The Synergistic Effect of Visible Light and Gentamycin on <em>Pseudomona aeruginosa</em> Microorganisms

Recently there were several publications on the  bactericidal effect of visible light, most of them claiming that blue part of  the spectrum (400 nm-500 ...

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The cytoskeleton is a dynamic network that undergoes restructuring during a variety of cellular events including cell contact formation, cell invasion and the mitotic phase of the cell cycle. Here, we review the contribution of the cytoskeletal network to the inductive activity of glucocorticoids by focusing on the hormonal control of glutamine synthetase in the chick neural retina. Depolymerization of the cytoskeleton in cells of the intact retinal tissue inhibits the hormonal induction of glutamine synthetase, but does not alter the cellular amount of the glucocorticoid-receptor protein or the ability of the receptor molecules to translocate into the nucleus. Inhibition of glutamine synthetase induction occurs via a mechanism that involves elevation of c-Jun protein accumulation and repression of glucocorticoid-receptor transcriptional activity. Unlike growth factors and other c-Jun inducing stimuli that control the transcription of the c-Jun gene, depolymerization of the cytoskeleton elevates c-Jun accumulation by upregulating the translation of the c-Jun transcript. We postulate that the cytoskeletal-dependent increase in c-Jun accumulation is involved in cell contact control of both cell proliferation and transcriptional activity of the glucocorticoid-receptor protein.

Cytoskeletal and cell contact control of the glucocorticoid pathway.

Le cytosquelette est un r&eacute;seau dynamique qui subit une restructuration au cours de divers &eacute;v&eacute;nements cellulaires, y compris la formation contact des cellules, invasion des cellules et la phase mitotique du cycle cellulaire. Nous r&eacute;sumons ici, la contribution du r&eacute;seau cytosquelettique pour l&#39;activit&eacute; inductive des glucocortico&iuml;des en mettant l&#39;accent sur le contr&ocirc;le hormonal de la glutamine synth&eacute;tase dans la r&eacute;tine neurale de poussin. D&eacute;polym&eacute;risation du cytosquelette dans les cellules du tissu r&eacute;tinien intact inhibe l&#39;induction hormonale de la glutamine synth&eacute;tase, mais ne modifie pas le montant cellulaire de la prot&eacute;ine du r&eacute;cepteur des glucocortico&iuml;des ou la capacit&eacute; des mol&eacute;cules r&eacute;ceptrices de translocation dans le noyau. L&#39;inhibition de l&#39;induction de glutamine synth&eacute;tase s&#39;effectue via un m&eacute;canisme qui implique une &eacute;l&eacute;vation de l&#39;accumulation de la prot&eacute;ine c-Jun et r&eacute;pression de l&#39;activit&eacute; transcriptionnelle de r&eacute;cepteur des glucocortico&iuml;des. Contrairement aux facteurs de croissance et autres stimuli induisant de c-Jun qui contr&ocirc;lent la transcription du g&egrave;ne c-Jun, d&eacute;polym&eacute;risation du cytosquelette &eacute;l&egrave;ve c-Jun accumulation de r&eacute;gulariser la traduction des notes st&eacute;nographiques c-Jun. Nous postulons que l&#39;augmentation d&eacute;pendant du cytosquelette dans l&#39;accumulation de c-Jun est impliqu&eacute;e dans le contr&ocirc;le contact cellule de fois la prolif&eacute;ration cellulaire et l&#39;activit&eacute; transcriptionnelle de la prot&eacute;ine du r&eacute;cepteur des glucocortico&iuml;des.

Cytoskeletal et cellule communiquer avec contr&ocirc;le de la voie de glucocortico&iuml;des.

Il citoscheletro &egrave; una rete dinamica sottoposta a ristrutturazione durante una variet&agrave; di eventi cellulari tra cui contatto formazione delle cellule, invasione delle cellule e la fase mitotica del ciclo cellulare. Qui, passiamo in rassegna il contributo della rete del citoscheletro all&#39;attivit&agrave; induttiva di glucocorticoidi concentrandosi sul controllo ormonale della sintetasi della glutammina nella retina neurale pulcino. Depolimerizzazione del citoscheletro in cellule del tessuto retinico intatto inibisce l&#39;induzione ormonale della sintetasi della glutammina, ma non altera la quantit&agrave; cellulare della proteina recettore glucocorticoidi o la capacit&agrave; delle molecole del recettore di traslocano nel nucleo. Inibizione di induzione di glutamina sintetasi avviene tramite un meccanismo che coinvolge l&#39;elevazione di accumulo della proteina c-Jun e repressione dell&#39;attivit&agrave; trascrizionale glucocorticoide-recettore. A differenza dei fattori di crescita e altri stimoli di induzione di c-Jun che controllano la trascrizione del gene c-Jun, depolimerizzazione del citoscheletro eleva c-Jun accumulo di upregulating la traduzione della trascrizione di c-Jun. Abbiamo postulato che l&#39;aumento del citoscheletro-dipendente in accumulo di c-Jun &egrave; coinvolto nel controllo contatto delle cellule di proliferazione cellulare sia e attivit&agrave; trascrizionale della proteina glucocorticoide-recettore.

Controllo del percorso glucocorticoide il contatto Citoscheletali e cella.

The target of rapamycin (TOR), a central controller of cell growth, is found in two distinct, highly conserved multiprotein complexes. Three recent papers in Cell (Jacinto et al., 2006), Developmental Cell (shiota et al., 2006; this issue), and Current Biology (Frias et al., 2006) shed light on mTOR complex 2 (mTORC2) composition and in vivo function. An important new finding is that mTORC2 determines Akt/PKB substrate specificity rather than absolute activity.

mTORC2 Caught in a SINful Akt.

La cible de la rapamycine (TOR), un contr&ocirc;leur central de la croissance cellulaire, se trouve dans deux complexes multiprot&eacute;iques distinctes, hautement conserv&eacute;es. Trois r&eacute;cents papiers en cellule (Jacinto et coll., 2006), Developmental Cell (shiota et al., 2006 ; cette question) et Current Biology (Frias et coll., 2006) faire la lumi&egrave;re sur la composition (mTORC2) 2 complexe de mTOR et fonction in vivo. Une nouvelle d&eacute;couverte importante est que mTORC2 d&eacute;termine la sp&eacute;cificit&eacute; de substrat Akt/PKB plut&ocirc;t que l&#39;activit&eacute; absolue.

mTORC2 coinc&eacute; entre une p&eacute;cheresse Akt.

Il bersaglio della rapamicina (TOR), un controller centrale di crescita delle cellule, &egrave; trovato in due complessi multiproteici distinte, altamente conservate. Tre recenti carte in cella (Jacinto et al., 2006), Developmental Cell (shiota et al., 2006; questo problema), e Current Biology (Frias et al., 2006) gettare luce su mTOR complex 2 (mTORC2) composizione e funzione in vivo. Un importante nuovo ritrovamento &egrave; che quello mTORC2 determina la specificit&agrave; di substrato di Akt/PKB, piuttosto che attivit&agrave; assoluta.

mTORC2 Caught in un peccaminoso Akt.

TOR (cible de la rapamycine) est une prot&eacute;ine hautement conserv&eacute;e kinase et un contr&ocirc;leur central de la croissance cellulaire. TOR se trouve dans deux fonctionnellement et structurellement diff&eacute;rentes complexes multiprot&eacute;iques appel&eacute; TOR 1 complexe (TORC1) et TOR 2 complexes (TORC2). Dans la pr&eacute;sente &eacute;tude, nous avons &eacute;labor&eacute; une strat&eacute;gie de prot&eacute;omiques de spectrom&eacute;trie de masse (LC-MS/MS 2D) bas&eacute;e de tandem chromatographie &agrave; deux dimensions afin d&#39;identifier de nouveaux mammif&egrave;res TOR (mTOR), prot&eacute;ines de liaison. Nous rapportons l&#39;identification d&#39;un substrat riche en Proline Akt (PRAS40) et la prot&eacute;ine hypoth&eacute;tique Q6MZQ0/FLJ14213/CAE45978 comme nouvelles prot&eacute;ines de liaison de mTOR. PRAS40 lie mTORC1 via Raptor et est un substrat de la phosphorylation de mTOR. PRAS40 inhibe mTORC1 autophosphorylation et activit&eacute; kinase mTORC1 vers FEI-4E GRB2 (4E-BP) et la PRAS40 elle-m&ecirc;me. Les cellules HeLa dans lequel PRAS40 a &eacute;t&eacute; renvers&eacute; &eacute;taient prot&eacute;g&eacute;s contre l&#39;induction de l&#39;apoptose par TNFalpha et la cycloheximide. La rapamycine a &eacute;chou&eacute; imiter l&#39;effet pro-apoptotique de la PRAS40, sugg&eacute;rant que PRAS40 intervient dans l&#39;apoptose, ind&eacute;pendamment de son effet inhibiteur sur mTORC1. Q6MZQ0 est structurellement similaire &agrave; la prot&eacute;ine riche proline 5 (PRR5) et fut donc nomm&eacute; PRR5-Like (PRR5L). PRR5L se lie sp&eacute;cifiquement &agrave; mTORC2, par Rictor et/ou SIN1. Contrairement aux autres membres de la mTORC2, PRR5L n&#39;est pas n&eacute;cessaire pour l&#39;activit&eacute; de l&#39;int&eacute;grit&eacute; ou de la kinase mTORC2, mais il se dissocie de la mTORC2 sur knock down de scl&eacute;rose tub&eacute;reuse de Bourneville 1 complexe (TSC1) et TSC2. Hyperactivation de mTOR par TSC1/2 abattre l&#39;apoptose accrue alors que PRR5L abattre l&#39;apoptose r&eacute;duite. PRR5L knock down apoptose r&eacute;duit &eacute;galement dans les cellules d&eacute;ficientes mTORC2. Ce qui pr&eacute;c&egrave;de sugg&egrave;re que PRR5L mTORC2 dissoci&eacute;es peuvent promouvoir l&#39;apoptose quand mTOR est hyperactif. Ainsi, PRAS40 et PRR5L sont des prot&eacute;ines nouvelles associ&eacute;s &agrave; mTOR qui contr&ocirc;lent l&#39;&eacute;quilibre entre la croissance cellulaire et l&#39;apoptose.

PRAS40 et PRR5-like protein sont nouveau Interactiens de mTOR qui r&eacute;gulent l&#39;apoptose.

TOR (Target of Rapamycin) is a highly conserved protein kinase and a central controller of cell growth. TOR is found in two functionally and structurally distinct multiprotein complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). In the present study, we developed a two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) based proteomic strategy to identify new mammalian TOR (mTOR) binding proteins. We report the identification of Proline-rich Akt substrate (PRAS40) and the hypothetical protein Q6MZQ0/FLJ14213/CAE45978 as new mTOR binding proteins. PRAS40 binds mTORC1 via Raptor, and is an mTOR phosphorylation substrate. PRAS40 inhibits mTORC1 autophosphorylation and mTORC1 kinase activity toward eIF-4E binding protein (4E-BP) and PRAS40 itself. HeLa cells in which PRAS40 was knocked down were protected against induction of apoptosis by TNFalpha and cycloheximide. Rapamycin failed to mimic the pro-apoptotic effect of PRAS40, suggesting that PRAS40 mediates apoptosis independently of its inhibitory effect on mTORC1. Q6MZQ0 is structurally similar to proline rich protein 5 (PRR5) and was therefore named PRR5-Like (PRR5L). PRR5L binds specifically to mTORC2, via Rictor and/or SIN1. Unlike other mTORC2 members, PRR5L is not required for mTORC2 integrity or kinase activity, but dissociates from mTORC2 upon knock down of tuberous sclerosis complex 1 (TSC1) and TSC2. Hyperactivation of mTOR by TSC1/2 knock down enhanced apoptosis whereas PRR5L knock down reduced apoptosis. PRR5L knock down reduced apoptosis also in mTORC2 deficient cells. The above suggests that mTORC2-dissociated PRR5L may promote apoptosis when mTOR is hyperactive. Thus, PRAS40 and PRR5L are novel mTOR-associated proteins that control the balance between cell growth and cell death.

PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis.

TOR (Target di rapamicina) &egrave; una chinasi di proteina altamente conservata e un controller centrale della crescita cellulare. TOR &egrave; trovato in due funzionalmente e strutturalmente distinti complessi multiproteici chiamato TOR complesso 1 (TORC1) e TOR complesso 2 (TORC2). Nel presente studio, abbiamo sviluppato una strategia di proteomic bidimensionale cromatografia liquida spettrometria di massa (2D LC-MS/MS) basato su tandem per identificare nuove TOR dei mammiferi (mTOR) proteine di legame. Riportiamo l&#39;identificazione del substrato ricco di prolina Akt (PRAS40) e la proteina ipotetica Q6MZQ0/FLJ14213/CAE45978 come nuovo mTOR binding proteins. PRAS40 associa mTORC1 via Raptor ed &egrave; un substrato della fosforilazione di mTOR. PRAS40 inibisce autophosphorylation mTORC1 e attivit&agrave; della chinasi mTORC1 verso la proteina FEI-4E (4E-BP) e PRAS40 stesso. Cellule HeLa PRAS40 fu abbattuto in cui erano protetti contro induzione di apoptosi da TNFalpha e cicloeximide. Rapamicina non &egrave; riuscito a imitare l&#39;effetto pro-apoptotico della PRAS40, suggerendo che PRAS40 da intermediario apoptosi indipendentemente dal suo effetto inibente sulla mTORC1. Q6MZQ0 &egrave; strutturalmente simile alla proteina ricca di prolina 5 (PRR5) e quindi &egrave; stato denominato come PRR5 (PRR5L). PRR5L lega specificamente a mTORC2, via Rictor e/o SIN1. A differenza di altri membri mTORC2, PRR5L non &egrave; richiesta per attivit&agrave; di integrit&agrave; o chinasi mTORC2, ma si dissocia da mTORC2 su knock down di sclerosi tuberosa complessa 1 (TSC1) e TSC2. Hyperactivation di mTOR da TSC1/2 abbattere apoptosi avanzata considerando che PRR5L abbattere ridotta apoptosi. PRR5L abbattere ridotta apoptosi anche nelle cellule carenti mTORC2. Quanto sopra suggerisce che PRR5L mTORC2 dissociato pu&ograve; promuovere apoptosis quando mTOR &egrave; iperattivo. Cos&igrave;, PRAS40 e PRR5L sono romanzo mTOR-associated proteins che controllano l&#39;equilibrio tra la crescita cellulare e morte cellulare.

PRAS40 e PRR5-come proteina sono nuovi interattori mTOR che regolano l&#39;apoptosi.

raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity. Leanness was in spite of reduced physical activity and unaffected caloric intake, lipolysis, and absorption of lipids from the food. White adipose tissue of raptor(ad-/-) mice displayed enhanced expression of genes encoding mitochondrial uncoupling proteins characteristic of brown fat. Leanness of the raptor(ad-/-) mice was attributed to elevated energy expenditure due to mitochondrial uncoupling. These results suggest that adipose mTORC1 is a regulator of adipose metabolism and, thereby, controls whole-body energy homeostasis.

Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration.

Raptor est un composant sp&eacute;cifique et essentiel de mammif&egrave;res TOR 1 complexe (mTORC1), un r&eacute;gulateur cl&eacute; de la croissance cellulaire et le m&eacute;tabolisme. Afin d&#39;&eacute;tudier un r&ocirc;le d&#39;adipeuse mTORC1 dans la r&eacute;gulation du m&eacute;tabolisme du tissu adipeux et de tout le corps, nous avons g&eacute;n&eacute;r&eacute; des souris avec un knockout adipeux sp&eacute;cifiques de raptor (raptor(ad-/-)). Compar&eacute; pour contr&ocirc;ler la m&ecirc;me port&eacute;e, raptor(ad-/-) souris avaient sensiblement moins le tissu adipeux, &eacute;taient prot&eacute;g&eacute;s contre l&#39;hypercholest&eacute;rol&eacute;mie et l&#39;ob&eacute;sit&eacute; induite par l&#39;alimentation et pr&eacute;sentaient la sensibilit&eacute; &agrave; l&#39;insuline am&eacute;lior&eacute;e. Maigreur &eacute;tait en d&eacute;pit de la r&eacute;duction de l&#39;activit&eacute; physique et pas affect&eacute; l&#39;apport calorique, lipolyse et absorption des lipides de la nourriture. Le tissu adipeux blanc de souris raptor(ad-/-) affiche une expression accrue des g&egrave;nes codant la caract&eacute;ristique de prot&eacute;ines d&eacute;couplantes mitochondriale de la graisse brune. Maigreur des souris raptor(ad-/-) a &eacute;t&eacute; attribu&eacute; &agrave; la d&eacute;pense d&#39;&eacute;nergie &eacute;lev&eacute;e due &agrave; mitochondrial d&eacute;telage de la remorque. Ces r&eacute;sultats sugg&egrave;rent que mTORC1 adipeuse est un r&eacute;gulateur du m&eacute;tabolisme du tissu adipeux et, ainsi, contr&ocirc;le de l&#39;hom&eacute;ostasie &eacute;nerg&eacute;tique de l&#39;ensemble du corps.

Knockout adipeux sp&eacute;cifiques de raptor se traduit par souris maigres avec la respiration mitochondriale am&eacute;lior&eacute;e.

Raptor &egrave; un componente essenziale e specifico di mammiferi TOR complesso 1 (mTORC1), un regolatore chiave della crescita cellulare e il metabolismo. Per indagare su un ruolo di mTORC1 adiposo nella regolazione del metabolismo adiposo e tutto il corpo, abbiamo generato topi con un knockout adiposo specifici di raptor (raptor(ad-/-)). Rispetto per controllare littermates, raptor(ad-/-) topi avevano sostanzialmente meno tessuto adiposo, sono stati protetti contro l&#39;ipercolesterolemia e l&#39;obesit&agrave; indotta da dieta ed esposta la sensibilit&agrave; all&#39;insulina migliorata. Magrezza &egrave; stato nonostante la ridotta attivit&agrave; fisica e apporto calorico inalterato, lipolisi e assorbimento dei lipidi dal cibo. Tessuto adiposo bianco di topi raptor(ad-/-) visualizzata una maggiore espressione dei geni che codificano la caratteristica di proteine disgiungente mitocondriale di grasso marrone. Magrezza dei topi raptor(ad-/-) fu attribuito a dispendio energetico elevato dovuto disgiungere mitocondriale. Questi risultati suggeriscono che mTORC1 adiposa &egrave; un regolatore del metabolismo adiposo e, quindi, controlla l&#39;omeostasi energetica del corpo intero.

Adiposo specifici ad eliminazione diretta dei risultati di raptor in topi magri con una maggiore respirazione mitocondriale.

Mammalian Target of Rapamycin (mTOR) is a highly conserved protein kinase that functions as part of two distinct multiprotein complexes to regulate growth and metabolism. This review describes the most important recent advances in the mTOR signaling field. In addition, we provide an overview on the functions of mTOR in different organs, with a special focus on the role of mTOR in whole body energy metabolism.

mTOR and the control of whole body metabolism.

Mammif&egrave;res cible de la rapamycine (mTOR) est une prot&eacute;ine hautement conserv&eacute;e kinase qui fonctionne dans le cadre de deux complexes multiprot&eacute;iques distinctes pour r&eacute;guler la croissance et le m&eacute;tabolisme. Cette revue d&eacute;crit les plus importants progr&egrave;s r&eacute;cents dans la mTOR champ de signalisation. En outre, nous offrons un aper&ccedil;u sur les fonctions de mTOR dans diff&eacute;rents organes, avec un accent particulier sur le r&ocirc;le de mTOR dans le m&eacute;tabolisme &eacute;nerg&eacute;tique de tout le corps.

mTOR et le contr&ocirc;le du m&eacute;tabolisme du corps entier.

Mammiferi Target of Rapamycin (mTOR) &egrave; una chinasi di proteina altamente conservata che funzioni come parte di due distinti complessi multiproteici a regolare la crescita e il metabolismo. Questa review descrive i pi&ugrave; importanti progressi in mTOR segnalazione campo. Inoltre, forniamo una panoramica sulle funzioni di mTOR in diversi organi, con un focus particolare sul ruolo di mTOR nel metabolismo energetico di tutto il corpo.

mTOR e il controllo del metabolismo di tutto il corpo.

Mammalian target of rapamycin (mTOR), a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors, is found in 2 structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. mTORC2, which consists of rictor, mSIN1, mLST8, and mTOR, is activated by insulin/IGF1 and phosphorylates Ser-473 in the hydrophobic motif of Akt/PKB. Though the role of mTOR in single cells is relatively well characterized, the role of mTOR signaling in specific tissues and how this may contribute to overall body growth is poorly understood. To examine the role of mTORC2 in an individual tissue, we generated adipose-specific rictor knockout mice (rictor(ad-/-)). Rictor(ad-/-) mice are increased in body size due to an increase in size of nonadipose organs, including heart, kidney, spleen, and bone. Furthermore, rictor(ad-/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic, but glucose tolerant, and display elevated levels of insulin-like growth factor 1 (IGF1) and IGF1 binding protein 3 (IGFBP3). These effects are observed in mice on either a high-fat or a normal diet, but are generally more pronounced in mice on a high-fat diet. Our findings suggest that adipose tissue, in particular mTORC2 in adipose tissue, plays an unexpectedly central role in controlling whole-body growth.

mTOR complex 2 in adipose tissue negatively controls whole-body growth.

Mammalian target of rapamycin (mTOR), une kinase de prot&eacute;ine hautement conserv&eacute;e qui contr&ocirc;le la croissance cellulaire et le m&eacute;tabolisme en r&eacute;ponse &agrave; des nutriments et de facteurs de croissance, se trouve &agrave; 2 structurellement et fonctionnellement distinctes complexes multiprot&eacute;iques appel&eacute;e mTOR complexe 1 (mTORC1) et mTORC2. mTORC2, qui se compose de rictor, mSIN1, mLST8 et mTOR, est activ&eacute;e par l&#39;insuline/IGF1 et phosphoryle Ser-473 dans le motif hydrophobe de Akt/PKB. Bien que le r&ocirc;le de mTOR dans des cellules individuelles est relativement bien caract&eacute;ris&eacute;, le r&ocirc;le de la signalisation dans les tissus sp&eacute;cifiques et comment cela peut contribuer &agrave; la croissance globale de mTOR est mal compris. Pour examiner le r&ocirc;le de mTORC2 dans un tissu individuel, nous avons g&eacute;n&eacute;r&eacute; rictor adipeux sp&eacute;cifiques chez des souris knockout (rictor(ad-/-)). Rictor(AD-/-) souris sont augment&eacute;es dans la taille du corps due &agrave; une augmentation de taille des organes adipeux, y compris le coeur, rein, rate et OS. En outre, rictor(ad-/-) souris ont un pancr&eacute;as d&eacute;mesur&eacute;ment &eacute;largi sont hyperinsulin&eacute;mique, mais la tol&eacute;rance de glucose et affichent des taux &eacute;lev&eacute;s d&#39;insuline-like growth factor 1 (IGF1) et IGF1 GRB2 3 (IGFBP3). Ces effets sont observ&eacute;s chez la souris une forte teneur en graisses ou un r&eacute;gime alimentaire normal, mais sont g&eacute;n&eacute;ralement plus prononc&eacute;e chez la souris sur une alimentation riche en graisses. Nos r&eacute;sultats sugg&egrave;rent que le tissu adipeux, en particulier mTORC2 dans le tissu adipeux, joue un r&ocirc;le central inopin&eacute;ment &agrave; contr&ocirc;ler la croissance de l&#39;ensemble du corps.

mTOR complexe 2 dans le tissu adipeux contr&ocirc;le n&eacute;gativement la croissance corporelle.

Destinazione dei mammiferi del rapamycin (mTOR), una chinasi di proteina altamente conservata che controlla la crescita cellulare e il metabolismo in risposta a sostanze nutritive e fattori di crescita, &egrave; trovato in 2 strutturalmente e funzionalmente distinti complessi multiproteici chiamato mTOR complex 1 (mTORC1) e mTORC2. mTORC2, che consiste di rictor, mSIN1, mLST8 e mTOR, viene attivato dall&#39;insulina/IGF1 e fosforila Ser-473 il motivo idrofobo di Akt/PKB. Anche se il ruolo di mTOR in singole celle &egrave; relativamente ben caratterizzato, il ruolo di mTOR segnalazione in specifici tessuti e come questo pu&ograve; contribuire alla crescita complessiva del corpo &egrave; poco conosciuto. Per esaminare il ruolo di mTORC2 in un tessuto individuale, abbiamo generato topi knockout adiposo specifici rictor (rictor(ad-/-)). Rictor(ad-/-) topi sono aumentati nelle dimensioni del corpo a causa di un aumento delle dimensioni degli organi nonadipose, compreso il cuore, reni, milza e ossa. Inoltre, rictor(ad-/-) topi hanno un pancreas sproporzionatamente allargato sono iperinsulinemica, ma glucosio tollerante e visualizzare i livelli elevati del fattore di crescita insulino-simile 1 (IGF1) e IGF1 binding protein 3 (IGFBP3). Questi effetti sono stati osservati in topi su un alto contenuto di grassi o una dieta normale, ma generalmente sono pi&ugrave; pronunciati nei topi una dieta ad alto contenuto di grassi. I nostri risultati suggeriscono che tessuto adiposo, in particolare mTORC2 nel tessuto adiposo, svolge un ruolo centrale in modo imprevisto nel controllo della crescita di tutto il corpo.

mTOR complex 2 nel tessuto adiposo negativamente controlla la crescita di tutto il corpo.

Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.

Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c.

Mammalian target of rapamycin complex 2 (mTORC2) phosphoryle et active des membres de la famille de kinase AGC, dont l&#39;Akt, SGK1 et PKC, en r&eacute;ponse &agrave; l&#39;insuline/IGF1. Le foie est un organe clef en insuline-r&eacute;gulation du m&eacute;tabolisme. Pour &eacute;valuer le r&ocirc;le de mTORC2 h&eacute;patique, nous avons g&eacute;n&eacute;r&eacute; rictor sp&eacute;cifiques du foie chez des souris knockout (LiRiKO). LiRiKO nourris de souris affichent la perte de la phosphorylation de l&#39;Akt Ser473 et r&eacute;duit la glucokinase et SREBP1c l&#39;activit&eacute; dans le foie, conduisant &agrave; la glucon&eacute;ogen&egrave;se constitutive et ayant une d&eacute;ficience de la glycolyse et la lipogen&egrave;se, sugg&eacute;rant que le foie d&eacute;ficient en mTORC2 est incapable de sati&eacute;t&eacute; de sens. Ces d&eacute;fauts de foie sp&eacute;cifique conduit &agrave; hypolipidemia, hyperinsulin&eacute;mie et hyperglyc&eacute;mie syst&eacute;mique. Expression d&#39;Akt2 constitutivement actif dans les h&eacute;patocytes d&eacute;ficients en mTORC2 restaur&eacute; les flux de glucose et la lipogen&egrave;se, consid&eacute;rant que la surexpression de la glucokinase a sauv&eacute; les flux de glucose mais pas la lipogen&egrave;se. Ainsi, mTORC2 r&eacute;gule h&eacute;patique de glucose et m&eacute;tabolisme des lipides par l&#39;interm&eacute;diaire de Akt induite par l&#39;insuline de signalisation contr&ocirc;ler l&#39;hom&eacute;ostasie m&eacute;tabolique du corps entier. Ces conclusions ont des r&eacute;percussions sur nouvelles pharmacoth&eacute;rapies que mTORC2 de la cible.

MTORC2 h&eacute;patique active la glycolyse et la lipogen&egrave;se Akt, glucokinase et SREBP1c.

Mammalian target di rapamicina complesso 2 (mTORC2) fosforila e attiva AGC chinasi familiari, tra cui Akt, SGK1 e PKC, in risposta all&#39;insulina/IGF1. Il fegato &egrave; un organo chiave nel regolamento insulino-mediata del metabolismo. Per valutare il ruolo di mTORC2 epatica, abbiamo generato topi knockout (LiRiKO) rictor specifici del fegato. Topi nutriti LiRiKO visualizzato perdita della fosforilazione di Akt Ser473 e ridotto glucochinasi e attivit&agrave; SREBP1c nel fegato, che porta a gluconeogenesi costitutiva e compromessa la glicolisi e lipogenesi, suggerendo che il fegato mTORC2-carente &egrave; in grado di saziet&agrave; senso. Questi difetti specifici del fegato provocato sistemica iperglicemia, iperinsulinemia e hypolipidemia. Espressione di Akt2 costitutivamente attive in deficit di mTORC2 epatociti restaurato sia flusso di glucosio e lipogenesi, considerando che la sovraespressione di glucochinasi salvato flusso di glucosio ma non lipogenesi. Cos&igrave;, mTORC2 regola glucosio epatico e metabolismo lipidico via Akt insulino-indotta di segnalazione per controllare l&#39;omeostasi metabolica del corpo intero. Questi risultati hanno implicazioni per le terapie farmacologiche emergenti mTORC2 tale destinazione.

MTORC2 epatica attiva glicolisi e lipogenesi attraverso Akt, glucochinasi e SREBP1c.

Detection of DNA mutations is critical for scientific research and diagnostic procedures. Here, we propose a novel interdisciplinary method for rapid and simple detection of DNA mutations. We show that heating a solution containing DNA and gold nanoparticles results in degradation of the DNA. Surprisingly, we found that the DNA can be protected against degradation, if an oligonucleotide that matches the DNA is added to the solution. Moreover, the level of degradation indicates the presence of mutations in the DNA. The method is sensitive enough to indicate even a single nucleotide difference, and has the potential to ultimately replace initial medical genetic tests. As proof of concept, we demonstrate a clear detection of two of the most common mutations leading to Cystic Fibrosis.

Gold nanoparticles-based biosensing of single nucleotide DNA mutations.

D&eacute;tection de mutations de l&#39;ADN est cruciale pour la recherche scientifique et des proc&eacute;dures de diagnostic. Ici, nous vous proposons une nouvelle m&eacute;thode interdisciplinaire pour la d&eacute;tection rapide et simple des mutations de l&#39;ADN. Nous montrons que le chauffage d&#39;une solution contenant l&#39;ADN et les r&eacute;sultats de nanoparticules d&#39;or dans la d&eacute;gradation de l&#39;ADN. &Eacute;tonnamment, nous avons constat&eacute; que l&#39;ADN peut &ecirc;tre prot&eacute;g&eacute; contre la d&eacute;gradation, si un oligonucl&eacute;otide qui correspond &agrave; l&#39;ADN est ajout&eacute; &agrave; la solution. En outre, le niveau de d&eacute;gradation indique la pr&eacute;sence de mutations de l&#39;ADN. La m&eacute;thode est assez sensible pour indiquer encore une diff&eacute;rence de nucl&eacute;otide et a le potentiel pour remplacer en fin de compte les premiers tests de g&eacute;n&eacute;tiques m&eacute;dicales. Comme preuve de concept, nous d&eacute;montrons une d&eacute;tection claire de deux des principales mutations conduisant &agrave; la fibrose kystique.

Or biod&eacute;tection ax&eacute;e sur les nanoparticules de mutations nucl&eacute;otidiques de l&#39;ADN.

Rilevazione di mutazioni del DNA &egrave; fondamentale per la ricerca scientifica e le procedure diagnostiche. Qui, vi proponiamo un nuovo metodo interdisciplinare per la rilevazione rapida e semplice di mutazioni del DNA. Mostriamo che riscaldamento una soluzione contenente il DNA e le nanoparticelle d&#39;oro risultati nella degradazione del DNA. Sorprendentemente, abbiamo scoperto che il DNA pu&ograve; essere protetto contro la degradazione, se un oligonucleotide che corrisponde al DNA &egrave; aggiunto alla soluzione. Inoltre, il livello di degrado indica la presenza di mutazioni nel DNA. Il metodo &egrave; abbastanza sensibile per indicare anche una differenza di singolo nucleotide e ha il potenziale per sostituire in ultima analisi iniziale test di genetica medica. Come prova di concetto, dimostriamo una chiara individuazione di due delle pi&ugrave; comuni mutazioni che portano a fibrosi cistica.

Biosensori basati su nanoparticelle d&#39;oro di mutazioni di singolo nucleotide del DNA.

In this article, we investigate the thermal degradation of deoxyribonucleic acid (DNA). We find that under dry conditions, complete DNA degradation occurs at above 190Â°C. In addition, as the boiling temperature of water is pressure dependent, we have investigated the thermal degradation of the DNA in water for different applied partial pressures. This information is important for fundamental understanding of DNA structure and energetics, and can be useful for biomedical applications such as thermal targeting of DNA in cancer cells, as well as for basic research.

Thermal degradation of DNA.

Dans cet article, nous &eacute;tudions la d&eacute;gradation thermique de l&#39;acide d&eacute;soxyribonucl&eacute;ique (ADN). Nous trouvons que dans des conditions s&egrave;ches, d&eacute;gradation compl&egrave;te de l&#39;ADN s&#39;effectue &agrave; 190&deg; c. En outre, comme la temp&eacute;rature d&#39;&eacute;bullition de l&#39;eau est d&eacute;pendante de la pression, nous avons &eacute;tudi&eacute; la d&eacute;gradation thermique de l&#39;ADN dans l&#39;eau pour diff&eacute;rentes pressions partielles d&#39;appliqu&eacute;s. Cette information est importante pour la compr&eacute;hension fondamentale de la structure de l&#39;ADN et &eacute;nerg&eacute;tiques et peut &ecirc;tre utile pour des applications biom&eacute;dicales telles que le ciblage thermique de l&#39;ADN dans les cellules canc&eacute;reuses, ainsi que pour la recherche fondamentale.

D&eacute;gradation thermique de l&#39;ADN.

In questo articolo, indaghiamo la degradazione termica dell&#39;acido desossiribonucleico (DNA). Troviamo che in condizioni di asciutto, completa degradazione del DNA avviene a oltre 190&deg; C. Inoltre, come la temperatura di ebollizione dell&#39;acqua &egrave; dipendente dalla pressione, abbiamo studiato la degradazione termica del DNA in acqua per diverse pressioni parziali applicati. Questa informazione &egrave; importante per la comprensione fondamentale della struttura del DNA e l&#39;energetica e pu&ograve; essere utile per applicazioni biomedicali come targeting termica del DNA nelle cellule tumorali, cos&igrave; come per la ricerca di base.

Pazit Polak

Faculty of Engineering

Libraries and Information System of Bar-Ilan University

The Synergistic Effect of Visible Light and Gentamycin on Pseudomona aeruginosa Microorganisms

Pazit Polak

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Faculty of Engineering

Libraries and Information System of Bar-Ilan University

The Synergistic Effect of Visible Light and Gentamycin on Pseudomona aeruginosa Microorganisms

Faculty of Engineering