bluuebunny/crossref_metadata_2025 huggingface dataset:
Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering
Authors: Sandberg Anders , Luheshi Leila M. , Söllvander Sofia , Pereira de Barros Teresa , Macao Bertil , Knowles Tuomas P. J. , Biverstål Henrik , Lendel Christofer , Ekholm-Petterson Frida , Dubnovitsky Anatoly , Lannfelt Lars , Dobson Christopher M. , Härd Torleif
Published: August 2010

Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a double-cysteine mutant (called Aβcc) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ40ccand Aβ42ccboth spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Aβccoligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ42ccoligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ42, in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ42is more toxic than the shorter Aβ40, and why certain inherited mutations are linked to protofibril formation and early-onset AD.
NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
Authors: Kuroda Junya , Ago Tetsuro , Matsushima Shouji , Zhai Peiyong , Schneider Michael D. , Sadoshima Junichi
Published: August 2010

NAD(P)H oxidases (Noxs) produce O
2
−
and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific
Nox4
−/−
(c-
Nox4
−/−
) mice. Nox4 expression was inhibited in c-
Nox4
−/−
mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O
2
−
in the heart, indicating that Nox4 is a significant source of O
2
−
in cardiac myocytes. The baseline cardiac phenotype was normal in young c-
Nox4
−/−
mice. In response to pressure overload (PO), however, increases in Nox4 expression and O
2
−
production in mitochondria were abolished in c-
Nox4
−/−
mice, and c-
Nox4
−/−
mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome
c
release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-
Nox4
−/−
mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.
β1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression
Authors: Huck L. , Pontier S. M. , Zuo D. M. , Muller W. J.
Published: August 2010

Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of β1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional β1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated
erbB2
(herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the β1-integrin–deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as β1-integrin–null. Animals bearing β1-integrin–deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, β1-integrin–deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although β1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression.
Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification
Authors: Caballero Ricardo , Dolz-Gaitón Pablo , Gómez Ricardo , Amorós Irene , Barana Adriana , González de la Fuente Marta , Osuna Lourdes , Duarte Juan , López–Izquierdo Angelica , Moraleda Ignacio , Gálvez Enrique , Sánchez–Chapula José Antonio , Tamargo Juan , Delpón Eva
Published: August 2010

Both increase and decrease of cardiac inward rectifier current (IK1) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease IK1(Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (IKir2.1) and IK1recorded in ventricular myocytes. Flecainide increases outward IKir2.1generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase IKir2.2and IKir2.3, because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification.
An explanation for conflicting records of Triassic–Jurassic plant diversity
Authors: Mander Luke , Kürschner Wolfram M. , McElwain Jennifer C.
Published: August 2010

Macrofossils (mostly leaves) and sporomorphs (pollen and spores) preserve conflicting records of plant biodiversity during the end-Permian (P-Tr), Triassic–Jurassic (Tr-J), and end-Cretaceous (K-T) mass extinctions. Estimates of diversity loss based on macrofossils are typically much higher than estimates of diversity loss based on sporomorphs. Macrofossils from the Tr-J of East Greenland indicate that standing species richness declined by as much as 85% in the Late Triassic, whereas sporomorph records from the same region, and from elsewhere in Europe, reveal little evidence of such catastrophic diversity loss. To understand this major discrepancy, we have used a new high-resolution dataset of sporomorph assemblages from Astartekløft, East Greenland, to directly compare the macrofossil and sporomorph records of Tr-J plant biodiversity. Our results show that sporomorph assemblages from the Tr-J boundary interval are 10–12% less taxonomically diverse than sporomorph assemblages from the Late Triassic, and that vegetation composition changed rapidly in the boundary interval as a result of emigration and/or extirpation of taxa rather than immigration and/or origination of taxa. An analysis of the representation of different plant groups in the macrofossil and sporomorph records at Astartekløft reveals that reproductively specialized plants, including cycads, bennettites and the seed-fern
Lepidopteris
are almost absent from the sporomorph record. These results provide a means of reconciling the macrofossil and sporomorph records of Tr-J vegetation change, and may help to understand vegetation change during the P-Tr and K-T mass extinctions and around the Paleocene–Eocene Thermal Maximum.
Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes
Authors: Taube Joseph H. , Herschkowitz Jason I. , Komurov Kakajan , Zhou Alicia Y. , Gupta Supriya , Yang Jing , Hartwell Kimberly , Onder Tamer T. , Gupta Piyush B. , Evans Kurt W. , Hollier Brett G. , Ram Prahlad T. , Lander Eric S. , Rosen Jeffrey M. , Weinberg Robert A. , Mani Sendurai A.
Published: August 2010

The epithelial-to-mesenchymal transition (EMT) produces cancer cells that are invasive, migratory, and exhibit stem cell characteristics, hallmarks of cells that have the potential to generate metastases. Inducers of the EMT include several transcription factors (TFs), such as Goosecoid, Snail, and Twist, as well as the secreted TGF-β1. Each of these factors is capable, on its own, of inducing an EMT in the human mammary epithelial (HMLE) cell line. However, the interactions between these regulators are poorly understood. Overexpression of each of the above EMT inducers up-regulates a subset of other EMT-inducing TFs, with Twist, Zeb1, Zeb2, TGF-β1, and FOXC2 being commonly induced. Up-regulation of Slug and FOXC2 by either Snail or Twist does not depend on TGF-β1 signaling. Gene expression signatures (GESs) derived by overexpressing EMT-inducing TFs reveal that the Twist GES and Snail GES are the most similar, although the Goosecoid GES is the least similar to the others. An EMT core signature was derived from the changes in gene expression shared by up-regulation of Gsc, Snail, Twist, and TGF-β1 and by down-regulation of E-cadherin, loss of which can also trigger an EMT in certain cell types. The EMT core signature associates closely with the claudin-low and metaplastic breast cancer subtypes and correlates negatively with pathological complete response. Additionally, the expression level of FOXC1, another EMT inducer, correlates strongly with poor survival of breast cancer patients.
Common genetic variation in Neuregulin 3 (
NRG3
) influences risk for schizophrenia and impacts
NRG3
expression in human brain
Authors: Kao Wee-Tin , Wang Yanhong , Kleinman Joel E. , Lipska Barbara K. , Hyde Thomas M. , Weinberger Daniel R. , Law Amanda J.
Published: August 2010

Structural and polymorphic variations in Neuregulin 3 (
NRG3
), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5′ exon (
P
= 1.097E
−12
to 1.445E
−15
). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association.
Humanized nonobese diabetic-scid IL2rγnullmice are susceptible to lethalSalmonellaTyphi infection
Authors: Libby Stephen J. , Brehm Michael A. , Greiner Dale L. , Shultz Leonard D. , McClelland Michael , Smith Kelly D. , Cookson Brad T. , Karlinsey Joyce E. , Kinkel Traci L. , Porwollik Steffen , Canals Rocio , Cummings Lisa A. , Fang Ferric C.
Published: August 2010

Salmonella entericaserovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show thatS.Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rγnullmice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast,S.Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknownSalmonellavirulence determinants, includingSalmonellaPathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication ofS.Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights intoS.Typhi pathogenesis and devise strategies for the prevention of typhoid fever.
Megafaunal meiolaniid horned turtles survived until early human settlement in Vanuatu, Southwest Pacific
Authors: White Arthur W. , Worthy Trevor H. , Hawkins Stuart , Bedford Stuart , Spriggs Matthew
Published: August 2010

Meiolaniid or horned turtles are members of the extinct Pleistocene megafauna of Australia and the southwest Pacific. The timing and causes of their extinction have remained elusive. Here we report the remains of meiolaniid turtles from cemetery and midden layers dating 3,100/3,000 calibrated years before present to approximately 2,900/2,800 calibrated years before present in the Teouma Lapita archaeological site on Efate in Vanuatu. The remains are mainly leg bones; shell fragments are scant and there are no cranial or caudal elements, attesting to off-site butchering of the turtles. The new taxon differs markedly from other named insular terrestrial horned turtles. It is the only member of the family demonstrated to have survived into the Holocene and the first known to have become extinct after encountering humans.
New strategy for the synthesis of chemically modified RNA constructs exemplified by hairpin and hammerhead ribozymes
Authors: El-Sagheer Afaf H. , Brown Tom
Published: August 2010

The CuAAC reaction (click chemistry) has been used in conjunction with solid-phase synthesis to produce catalytically active hairpin ribozymes around 100 nucleotides in length. Cross-strand ligation through neighboring nucleobases was successful in covalently linking presynthesized RNA strands with high efficiency (
trans
-ligation). In an alternative strategy, intrastrand click ligation was employed to produce a functional hammerhead ribozyme containing a novel nucleic acid backbone mimic at the catalytic site (
cis
-ligation). The ability to synthesize long RNA strands by a combination of solid-phase synthesis and click ligation is an important addition to RNA chemistry. It is compatible with a plethora of site-specific modifications and is applicable to the synthesis of many biologically important RNA molecules.
Social interactions, information use, and the evolution of collective migration
Authors: Guttal Vishwesha , Couzin Iain D.
Published: August 2010

Migration of organisms (or cells) is typically an adaptive response to spatiotemporal variation in resources that requires individuals to detect and respond to long-range and noisy environmental gradients. Many organisms, from wildebeest to bacteria, migrate en masse in a process that can involve a vast number of individuals. Despite the ubiquity of collective migration, and the key function it plays in the ecology of many species, it is still unclear what role social interactions play in the evolution of migratory strategies. Here, we explore the evolution of migratory behavior using an individual-based spatially explicit model that incorporates the costs and benefits of obtaining directional cues from the environment and evolvable social interactions among migrating individuals. We demonstrate that collective migratory strategies evolve under a wide range of ecological scenarios, even when social encounters are rare. Although collective migration appears to be a shared navigational process, populations typically consist of small proportions of individuals actively acquiring directional information from their environment, whereas the majorities use a socially facilitated movement behavior. Because many migratory species face severe threat through anthropogenic influences, we also explore the microevolutionary response of migratory strategies to environmental pressures. We predict a gradual decline of migration due to increasing habitat destruction and argue that much greater restoration is required to recover lost behaviors (i.e., a strong hysteresis effect). Our results provide insights into both the proximate and ultimate factors that underlie evolved migratory behavior in nature.
Noninvasive molecular imaging of c-Myc activation in living mice
Authors: Fan-Minogue Hua , Cao Zhongwei , Paulmurugan Ramasamy , Chan Carmel T. , Massoud Tarik F. , Felsher Dean W. , Gambhir Sanjiv S.
Published: August 2010

The cytoplasmic Myc protein (c-Myc) regulates various human genes and is dysregulated in many human cancers. Phosphorylation mediates the protein activation of c-Myc and is essential for the function of this transcription factor in normal cell behavior and tumor growth. To date, however, the targeting of Myc as a therapeutic approach for cancer treatment has been achieved primarily at the nonprotein level. We have developed a molecular imaging sensor for noninvasive imaging of c-Myc activity in living subjects using a split Firefly luciferase (FL) complementation strategy to detect and quantify the phosphorylation-mediated interaction between glycogen synthase kinase 3β (GSK3β) and c-Myc. This sensor system consists of two fusion proteins, GSK 35–433-CFL and NFL-c-Myc, in which specific fragments of GSK3β and c-Myc are fused with C-terminal and N-terminal fragments of the split FL, respectively. The sensor detects phosphorylation-specific GSK3β–c-Myc interaction, the imaging signal of which correlates with the steady-state and temporal regulation of c-Myc phosphorylation in cell culture. The sensor also detects inhibition of c-Myc activity via differential pathways, allowing noninvasive monitoring of c-Myc–targeted drug efficacy in intact cells and living mice. Notably, this drug inhibition is detected before changes in tumor size are apparent in mouse xenograft and liver tumor models. This reporter system not only provides an innovative way to investigate the role of functional c-Myc in normal and cancer-related biological processes, but also facilitates c-Myc–targeted drug development by providing a rapid quantitative approach to assessing cancer response to therapy in living subjects.
Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM
Authors: Yao Hongwei , Arunachalam Gnanapragasam , Hwang Jae-woong , Chung Sangwoon , Sundar Isaac K. , Kinnula Vuokko L. , Crapo James D. , Rahman Irfan
Published: August 2010

Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O
2
• ─
. ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m
3
) to 6 mo (100 mg/m
3
total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.
Herbivore physiological response to predation risk and implications for ecosystem nutrient dynamics
Authors: Hawlena Dror , Schmitz Oswald J.
Published: August 2010

The process of nutrient transfer through an ecosystem is an important determinant of production, food-chain length, and species diversity. The general view is that the rate and efficiency of nutrient transfer up the food chain is constrained by herbivore-specific capacity to secure N-rich compounds for survival and production. Using feeding trials with artificial food, we show, however, that physiological stress-response of grasshopper herbivores to spider predation risk alters the nature of the nutrient constraint. Grasshoppers facing predation risk had higher metabolic rates than control grasshoppers. Elevated metabolism accordingly increased requirements for dietary digestible carbohydrate-C to fuel-heightened energy demands. Moreover, digestible carbohydrate-C comprises a small fraction of total plant tissue-C content, so nutrient transfer between plants and herbivores accordingly becomes more constrained by digestible plant C than by total plant C:N. This shift in herbivore diet to meet the altered nutrient requirement increased herbivore body C:N content, the C:N content of the plant community from which grasshoppers select their diet, and grasshopper fecal C:N content. Chronic predation risk thus alters the quality of animal and plant tissue that eventually enters the detrital pool to become decomposed. Our results demonstrate that herbivore physiology causes C:N requirements and nutrient intake to become flexible, thereby providing a mechanism to explain context dependence in the nature of trophic control over nutrient transfer in ecosystems.
Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein
Authors: Kao Der-I , Aldridge Georgina M. , Weiler Ivan Jeanne , Greenough William T.
Published: August 2010

Fragile X syndrome is caused by the absence of functional fragile X mental retardation protein (FMRP), an RNA binding protein. The molecular mechanism of aberrant protein synthesis in
fmr1
KO mice is closely associated with the role of FMRP in mRNA transport, delivery, and local protein synthesis. We show that GFP-labeled
Fmr1
and CaMKIIα mRNAs undergo decelerated motion at 0–40 min after group I mGluR stimulation, and later recover at 40–60 min. Then we investigate targeting of mRNAs associated with FMRP after neuronal stimulation. We find that FMRP is synthesized closely adjacent to stimulated mGluR5 receptors. Moreover, in WT neurons, CaMKIIα mRNA can be delivered and translated in dendritic spines within 10 min in response to group I mGluR stimulation, whereas KO neurons fail to show this response. These data suggest that FMRP can mediate spatial mRNA delivery for local protein synthesis in response to synaptic stimulation.
PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair
Authors: Pluciennik Anna , Dzantiev Leonid , Iyer Ravi R. , Constantin Nicoleta , Kadyrov Farid A. , Modrich Paul
Published: August 2010

MutLα (MLH1–PMS2) is a latent endonuclease that is activated in a mismatch-, MutSα-, proliferating cell nuclear antigen (PCNA)-, replication factor C (RFC)-, and ATP-dependent manner, with nuclease action directed to the heteroduplex strand that contains a preexisting break. RFC depletion experiments and use of linear DNAs indicate that RFC function in endonuclease activation is limited to PCNA loading. Whereas nicked circular heteroduplex DNA is a good substrate for PCNA loading and for endonuclease activation on the incised strand, covalently closed, relaxed circular DNA is a poor substrate for both reactions. However, covalently closed supercoiled or bubble-containing relaxed heteroduplexes, which do support PCNA loading, also support MutLα activation, but in this case cleavage strand bias is largely abolished. Based on these findings we suggest that PCNA has two roles in MutLα function: The clamp is required for endonuclease activation, an effect that apparently involves interaction of the two proteins, and by virtue of its loading orientation, PCNA determines the strand direction of MutLα incision. These results also provide a potential mechanism for activation of mismatch repair on nonreplicating DNA, an effect that may have implications for the somatic phase of triplet repeat expansion.
Short-term meditation induces white matter changes in the anterior cingulate
Authors: Tang Yi-Yuan , Lu Qilin , Geng Xiujuan , Stein Elliot A. , Yang Yihong , Posner Michael I.
Published: August 2010

The anterior cingulate cortex (ACC) is part of a network implicated in the development of self-regulation and whose connectivity changes dramatically in development. In previous studies we showed that 3 h of mental training, based on traditional Chinese medicine (integrative body–mind training, IBMT), increases ACC activity and improves self-regulation. However, it is not known whether changes in white matter connectivity can result from small amounts of mental training. We here report that 11 h of IBMT increases fractional anisotropy (FA), an index indicating the integrity and efficiency of white matter in the corona radiata, an important white-matter tract connecting the ACC to other structures. Thus IBMT could provide a means for improving self-regulation and perhaps reducing or preventing various mental disorders.
Ghrelin secretion stimulated by β
1
-adrenergic receptors in cultured ghrelinoma cells and in fasted mice
Authors: Zhao Tong-Jin , Sakata Ichiro , Li Robert Lin , Liang Guosheng , Richardson James A. , Brown Michael S. , Goldstein Joseph L. , Zigman Jeffrey M.
Published: August 2010

Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding β
1
-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective β
1
-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on β
1
receptors on the ghrelin-secreting cells of the stomach.
Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis
Authors: Nezis Ioannis P. , Shravage Bhupendra V. , Sagona Antonia P. , Lamark Trond , Bjørkøy Geir , Johansen Terje , Rusten Tor Erik , Brech Andreas , Baehrecke Eric H. , Stenmark Harald
Published: August 2010

Autophagy is an evolutionarily conserved pathway responsible for degradation of cytoplasmic material via the lysosome. Although autophagy has been reported to contribute to cell death, the underlying mechanisms remain largely unknown. In this study, we show that autophagy controls DNA fragmentation during late oogenesis in Drosophila melanogaster. Inhibition of autophagy by genetically removing the function of the autophagy genes atg1, atg13, and vps34 resulted in late stage egg chambers that contained persisting nurse cell nuclei without fragmented DNA and attenuation of caspase-3 cleavage. The Drosophila inhibitor of apoptosis (IAP) dBruce was found to colocalize with the autophagic marker GFP-Atg8a and accumulated in autophagy mutants. Nurse cells lacking Atg1 or Vps34 in addition to dBruce contained persisting nurse cell nuclei with fragmented DNA. This indicates that autophagic degradation of dBruce controls DNA fragmentation in nurse cells. Our results reveal autophagic degradation of an IAP as a novel mechanism of triggering cell death and thereby provide a mechanistic link between autophagy and cell death.
Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors: a possible link to Rho family GTPases
Authors: Lee Chan-Soo , Choi Chang-Ki , Shin Eun-Young , Schwartz Martin Alexander , Kim Eung-Gook
Published: August 2010

Cell migration requires the coordinated spatiotemporal regulation of actomyosin contraction and cell protrusion/adhesion. Nonmuscle myosin II (MII) controls Rac1 and Cdc42 activation, and cell protrusion and focal complex formation in migrating cells. However, these mechanisms are poorly understood. Here, we show that MII interacts specifically with multiple Dbl family guanine nucleotide exchange factors (GEFs). Binding is mediated by the conserved tandem Dbl homology–pleckstrin homology module, the catalytic site of these GEFs, with dissociation constants of ∼0.3 µM. Binding to the GEFs required assembly of the MII into filaments and actin-stimulated ATPase activity. Binding of MII suppressed GEF activity. Accordingly, inhibition of MII ATPase activity caused release of GEFs and activation of Rho GTPases. Depletion of βPIX GEF in migrating NIH3T3 fibroblasts suppressed lamellipodial protrusions and focal complex formation induced by MII inhibition. The results elucidate a functional link between MII and Rac1/Cdc42 GTPases, which may regulate protrusion/adhesion dynamics in migrating cells.
Oxidative status of muscle is determined by p107 regulation of PGC-1α
Authors: Scimè Anthony , Soleimani Vahab D. , Bentzinger C. Florian , Gillespie Mark A. , Le Grand Fabien , Grenier Guillaume , Bevilacqua Lisa , Harper Mary-Ellen , Rudnicki Michael A.
Published: August 2010

Mice lacking p107 exhibit a white adipose deficiency yet do not manifest the metabolic changes typical for lipodystrophy, and instead exhibit low levels of serum triglycerides and a normal liver phenotype. When fed a high fat diet, p107-null mice still did not accumulate fat in the liver, and display markedly elevated energy expenditures together with an increased energy preference for lipids. Skeletal muscle was therefore examined, as this is normally the major tissue involved in whole body lipid metabolism. Notably, p107-deficient muscle express increased levels of peroxisome proliferator–activated receptor gamma co-activator-1α (PGC-1α) and contained increased numbers of the pro-oxidative type I and type IIa myofibers. Chromatin immunoprecipitation revealed binding of p107 and E2F4 to the PGC-1α proximal promoter, and this binding repressed promoter activity in transient transcription assays. Ectopic expression of p107 in muscle tissue in vivo results in a pronounced 20% decrease in the numbers of oxidative type IIa myofibers. Lastly, isolated p107-deficient muscle tissue display a threefold increase in lipid metabolism. Therefore, p107 determines the oxidative state of multiple tissues involved in whole body fat metabolism, including skeletal muscle.
Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response
Authors: Markowska Anna I. , Liu Fu-Tong , Panjwani Noorjahan
Published: August 2010

Recent studies have shown that a carbohydrate-binding protein, galectin-3, is a novel pro-angiogenic molecule. The mechanism by which galectin-3 promotes angiogenesis remains unknown. We demonstrate here that galectin-3 is a mediator of vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenic response. Angiogenesis assays revealed that galectin-3 inhibitors, β-lactose and dominant-negative galectin-3, reduce VEGF- and bFGF-mediated angiogenesis in vitro and that VEGF- and bFGF-mediated angiogenic response is reduced in galectin-3 knockdown cells and Gal3−/− animals. Integrin αvβ3 was identified as the major galectin-3–binding protein and anti-αv, -β3, and -αvβ3 integrin function-blocking antibodies significantly inhibited the galectin-3–induced angiogenesis. Furthermore, galectin-3 promoted the clustering of integrin αvβ3 and activated focal adhesion kinase. Knockdown of GnTV, an enzyme that synthesizes high-affinity glycan ligands for galectin-3, substantially reduced: (a) complex N-glycans on αvβ3 integrins and (b) VEGF- and bFGF-mediated angiogenesis. Collectively, these data suggest that galectin-3 modulates VEGF- and bFGF-mediated angiogenesis by binding via its carbohydrate recognition domain, to the GnTV synthesized N-glycans of integrin αvβ3, and subsequently activating the signaling pathways that promote the growth of new blood vessels. These findings have broad implications for developing novel, carbohydrate-based therapeutic agents for inhibition of angiogenesis.
A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function
Authors: Falet Hervé , Pollitt Alice Y. , Begonja Antonija Jurak , Weber Sarah E. , Duerschmied Daniel , Wagner Denisa D. , Watson Steve P. , Hartwig John H.
Published: August 2010

Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnAloxP/loxP females with GATA1-Cre males. FlnAloxP/y GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIbα because they lack the normal cytoskeletal linkage of GPIbα to underlying actin filaments. This results in ∼70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like–mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased α-granule secretion, integrin αIIbβ3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C–γ2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA–Syk interaction, as Syk binds to FlnA at immunoglobulin-like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like–containing receptor signaling and platelet function.
Reducing the Incidence of Intraventricular Catheter–Related Ventriculitis in the Neurology-Neurosurgical Intensive Care Unit at a Tertiary Care Center in St Louis, Missouri: An 8-Year Follow-Up Study
Authors: Honda Hitoshi , Jones Jeffrey C. , Craighead Martha C. , Diringer Michael N. , Dacey Ralph G. , Warren David K.
Published: August 2010

We reviewed the effect of 3 interventions to reduce the incidence of intraventricular catheter–related ventriculitis, conducted at a tertiary care center in St Louis, Missouri, during an 8-year period. The incidence density of intraventricular catheter-related ventriculitis decreased substantially after the implementation of standardized management of intraventricular catheters.
Response to Letter to the Editor by Philip Good on To Permute or Not to Permute
Authors: Calian Violeta , Hsu Jason C.
Published: August 2010

Contact:  calian@raunvis.hi.is
Out of the deep sea into a land-based aquarium environment: investigating physiological adaptations in the hydrothermal vent mussel Bathymodiolus azoricus
Authors: Bettencourt Raul , Costa Valentina , Laranjo Mário , Rosa Domitília , Pires Luís , Colaço Ana , Lopes Humberto , Serrão Santos Ricardo
Published: August 2010

Bettencourt, R., Costa, V., Laranjo, M., Rosa, D., Pires, L., Colaço, A., Lopes, H., and Serrão Santos, R. 2011. Out of the deep sea into a land-based aquarium environment: investigating physiological adaptations in the hydrothermal vent mussel Bathymodiolus azoricus. – ICES Journal of Marine Science, 68: 357–364. Deep-sea hydrothermal vents are considered to be some of the most extreme environments in the world, yet the animals dwelling around the vent sites exhibit high productivity and must therefore deal with unusual levels of heavy metals, pH, temperature, CO2, and sulphides, in addition to environmental microbes. In an attempt to understand the physiological reactions of animals able to endure these extreme conditions, adaptation processes in the mussel Bathymodiolus azoricus maintained for long periods under laboratory conditions were investigated. Even in the absence of the characteristic high hydrostatic pressure found at deep-sea vent sites and without methane and/or sulphide supplementation, vent mussels seem to survive well in aquarium conditions. Therefore, the maintenance of live vent mussels in our laboratory is a key factor in gaining insights into their physiology, as well as into the study of evolutionary conserved molecules commonly found in other marine bivalves. With the aim of finding distinct genetic signatures in the expression of genes such as the metal-binding protein metallothionein (MT), the present work centred on cellular and humoral mechanisms in animals acclimatized to “sea-level” conditions. In addition, we also conducted experiments under hydrostatic pressure, using the hyperbaric chamber IPOCAMP to establish an in vitro experimental system in which the expression of genes that typically respond to heavy metal contaminants and oxidative stress could be studied under controlled hyperbaric pressure. We also analysed the occurrence of glycosylation in mantle and gill tissues from mussels subjected to elevated hyperbaric pressure, as well as the variation in haemocyte total counts as a result of increased pressure. Our results suggest that even after prolonged aquarium maintenance at atmospheric pressure, mussels were still able to induce the MT gene, whether or not they had been subjected to repressurization in the IPOCAMP chamber. Taken together, our results suggest that B. azoricus can be used as a model species and is particularly useful for the assessment of expression levels of critical genes, such as MT, in response to experimentally induced hydrostatic pressure.
LabHorta: a controlled aquarium system for monitoring physiological characteristics of the hydrothermal vent mussel Bathymodiolus azoricus
Authors: Colaço Ana , Bettencourt Raul , Costa Valentina , Lino Silvia , Lopes Humberto , Martins Inês , Pires Luis , Prieto Catarina , Serrão Santos Ricardo
Published: August 2010

Colaço, A., Bettencourt, R., Costa, V., Lino, S., Lopes, H., Martins, I., Pires, L., Prieto, C., and Serrão Santos, R. 2011. LabHorta: a controlled aquarium system for monitoring physiological characteristics of the hydrothermal vent mussel Bathymodiolus azoricus. – ICES Journal of Marine Science, 68: 349–356. LabHorta is a facility composed of laboratories and retrievable deep-sea cages created to support and expand the capabilities of research cruises. It also enhances the ability to conduct experimental studies with organisms from deep-sea hydrothermal vents and other deep-sea environments, while keeping them under controlled conditions of pressure and water chemistry. This paper presents a case study with the vent mussel Bathymodiolus azoricus (which harbours a dual symbiosis) collected at the Menez Gwen hydrothermal vent field at 840-m depth, transported to experimental aquaria at atmospheric pressure and maintained under four different controlled experimental conditions to study their comparative condition index (CI). Environmental parameters were monitored daily and efforts were made to keep these constant. During the first few months, there were differences between the CI scores of mussels kept under the various conditions. After 6 months, the differences are not so clear but mussels still had sulphur-oxidizing bacteria when fed with sulphide. The methane oxidizer bacteria disappear even in the presence of methane. A range of CI scores appeared as a function of the culture type. The LabHorta facility is a good tool for performing long-term physiological studies of deep-sea organisms, simulating possible changes in the natural environmental where they normally thrive.
Modeling Heterogeneity and Serial Correlation in Binary Time-Series Cross-sectional Data: A Bayesian Multilevel Model with AR(p) Errors
Authors: Pang Xun
Published: August 2010

This paper proposes a Bayesian generalized linear multilevel model with apth-order autoregressive error process to analyze unbalanced binary time-series cross-sectional (TSCS) data. The model specification is motivated by the generic TSCS data structure and is intended to handle the associated inefficiency and endogeneity problems. It accommodates heterogeneity across units and between time periods in the form of random intercepts and random-effect coefficients. At the same time, itspth-order autoregressive error process, employed either by itself or in concert with other dynamic methods, adequately corrects serial correlation and improves statistical inference and forecasting. With a stationarity restriction on the error process, the model can also be used as a residual-based cointegration test on discrete TSCS data. This is especially valuable because cointegration testing on discrete TSCS data is methodologically challenging and rarely conducted in practice. To handle the estimation difficulties, I developed an efficient Markov chain Monte Carlo (MCMC) algorithm by orthogonalizing the error term with the Cholesky decomposition and adding an auxiliary variable. The parameter expansion method, that is, partial group move—multigrid Monte Carlo updating (PGM-MGMC), is employed to further improve MCMC mixing and speed up convergence. The paper also provides a computational scheme to approximate the Bayes's factor for the purposes of serial correlation diagnostics, lag order determination, and variable selection. Simulated and empirical examples are used to assess the model and techniques.
Functional microdomains in bacterial membranes
Authors: López Daniel , Kolter Roberto
Published: August 2010

The membranes of eukaryotic cells harbor microdomains known as lipid rafts that contain a variety of signaling and transport proteins. Here we show that bacterial membranes contain microdomains functionally similar to those of eukaryotic cells. These membrane microdomains from diverse bacteria harbor homologs of Flotillin-1, a eukaryotic protein found exclusively in lipid rafts, along with proteins involved in signaling and transport. Inhibition of lipid raft formation through the action of zaragozic acid—a known inhibitor of squalene synthases—impaired biofilm formation and protein secretion but not cell viability. The orchestration of physiological processes in microdomains may be a more widespread feature of membranes than previously appreciated.
Canonical and alternate functions of the microRNA biogenesis machinery
Authors: Chong Mark M.W. , Zhang Guoan , Cheloufi Sihem , Neubert Thomas A. , Hannon Gregory J. , Littman Dan R.
Published: August 2010

The canonical microRNA (miRNA) biogenesis pathway requires two RNaseIII enzymes: Drosha and Dicer. To understand their functions in mammals in vivo, we engineered mice with germline or tissue-specific inactivation of the genes encoding these two proteins. Changes in proteomic and transcriptional profiles that were shared in Dicer- and Drosha-deficient mice confirmed the requirement for both enzymes in canonical miRNA biogenesis. However, deficiency in Drosha or Dicer did not always result in identical phenotypes, suggesting additional functions. We found that, in early-stage thymocytes, Drosha recognizes and directly cleaves many protein-coding messenger RNAs (mRNAs) with secondary stem–loop structures. In addition, we identified a subset of miRNAs generated by a Dicer-dependent but Drosha-independent mechanism. These were distinct from previously described mirtrons. Thus, in mammalian cells, Dicer is required for the biogenesis of multiple classes of miRNAs. Together, these findings extend the range of function of RNaseIII enzymes beyond canonical miRNA biogenesis, and help explain the nonoverlapping phenotypes caused by Drosha and Dicer deficiency.
Treatment Expectations and Treatment Experience of Chinese Families Towards Family Therapy: appraisal of a common belief
Authors: Ma Joyce L.C.
Published: August 2010

This paper reports results of a qualitative study on family therapy conducted in Hong Kong, which aims to identify Chinese families’ treatment expectations, delineate their subjective experience and the outcome in treatment. By comparing the expectations, the experience and the outcome, this study examines and challenges the belief that the practice of family therapy should necessarily be fundamentally adapted to be ‘culture‐specific’, an assumption that has hitherto been untested and possibly based on overgeneralized cultural stereotyping. This study provides empirical evidence for family therapists who have interests in working with local and overseas Chinese families to improve their practice.
Exploring the Use of Family Therapy with Adults with a Learning Disability
Authors: Fidell Beverley
Published: August 2010

Clients with a learning disability have received little attention so far from psychotherapeutic services. Systems thinking seems to have obvious potential for this group, given the stresses which such a disability puts on the client and his family and the variety of different organizations with which they become involved. This paper describes the use of family therapy within a clinic setting and considers similarities to and differences from general family therapy practice. Ways of overcoming communication difficulties are highlighted, as is the need to redress the power imbalance within the therapeutic situation.