675 research outputs found
mTOR complex 2 - akt signaling is physically and functionally at mam
No full textThe target of rapamycin (TOR) is a conserved protein kinase and a
central controller of growth. TOR can be part of two structurally and
functionally distinct complexes, termed TOR complex 1 and TOR
complex 2. Mammalian TOR complex 2 (mTORC2) is composed of
mTOR, Rictor, Sin1 and mLST8. Both mTORC1 and mTORC2 are activated
by growth factors. The mechanism via which growth factors
regulate mTORC2 has been elusive until recently. mTORC2 binds ribosomes
in a growth factor stimulated manner and this association is
required for mTORC2 activity.
mTOR complex 2 functions include control of spatial cell growth
and metabolism and thus, mTORC2 deregulation has been linked
to various disorders including cancer and diabetes. mTORC2 phosphorylates
and thereby activates the AGC kinase family member Akt
(PKB). Akt has many different targets and functions, not all of which
depend on mTORC2 mediated Akt phosphorylation.
In order to gain a better understanding of mTORC2 function, we
asked where mTORC2 signaling is localized. A number of studies
localized mTORC2, functionally or physically, either to the endoplasmic
reticulum (ER) or to mitochondria.We investigated whether these
seemingly unrelated observations concerning mTORC2 localization,
might be the consequence of mTORC2 signaling at MAM. MAM
or mitochondria-associated ER membrane is a quasi-synaptic subdomain
between the ER and mitochondria. MAM plays a crucial role in
the regulation of mitochondrial metabolism and cell survival by gating
both the calcium flux and phospholipid trafficking between the
ER and mitochondria.
First, we analyzed mTORC2 subcellular localization. mTORC2 is
localized to the ER adjacent to mitochondria and mTORC2 can be
biochemically isolated from MAM structures. mTOR complex 2 interacts
with the IP3R-Grp75-VDAC1 complex, a tether that connects ER
and mitochondria at MAM. Insulin stimulates mTORC2 localization
to MAM and mTORC2 interaction with the IP3R-Grp75-VDAC1 complex.
MAM localization of mTORC2 depends on mTORC2-ribosome
interaction.
Next we investigated the function of mTORC2 at MAM. Rictor
(mTORC2) knockout causes a decrease in MAM formation. Growth
factors stimulate MAM formation via mTORC2 and the Akt substrate
PACS2, a MAM resident protein. As expected for MAM deficient
cells, mTORC2 disruption changes the calcium flux from the ER to
mitochondria at MAM. Furthermore, we observe a reduction of Akt
mediated phosphorylation of the MAM calcium channel IP3R upon
Rictor knockout. Thus, mTORC2 signaling at MAM controls MAM mediated
calcium release via the Akt targets PACS2 and IP3R.
Since MAM disruption and calcium signaling both affect mitochondrial
metabolism, we proceeded by analyzing the mitochondrial physiology
of mTORC2 deficient cells. Rictor knockout cells exhibit a disruption
of VDAC1-HK2 binding, caused by a lack of Akt mediated
phosphorylation of HK2 at MAM. This, together with the defect in
MAM, induces an increase in basal respiration, mitochondrial inner
membrane potential, and ATP production in the mTORC2 deficient
cells, culminating in apoptosis. Thus, mTORC2 at MAM appears to
control several aspects of mitochondrial physiology.
These findings emphasize the role of MAM as a signaling hub that
controls cell physiology. By identifying the integral role of mTORC2
at the core of this platform, our results provide new insights on
the mechanisms that regulate growth and metabolism. These observations
may offer new therapeutic strategies against mTORC2 and
MAM driven diseases such as diabetes, Alzheimer’s and cancer
Mam: museum for a metropolis
No full textEste estudo examina as atividades iniciais do Museu de Arte Moderna de São Paulo (MAM) em face das questões culturais paulistanas no segundo pós-guerra, trazendo à tona a contribuição de personagens normalmente colocados num segundo plano quando da descrição freqüente do perído auroreal da entidade: os arquitetos e intelectuais envolvidos em tal tarefa. A escolha busca tirar do foco a análise do Museu como uma entidade única e estelar, para inserí-lo numa trama de vários acontecimentos e instituições, propiciadas pelos agentes participantes e pela possibilidade de diálogo motivada por sua localização física: o centro da Paulicéia no final dos anos 1940 e em grande parte da década seguinte, investigando as relações entre o espaço cultural da cidade e o MAM construção de um projeto moderno pela via institucional.This study examines the initial activities of the Museu de Arte Moderna (MAM) de São Paulo in context of the citys cultural questions after the II World War, showing contributions of actors, who are often placed in the background during the description of early years of the Museum: architects and intellectuals. This choice avoids to analyse the Museum like a main and isolated entity to insert it in an ensemble of several events and institutions generated by whom that participate in the creation of MAM and by possibility of dialogue due to its physical localization: the São Paulos downtown in later 1940 and 1950. The author investigates the relationships between São Paulos cultural environment and MAM construction of a modern project by institutional pathway
Mam: museum for a metropolis
No full textEste estudo examina as atividades iniciais do Museu de Arte Moderna de São Paulo (MAM) em face das questões culturais paulistanas no segundo pós-guerra, trazendo à tona a contribuição de personagens normalmente colocados num segundo plano quando da descrição freqüente do perído auroreal da entidade: os arquitetos e intelectuais envolvidos em tal tarefa. A escolha busca tirar do foco a análise do Museu como uma entidade única e estelar, para inserí-lo numa trama de vários acontecimentos e instituições, propiciadas pelos agentes participantes e pela possibilidade de diálogo motivada por sua localização física: o centro da Paulicéia no final dos anos 1940 e em grande parte da década seguinte, investigando as relações entre o espaço cultural da cidade e o MAM construção de um projeto moderno pela via institucional.This study examines the initial activities of the Museu de Arte Moderna (MAM) de São Paulo in context of the citys cultural questions after the II World War, showing contributions of actors, who are often placed in the background during the description of early years of the Museum: architects and intellectuals. This choice avoids to analyse the Museum like a main and isolated entity to insert it in an ensemble of several events and institutions generated by whom that participate in the creation of MAM and by possibility of dialogue due to its physical localization: the São Paulos downtown in later 1940 and 1950. The author investigates the relationships between São Paulos cultural environment and MAM construction of a modern project by institutional pathway
Trivialno in/ali sentimentalno?
No full textV prispevku izhajam iz vprašanja, ali je za pripovedno prozo Pavline Pajk ustrezna umestitev pod okrilje trivialne literature in v kolikšni meri so v tem besedilu prisotne prvine sentimentalnega pripovedništva. Izsledke analize motivnih, pripovednih in oblikovnih posebnosti romana Arabela soočam s spoznanji Mirana Hladnika v študiji Slovenski ženski roman v 19. stoletju, kjer je to delo na kratko primerjal z romanom Skrivnost stare gospodične nemške pisateljice Eugenie Marlitt in zapisal, da je slovenski ženski roman nastal ob zgledovanju pri njej. S primerjavo obeh romanov in recepcije nemške pisateljice na Slovenskem razmerje med njo in Pavlino Pajk na nov osvetljujem ter odgovarjam na vprašanje, zakaj so ji njeni sodobniki vztrajno očitali, da je bila posnemovalka Eugenie Mwrlitt.The author proceeds from the question whether it is appropriate to classify Pavlina Pajk\u27s prose as trivial literature and to what extent elements of sentimental narrative prose are present in her text. The results of the analysis of the thematic, narrative, and formal pecularities of the novel Arabela are juxtaposed with Miran Hladnik\u27s findings in his study Slovenski ženski roman v 19. stoletju [Slovene women\u27s novel in the 19th century], where he briefly compares this text with the novel The old mam´selle\u27s secret by E. Marlitt stating that the Slovene women´s novel was conceived based on the example of this German writer. By comparing both novels and the reception of E. Marlitt in the Slovene lands, the author sheds new light on the relationship between E. Marlit and Pavlina Pajk and answers the question why her contemporaries pesistently accused her of being E. Marlitt\u27s epigone
MDGA1, an IgSF molecule containing a MAM domain, heterophilically associates with axon- and muscle-associated binding partners through distinct structural domains.
No full textMolecules belonging to the immunoglobulin superfamily (IgSF) are reported to be involved in intercellular communication in the developing nervous system. We have identified a novel GPI-anchored IgSF molecule containing a MAM (meprin, A5 protein, PTPμ) domain, named MDGA1, by screening for genes that are expressed by subpopulations of cells in the embryonic chick spinal cord. MDGA1 is selectively expressed by brachial LMCm motor neurons, some populations of DRG neurons, and interneurons. We found that MDGA1 interacts heterophilically with axon-rich regions, mainly through its MAM domain. Interestingly, MDGA1 also interacts with differentiating muscle through its N-terminal region, which contains Ig domains. These results suggest that MDGA1 functions in MDGA1-expressing nerves en route to and at their target site
The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury
No full textEarlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis
A strategic road map for conserving the Endangered dhole Cuon alpinus in India
No full textThis is the peer reviewed version of the following article: [A strategic road map for conserving the Endangered dhole Cuon alpinus in India. Mammal Review 50, 4 p399-412 (2020)], which has been published in final form at https://doi.org/10.1111/mam.12209. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions: https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html#3.
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Bioinformatics' approaches to detect genetic variation in whole genome sequencing data
No full textCurrent genetic marker repositories are not sufficient or even are completely lacking for most farm animals. However, genetic markers are essential for the development of a research tool facilitating discovery of genetic factors that contribute to resistance to disease and the overall welfare and performance in farm animals. By large scale identification of Single Nucleotide Polymorphisms (SNPs) and Structural Variants (SVs) we aimed to contribute to the development of a repository of genetic variants for farm animals. For this purpose bioinformatics data pipelines were designed and validated to address the challenge of the cost effective identification of genetic markers in DNA sequencing data even in absence of a fully sequenced reference genome. To find SNPs in pig, we analysed publicly available whole genome shotgun sequencing datasets by sequence alignment and clustering. Sequence clusters were assigned to genomic locations using publicly available BAC sequencing and BAC mapping data. Within the sequence clusters thousands of SNPs were detected of which the genomic location is roughly known. For turkey and duck, species that both were lacking a sufficient sequence data repository for variant discovery, we applied next-generation sequencing (NGS) on a reduced genome representation of a pooled DNA sample. For turkey a genome reference was reconstructed from our sequencing data and available public sequencing data whereas in duck the reference genome constructed by a (NGS) project was used. SNPs obtained by our cost-effective SNP detection procedure still turned out to cover, at intervals, the whole turkey and duck genomes and are of sufficient quality to be used in genotyping studies. Allele frequencies, obtained by genotyping animal panels with a subset our SNPs, correlated well with those observed during SNP detection. The availability of two external duck SNP datasets allowed for the construction of a subset of SNPs which we had in common with these sets. Genotyping turned out that this subset was of outstanding quality and can be used for benchmarking other SNPs that we identified within duck. Ongoing developments in (NGS) allowed for paired end sequencing which is an extension on sequencing analysis that provides information about which pair of reads are coming from the outer ends of one sequenced DNA fragment. We applied this technique on a reduced genome representation of four chicken breeds to detect SVs. Paired end reads were mapped to the chicken reference genome and SVs were identified as abnormally aligned read pairs that have orientation or span sizes discordant from the reference genome. SV detection parameters, to distinguish true structural variants from false positives, were designed and optimized by validation of a small representative sample of SVs using PCR and traditional capillary sequencing. To conclude: we developed SNP repositories which fulfils a requirement for SNPs to perform linkage analysis, comparative genomics QTL studies and ultimately GWA studies in a range of farm animals. We also set the first step in developing a repository for SVs in chicken, a relatively new genetic marker in animal sciences. <br/
AGU hydrology days 2007
No full text2007 annual AGU hydrology days was held at Colorado State University on March 19 - March 21, 2007.Includes bibliographical references.Effects of land cover change over the Indian subcontinent during the preceding March through May (MAM) on early Indian summer monsoon (ISM) rainfall were examined using the Normalized Difference Vegetation Index (NDVI) and Global Precipitation Climatology Project precipitation for the period of 1982~2003. MAM NDVI anomalies have increased significantly in western and northern India. NDVI anomalies are correlated with the decreasing trend of early ISM rainfall. Decreasing rainfall originates from the decreased land-sea thermal contrast, which is due to the decreasing trend of July sensible heat flux in central and northern India. This is related to the increase in the preceding MAM NDVI anomalies because early ISM rainfall is significantly and negatively correlated with the standardized principal component of the first leading empirical orthogonal function for the preceding MAM NDVI anomalies. Also, composite differences of early ISM rainfall for the five years of highest and of lowest MAM NDVI anomalies demonstrate that early ISM rainfall is significantly less for the years of highest MAM NDVI anomalies. Composite differences of wind vectors and divergence in the upper level also support the conclusion that the weak early Indian summer monsoonal circulation is due to the increase in land cover during the preceding spring, which would promote an increase in latent heat flux and a decrease in sensible heat flux thereby favoring a reduced horizontal temperature gradient
International Trade, Productivity Growth, Education and Wage Differentials: A Case Study of Taiwan.
No full textThe source of changes in the wage differential between skilled and unskilled labor has been an important subject of debate for several decades. International trade and productivity growth are two main causes that have been suggested from large country studies. Recent research proposes education as another influence. All three causes have been significantly associated with Taiwan's economic development. This paper attempts to contribute to the literature by investigating wage differentials of Taiwan, a small open economy with a paucity of study on the issue of trade and wages. An Error Correction Model (ECM) incorporating both short and long term run effects is employed.WAGES ; INTERNATIONAL TRADE ; PRODUCTIVITY
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