sugars to implicate protein glycosylation mediated by way of the hexosamine pathway in the increase in TSP-1 mRNA abundance elicited by high glucose concentrations. Pharmacological analysis further supported a role for the hexosamine pathway and protein glycosylation in this response, as did experiments involving overexpression of GFAT (glutamine:fructose 6-phosphate amidotransferase, the rate-limiting enzyme in the hexosamine pathway). Glucose did not affect TSP-1 mRNA stability but enhanced its transcription, as well as that of a reporter gene containing the TSP-1 promoter. Glucose also increased the glycosylation of proteins in the nucleus. Glucose and analogs that enhanced TSP-1 production stimulated the proliferation of HASMC, an effect that was mimicked by exposure of cells to TSP-1 and was blocked by pharmacological inhibition of GFAT or of glycosylation, and by siRNA or antibodies directed against TSP-1. Thus, the authors conclude that the hexosamine pathway and the glycosylation of nuclear proteins may contribute to the development of atherosclerotic lesions in response to high glucose.

P. Raman, I. Krukovets, T. E. Marinic, P. Bornstein, O. I. Stenina, Glycosylation mediates up-regulation of a potent antiangiogenic and proatherogenic protein, thrombospondin-1, by glucose in vascular smooth muscle cells.
J. Biol. Chem.
282
, 5704-5714 (2007).
[Abstract]
[Full Text]
Preventing Muscle Degradation
Authors: Gough Nancy R.
Published: March 2007

Skeletal muscles not only provide the contractile forces required for movement but also serve to produce heat and to provide an energy reserve for organismal metabolism. This metabolic "buffering" capacity takes the form of protein catabolism, which occurs in times of adaptive muscle remodeling or organismal starvation or in certain pathological settings. Szewczyk
et al
. studied the signals that control muscle protein degradation in
Caenorhabditis elegans
using mutant animals expressing either green fluorescent protein (GFP) in the muscle or GFP myofibrillar fusion proteins. Under conditions in which insulin-like growth factor (IGF) signaling was inhibited, muscle protein degradation was stimulated. Mutations (or pharmacological agents) that inhibited the activity of the IGF receptor or the activity of phosphatidylinositol 3-kinase (PI3K) stimulated muscle protein degradation and decreased animal movement, whereas gain-of-function mutations in Akt or the lipid phosphatase that opposes PI3K function prevented muscle protein degradation triggered by the decreased IGF signaling. Fibroblast growth factor receptor (FGFR) activation of the Ras-MAPK (mitogen-activated protein kinase) pathway is known to stimulate muscle protein degradation in
C. elegans
. Szewczyk
et al
. showed that IGF signaling opposes FGF signaling to prevent muscle protein degradation. Mutations in the FGF-Ras-MAPK pathway prevented protein degradation in response to loss of PI3K activity. Inhibition of PI3K also stimulated the formation of the diphosphorylated activated form of MAPK, further supporting an intersection between IGF signaling and the Ras-MAPK pathway. Raf is a putative target for Akt phosphorylation, and animals expressing a mutant form of Raf that was not phosphorylatable by Akt showed increased muscle degradation and the appearance of the activated form of MAPK. The animals appear poised to degrade the muscle proteins in response to FGF signaling, and IGF signaling provides the brake preventing muscle protein degradation.

N. J. Szewczyk, B. K. Peterson, S. J. Barmada, L. P. Parkinson, L. A. Jacobson, Opposed growth factor signals control protein degradation in muscles of
Caenorhabditis elegans
.
EMBO J.
26
, 935-943 (2007).
[PubMed]
MAPK Cascade in Stomatal Specification
Authors: Gough Nancy R.
Published: March 2007

Stomata are special structures in plant leaves that allow gas and water vapor exchange between plants and the environment. Stomata are separated by pavement cells. Wang
et al
. used genetic approaches to show that in
Arabidopsis thaliana
stomatal specification involves a mitogen-activated protein kinase (MAPK) cascade. Because double knockout of
MPK3
and
MPK6
is embryonic-lethal and single loss-of-function mutants do not exhibit any phenotype, Wang
et al
. created single-knockout
mpk6
−/−
plants in which MPK3 was reduced by RNA interference. These plants arrested as seedlings and showed clustered stomata instead of the normal arrangement in which stomata are always separated by one pavement cell. A similar phenotype was observed in
mpk3
,
mpk6
double-mutant plants that were rescued with a steroid-inducible
MPK6
gene. MKK4 and MKK5 are the upstream kinases to MPK3 and MPK6 in stress response pathways, and RNA interference of these two MAPKKs simultaneously caused the seedling leaves to have all stomata with no pavement cells. Gain-of-function experiments were performed using a steroid-inducible, constitutively activated mutant of the tobacco homolog of MKK4 and MKK5 (GVG-Nt-MEK
DD
). These plants had no stomata, but when crossed into either
mpk6
−/−
or
mpk3
−/−
mutant background, then normal stomata and stomatal arrangement were restored. The dose of MAPK signaling appears important for proper specification of stomatal cell fate. Plants deficient in the MAPKKK Yoda (YDA) also have a clustered stomata phenotype, and GVG-Nt-MEK
DD
suppressed this clustered phenotype in a dose-dependent manner, with higher concentrations of steroid suppressing the clustering more effectively than lower concentrations. In-gel kinase assays showed that the activity of MPK3 and MPK6 was increased in plants in which YDA was constitutively activated. Examination of cotyledons in the various mutant plants at various times during development showed that the stomatal phenotypes were associated with aberrations in asymmetric cell divisions. Fewer asymmetric cell divisions occurred in plants in which the pathway was hyperactivated (GVG-Nt-MEK
DD
) and ectopic cell divisions occurred, all producing small stomatal cells in plants in which the pathway was inactivated (rescued
mpk3
,
mpk6
double mutants).

H. Wang, N. Ngwenyama, Y. Liu, J. C. Walker, S. Zhang, Stomatal development and patterning are regulated by environmentally responsive mitogen-activated protein kinases in
Arabidopsis
.
Plant Cell
19
, 63-73 (2007).
[Abstract]
[Full Text]
The Expanding Role for ITAM-Based Signaling Pathways in Immune Cells
Authors: Abram Clare L. , Lowell Clifford A.
Published: March 2007

The immunoreceptor tyrosine-based activation motif (ITAM) is the primary signaling domain used by classical immunoreceptors, such as the antigen receptors on B and T lymphocytes and the Fc receptors (FcRs) on myeloid cells. The ITAM is contained in the intracellular region of subunits associated with these receptors, often in pairs, or is part of the cytoplasmic domain of the receptors themselves. Data from many investigators have demonstrated that ITAMs are both necessary and sufficient for initiation of signaling downstream of all immunoreceptors. More recent reports indicate that ITAM signaling is used by additional receptors beyond the classical immunoreceptors: Cell adhesion molecules (integrins and PSGL-1), chemokine receptors (CXCR4), plexins, and lectin receptors all mediate immune cell function through ITAM-like signaling pathways. This convergence of intracellular signaling pathways in leukocytes illuminates the importance of tyrosine-based activation motifs in the immune system and suggests that inhibitors of ITAM signaling may have broader effects than originally envisioned.
Ubiquitination Controls Life or Death
Authors: Gough Nancy R.
Published: March 2007

Tumor necrosis factor (TNF) can trigger cell death or cell survival depending on the context into which the cell receives the signal. O'Donnell
et al
. show that if lysine 63 ubiquitination of receptor-interacting protein 1 (RIP1) was prevented in Jurkat T cells, the cells exhibited enhanced apoptosis in response to TNF when compared with TNF-treated cells expressing wild-type RIP1. RIP1 ubiquitination was blocked either by expression of a RIP mutant or by expression of dominant-negative forms of the ubiquitin-ligating enzymes TRAF2 (an E3 ubiquitin ligase) or UBC13 (an E2 ubiquitin-conjugating enzyme). The increase in apoptosis did not involve reduced signaling through the nuclear factor κB pathway. Cells expressing wild-type RIP1 exhibited the least apoptosis, whereas cells that were expressing RIP1 and in which TRAF2 activity was inhibited exhibited the most apoptosis, which suggests that the ubiquitination state of RIP1 dictates whether it will generate a proapoptotic signal or a prosurvival signal. RIP1 stimulates apoptosis by activation of caspase 8, and in the RIP1 ubiquitination mutant, RIP1 exhibited increased stimulus-dependent association with procaspase 8. The cells expressing the RIP1 ubiquitination mutant showed increased caspase 8 processing. Thus, ubiquitination of RIP1 appears to prevent its interaction with caspase 8. These results provide an explanation for the conflicting roles assigned to RIP1, as both a proapoptotic and prosurvival mediator. Lysine 63 ubiquitination of RIP1 by TRAF2 switches RIP1 from sending a proapoptotic signal to providing a prosurvival signal.

M. A. O'Donnell, D. Legarda-Addison, P. Skountzos, W. C. Yeh, A. T. Ting, Ubiquitination of RIP1 regulates an NF-κB-independent cell-death switch in TNF signaling.
Curr. Biol.
17
, 418-424 (2007).
[PubMed]
Checkpoint, What Checkpoint?
Authors: Ray L. Bryan
Published: March 2007

Cells use biochemical signaling mechanisms known as checkpoints to monitor the status of the cell so that cell division occurs only when conditions allow for successful mitosis. One such checkpoint allows cell division to occur only if DNA replication is complete and no active replication forks are present. However, Torres-Rosell
et al
. (see the Perspective by Weinert) describe experiments in which uncompleted replication of ribosomal DNA (rDNA) genes does not prevent cells from proceeding into anaphase. Thus, at least in the scenario studied, in which yeast bear mutations in the genes encoding the Smc5 and Smc6 proteins (which function as a heterodimer in DNA repair), the delayed replication of rDNA did not trigger a checkpoint that blocks progression of the cells into mitosis.

J. Torres-Rosell, G. De Piccoli, V. Cordon-Preciado, S. Farmer, A. Jarmuz, F. Machin, P. Pasero, M. Lisby, J. E. Haber, L. Aragón, Anaphase onset before complete DNA replication with intact checkpoint responses.
Science
315
, 1411-1415 (2007).
[Abstract]
[Full Text]

T. Weinert, What a cell should know (but may not).
Science
315
, 1374-1375 (2007).
[Summary]
[Full Text]
Cheering Up with VEGF
Authors: Adler Elizabeth M.
Published: March 2007

Although the molecular mechanisms of antidepressant action remain unclear, one hypothesis suggests that stimulation of growth factor signaling and of adult neurogenesis in the hippocampus may be implicated in their effects. Warner-Schmidt and Duman investigated the effects of different classes of antidepressants on hippocampal expression of the neurotrophic and pro-angiogenic factor VEGF (vascular endothelial growth factor), which their research group had previously shown to be enhanced by electroconvulsive seizure (ECS) treatment. The abundance of VEGF mRNA increased in the hippocampal granule cell layer of rats treated for 14 days with fluoxetine (a serotonin reuptake inhibitor) or desipramine (a norepinephrine reuptake inhibitor), as did the abundance of VEGF in hippocampal homogenates. Pharmacological blockade of the VEGF receptor Flk-1 inhibited the increase in cell proliferation in the hippocampal subgranular zone (SGZ) produced by ECS or chronic exposure to fluoxetine or desipramine, whereas intracerebroventricular delivery of a VEGF isoform stimulated SGZ cell proliferation. Furthermore, pharmacological blockade of Flk-1 inhibited the effects of desipramine on rat behavioral responses in chronic and subchronic models of antidepressant treatment, whereas VEGF had an antidepressant-like effect. Thus, the authors conclude that VEGF plays a key role in mediating both behavioral effects of several classes of antidepressants and their effects on SGZ cell proliferation. Noting that antidepressants promoted the proliferation of hippocampal endothelial cells as well as hippocampal neurogenesis, the authors speculated that this could play a role in the treatment of certain forms of depression that are associated with vascular abnormalities.

J. L. Warner-Schmidt, R. S. Duman, VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.
Proc. Natl. Acad. Sci. U.S.A.
104
, 4647-4652 (2007).
[Abstract]
[Full Text]
DEFORMATIONS AND INVERSION FORMULAS FOR FORMAL AUTOMORPHISMS IN NONCOMMUTATIVE VARIABLES
Authors: ZHAO WENHUA
Published: March 2007

Let z = (z1, z2,…, zn) be noncommutative free variables and t a formal parameter which commutes with z. Let k be any unital integral domain of any characteristic and Ft(z) = z - Ht(z) with Ht(z) ∈ k[[t]]〈〈z〉〉×n and the order o(Ht(z))≥ 2. Note that Ft(z) can be viewed as a deformation of the formal map F(z):= z - Ht=1(z) when it makes sense (for example, when Ht(z) ∈ k[t]〈〈z〉〉×n). The inverse map Gt(z) of Ft(z) can always be written as Gt(z) = z+Mt(z) with Mt(z) ∈ k[[t]]〈〈z〉〉×n and o(Mt(z)) ≥ 2. In this paper, we first derive the PDEs satisfied by Mt(z) and u(Ft), u(Gt) ∈ k[[t]]〈〈z〉〉 with u(z) ∈ k〈〈z〉〉 in the general case as well as in the special case when Ht(z) = tH(z) for some H(z) ∈ k〈〈z〉〉×n. We also show that the elements above are actually characterized by certain Cauchy problems of these PDEs. Secondly, we apply the derived PDEs to prove a recurrent inversion formula for formal maps in noncommutative variables. Finally, for the case char. k = 0, we derive an expansion inversion formula by the planar binary rooted trees.
ISOTACHOPHORETIC MEASUREMENTS OF LUMINESCENT SEMICONDUCTOR NANOCRYSTALS
Authors: BÜCKING WENDELIN , EHLERT OLIVER , RIEGLER JÜRGEN , RETTENMEIER CHRISTIAN , MERKOULOV ALEXEI , NANN THOMAS
Published: March 2007

Luminescent semiconductor nanocrystals of CdTe and CdSe were derivatised by mercaptocarboxylic acids. A direct synthesis in the solution of the ligand and a post-synthesis ligand exchange method was used. The two methods were compared and evaluated by isotachophoresis. The electrophoretic mobility as well as the colloidal stability and the coverage with the ligand, were determined. An alternative method for the concentration estimation of nanocrystals by means of isotachophoresis was introduced.
PRODUCTION AND BIOFUNCTIONALIZATION OF MAGNETIC NANOBEADS FOR MAGNETIC SEPARATION OF MESSENGER RNA
Authors: STEITZ BENEDIKT , HOFMANN HEINRICH , PETRI-FINK ALKE
Published: March 2007

The synthesis of nanosized beads of superparamagnetic iron oxide nanoparticles coated with 3-(aminopropyl)triethoxysilane is reported in this paper. The resulting beads are agglomerates of SPIONs with an open fractal like structure. These beads have been examined by means of transmission electron microscopy (TEM), photon correlation spectroscopy (PCS), and attenuated total reflection Fourier transformation infrared spectroscopy (ATR-FTIR). The resulting beads with a size of 88 nm have been further biofunctionalized with avidin and biotinylated oligo(dT).
Unwarranted Assumptions about Children's Testimonial Accuracy
Authors: Ceci Stephen J. , Kulkofsky Sarah , Klemfuss J. Zoe , Sweeney Charlotte D. , Bruck Maggie
Published: March 2007

We examine eight unwarranted assumptions made by expert witnesses, forensic interviewers, and legal scholars about the reliability of children's eyewitness reports. The first four assumptions modify some central beliefs about the nature of suggestive interviews, age-related differences in resistance to suggestion, and thresholds necessary to produce tainted reports. The fifth unwarranted assumption involves the influence of both individual and interviewer factors in determining children's suggestibility. The sixth unwarranted assumption concerns the claim that suggested reports are detectable. The seventh unwarranted assumption concerns new findings about how children deny, disclose, and/or recant their abuse. Finally, we examine unwarranted statements about the value of science to the forensic arena. It is important not only for researchers but also expert witnesses and court-appointed psychologists to be aware of these unwarranted assumptions.
Depression in Mothers
Authors: Goodman Sherryl H.
Published: March 2007

Whether one takes a biological, psychological, or psychosocial perspective, depression in mothers raises concerns about risks for the development of psychopathology in the children. This review addresses the complexity of that risk and the essential role of development in a model that explains processes of transmission. This article addresses the following aims: (a) to provide convincing evidence that depression in mothers is an important topic for clinical psychologists; (b) to summarize current theoretical models of mechanisms of risk for the development of psychopathology in children of depressed mothers and the status of empirical support for those models; (c) to examine the theoretical bases and current status of evidence for moderators of this risk; (d) to argue for the advantages to be gained from a developmental psychopathology perspective on this topic; and (e) to point to future directions for theory, research, and practice.
Sexual Orientation and Mental Health
Authors: Herek Gregory M. , Garnets Linda D.
Published: March 2007

This article provides an overview of current psychological research on mental health and sexual orientation, as well as clinical practice with sexual minorities. The historical context for current research questions and controversies is described, and the findings of recent empirical research on psychological well-being and distress among nonheterosexuals are summarized. The minority stress model is used to frame a discussion of stressors unique to sexual minorities and to consider their possible effects on psychological well-being. The possible ameliorative effects of adopting a sexual orientation identity are examined, followed by a discussion of how these ideas translate into contemporary clinical work with sexual minority clients. The review concludes with a brief discussion of priority areas for empirical research and clinical practice.
The Head Direction Signal: Origins and Sensory-Motor Integration
Authors: Taube Jeffrey S.
Published: March 2007

Navigation first requires accurate perception of one's spatial orientation within the environment, which consists of knowledge about location and directional heading. Cells within several limbic system areas of the mammalian brain discharge allocentrically as a function of the animal's directional heading, independent of the animal's location and ongoing behavior. These cells are referred to as head direction (HD) cells and are believed to encode the animal's perceived directional heading with respect to its environment. Although HD cells are found in several areas, the principal circuit for generating this signal originates in the dorsal tegmental nucleus and projects serially, with some reciprocal connections, to the lateral mammillary nucleus → anterodorsal thalamus → PoS, and terminates in the entorhinal cortex. HD cells receive multimodal information about landmarks and self-generated movements. Vestibular information appears critical for generating the directional signal, but motor/proprioceptive and landmark information are important for updating it.
The Micromachinery of Mechanotransduction in Hair Cells
Authors: Vollrath Melissa A. , Kwan Kelvin Y. , Corey David P.
Published: March 2007

Mechanical stimuli generated by head movements and changes in sound pressure are detected by hair cells with amazing speed and sensitivity. The mechanosensitive organelle, the hair bundle, is a highly elaborated structure of actin-based stereocilia arranged in precise rows of increasing height. Extracellular linkages contribute to its cohesion and convey forces to mechanically gated channels. Channel opening is nearly instantaneous and is followed by a process of sensory adaptation that keeps the channels poised in their most sensitive range. This process is served by motors, scaffolds, and homeostatic mechanisms. The molecular constituents of this process are rapidly being elucidated, especially by the discovery of deafness genes and antibody targets.
The Neural Basis of Decision Making
Authors: Gold Joshua I. , Shadlen Michael N.
Published: March 2007

The study of decision making spans such varied fields as neuroscience, psychology, economics, statistics, political science, and computer science. Despite this diversity of applications, most decisions share common elements including deliberation and commitment. Here we evaluate recent progress in understanding how these basic elements of decision formation are implemented in the brain. We focus on simple decisions that can be studied in the laboratory but emphasize general principles likely to extend to other settings.
Fundamental Components of Attention
Authors: Knudsen Eric I.
Published: March 2007

A mechanistic understanding of attention is necessary for the elucidation of the neurobiological basis of conscious experience. This chapter presents a framework for thinking about attention that facilitates the analysis of this cognitive process in terms of underlying neural mechanisms. Four processes are fundamental to attention: working memory, top-down sensitivity control, competitive selection, and automatic bottom-up filtering for salient stimuli. Each process makes a distinct and essential contribution to attention. Voluntary control of attention involves the first three processes (working memory, top-down sensitivity control, and competitive selection) operating in a recurrent loop. Recent results from neurobiological research on attention are discussed within this framework.
The Medial Temporal Lobe and Recognition Memory
Authors: Eichenbaum H. , Yonelinas A.P. , Ranganath C.
Published: March 2007

The ability to recognize a previously experienced stimulus is supported by two processes: recollection of the stimulus in the context of other information associated with the experience, and a sense of familiarity with the features of the stimulus. Although familiarity and recollection are functionally distinct, there is considerable debate about how these kinds of memory are supported by regions in the medial temporal lobes (MTL). Here, we review evidence for the distinction between recollection and familiarity and then consider the evidence regarding the neural mechanisms of these processes. Evidence from neuropsychological, neuroimaging, and neurophysiological studies of humans, monkeys, and rats indicates that different subregions of the MTL make distinct contributions to recollection and familiarity. The data suggest that the hippocampus is critical for recollection but not familiarity. The parahippocampal cortex also contributes to recollection, possibly via the representation and retrieval of contextual (especially spatial) information, whereas perirhinal cortex contributes to and is necessary for familiarity-based recognition. The findings are consistent with an anatomically guided hypothesis about the functional organization of the MTL and suggest mechanisms by which the anatomical components of the MTL interact to support the phenomenology of recollection and familiarity.