cell-patterning-on-photolithographically-defined-parylene-c-sio2

Cell Patterning on Photolithographically Defined 
Parylene-C: SiO<sub>2</sub> Substrates

Cell patterning platforms support broad research goals, such as construction of predefined in vitro neuronal networks and the exploration of certain ...

Western General Hospital

The function of the normal conformational isoform of prion protein, PrP(C), remains unclear although lines of research have suggested a role in the cellular response to oxidative stress. Here we investigate the expression of PrP(C) in hypoxic brain tissues to examine whether PrP(C) is in part regulated by neuronal stress. Cases of adult cerebral ischemia and perinatal hypoxic-ischemic injury in humans were compared with control tissues. PrP(C) immunoreactivity accumulates within neuronal processes in the penumbra of hypoxic damage in adult brain, and within neuronal soma in cases of perinatal hypoxic-ischemic injury, and in situ hybridization analysis suggests an up-regulation of PrP mRNA during hypoxia. Rodents also showed an accumulation of PrP(C) in neuronal soma within the penumbra of ischemic lesions. Furthermore, the infarct size in PrP-null mice was significantly greater than in the wild type, supporting the proposed role for PrP(C) in the neuroprotective adaptive cellular response to hypoxic injury.

Prion protein accumulation and neuroprotection in hypoxic brain damage.

The most common genetic predisposition to multiple schwannoma growth is mutation of the neurofibromatosis type 2 gene. We describe a patient with multiple schwannomas and mutation in the recently described INI1 gene, which also predisposes to the disease. We explore the implications for prognosis and outcome.

Multiple schwannomatosis caused by the recently described INI1 gene--molecular pathology, and implications for prognosis.

The PH domain leucine-rich repeat protein phosphatase, PHLPP, plays a central role in controlling the amplitude of growth factor signaling by directly dephosphorylating and thereby inactivating Akt. The cellular levels of PHLPP1 have recently been shown to be enhanced by its substrate, activated Akt, via modulation of a phosphodegron recognized by the E3 ligase β-TrCP1, thus providing a negative feedback loop to tightly control cellular Akt output. Here we show that this feedback loop is lost in aggressive glioblastoma but not less aggressive astrocytoma. Overexpression and pharmacological studies reveal that loss of the feedback loop does not result from a defect in PHLPP1 protein or in the upstream kinases that control its phosphodegron. Rather, the defect arises from altered localization of β-TrCP1; in astrocytoma cell lines and in normal brain tissue the E3 ligase is predominantly cytoplasmic, whereas in glioblastoma cell lines and patient-derived tumor neurospheres, the E3 ligase is confined to the nucleus and thus spatially separated from PHLPP1, which is cytoplasmic. Restoring the localization of β-TrCP1 to the cytosol of glioblastoma cells rescues the ability of Akt to regulate PHLPP1 stability. Additionally, we show that the degradation of another β-TrCP1 substrate, β-catenin, is impaired and accumulates in the cytosol of glioblastoma cell lines. Our findings reveal that the cellular localization of β-TrCP1 is altered in glioblastoma, resulting in dysregulation of PHLPP1 and other substrates such as β-catenin.

Mislocalization of the E3 ligase, β-transducin repeat-containing protein 1 (β-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt.

Our professional and personal lives depend increasingly on access to information via the Internet. As an open access resource, the Internet is on the whole unbridled by censorship and can facilitate the rapid propagation of ideas and discoveries. At the same time, this liberty in sharing information, being unregulated and often free from external validation, can be oppressive; overloading the user and hindering effective decision-making. It can be difficult, if not impossible, to reliably ascertain the provenance of data and opinion. We must, therefore, discern what is useful, relevant, and above all reliable if we are to harness the Internet's potential to improve training, delivery of care, research, and provision of patient information. This article profiles the resources currently available to neurosurgeons, asks how we can sort the informational wheat from the chaff, and explores where future developments might further influence neurosurgical practice.

The Internet for neurosurgeons: current resources and future challenges.

&#x53CD;&#x8F6C;&#x5F55;&#x8F6C;&#x5EA7;&#x5B50;&#x662F;&#x79FB;&#x52A8;&#x4F7F;&#x7528;&#x751F;&#x6B96;&#x590D;&#x5236;&#x7C98;&#x8D34;&#x673A;&#x5236;&#x6765;&#x904D;&#x5E03;&#x540E;&#x751F;&#x57FA;&#x56E0;&#x7EC4;&#x7684;&#x9057;&#x4F20;&#x8981;&#x7D20;&#x3002;&#x81F3;&#x5C11; 50%&#x7684;&#x4EBA;&#x7C7B;&#x57FA;&#x56E0;&#x7EC4;&#x88AB;&#x6765;&#x81EA;&#x53CD;&#x8F6C;&#x5F55;&#x8F6C;&#x5EA7;&#x5B50;&#xFF0C;&#x4E0E;&#x4E09;&#x4E2A;&#x6D3B;&#x8DC3;&#x7684;&#x5BB6;&#x5EAD; &#xFF08;L1&#x3001; Alu &#x548C;&#x5E7F;&#x7535;&#xFF09; &#x7684;&#x63D2;&#x5165;&#x7A81;&#x53D8;&#x4E0E;&#x75BE;&#x75C5;&#x76F8;&#x5173;&#x3002;&#x8868;&#x89C2;&#x9057;&#x4F20;&#x5B66;&#x4E0E;&#x8F6C;&#x5F55;&#x6291;&#x5236;&#x5757; retrotransposition &#x5728;&#x4F53;&#x7EC6;&#x80DE;&#xFF0C;&#x4E0D;&#x5305;&#x62EC;&#x65E9;&#x671F;&#x80DA;&#x80CE;&#x53D1;&#x80B2;&#x53CA;&#x67D0;&#x4E9B;&#x6076;&#x6027;&#x80BF;&#x7624;&#x3002;L1 &#x8868;&#x8FBE;&#x548C;&#x62F7;&#x8D1D;&#x6570;&#x53D8;&#x5F02;&#x4EBA;&#x7C7B;&#x5927;&#x8111;&#x4E2D;&#x7684;&#x6700;&#x8FD1;&#x7684;&#x62A5;&#x544A;&#x8868;&#x660E; L1 &#x8C03;&#x52A8;&#x4E5F;&#x53EF;&#x80FD;&#x51FA;&#x73B0;&#x5728;&#x540E;&#x6765;&#x7684;&#x53D1;&#x5C55;&#x8FC7;&#x7A0B;&#x3002;&#x4F46;&#x662F;&#xFF0C;&#x76F8;&#x5E94;&#x7684;&#x96C6;&#x6210;&#x7AD9;&#x70B9;&#x672A;&#x88AB;&#x6620;&#x5C04;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x91C7;&#x7528;&#x9AD8;&#x901A;&#x91CF;&#x65B9;&#x6CD5;&#x6765;&#x627E;&#x51FA;&#x65E0;&#x6570; L1&#x3001; Alu &#x548C;&#x5E7F;&#x7535;&#x80DA;&#x7CFB;&#x7A81;&#x53D8;&#xFF0C;&#x4EE5;&#x53CA; 7,743 &#x5047;&#x5B9A;&#x4F53;&#x7EC6;&#x80DE; L1 &#x63D2;&#x5165;&#xFF0C;&#x5728;&#x6D77;&#x9A6C;&#x548C;&#x5C3E;&#x72B6;&#x6838;&#x7684;&#x4E09;&#x4E2A;&#x4EBA;&#x3002;&#x5947;&#x602A;&#x7684;&#x662F;&#xFF0C;&#x6211;&#x4EEC;&#x8FD8;&#x53D1;&#x73B0; 13,692 &#x4F53;&#x7EC6;&#x80DE; Alu &#x63D2;&#x5165;&#x548C; 1,350 &#x4E0A;&#x6D77;&#x5E7F;&#x7535;&#x63D2;&#x5165;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x8868;&#x660E;&#x53CD;&#x8F6C;&#x5F55;&#x8F6C;&#x5EA7;&#x5B50;&#x8C03;&#x52A8;&#x5230;&#x86CB;&#x767D;&#x8D28;&#x7F16;&#x7801;&#x57FA;&#x56E0;&#x5DEE;&#x5F02;&#x8868;&#x8FBE;&#x4E0E;&#x6D3B;&#x8DC3;&#x5728;&#x5927;&#x8111;&#x4E2D;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x7531; retrotransposition &#x9A71;&#x52A8;&#x7684;&#x4F53;&#x7EC6;&#x80DE;&#x57FA;&#x56E0;&#x7EC4;&#x9576;&#x5D4C;&#x53EF;&#x80FD;&#x91CD;&#x5851;&#x9057;&#x4F20;&#x7684;&#x7535;&#x8DEF;&#xFF0C;&#x662F;&#x6B63;&#x5E38;&#x548C;&#x5F02;&#x5E38;&#x7684;&#x795E;&#x7ECF;&#x751F;&#x7269;&#x5B66;&#x8FC7;&#x7A0B;&#x7684;&#x57FA;&#x7840;&#x3002;

&#x4F53;&#x7EC6;&#x80DE; retrotransposition &#x9057;&#x4F20;&#x6539;&#x53D8;&#x4E86;&#x4EBA;&#x7C7B;&#x7684;&#x5927;&#x8111;&#x3002;

Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.

Somatic retrotransposition alters the genetic landscape of the human brain.

R&#xE9;trotransposons sont des &#xE9;l&#xE9;ments g&#xE9;n&#xE9;tiques mobiles qui utilisent un m&#xE9;canisme de lign&#xE9;e germinale &#x26;quot;copier-coller&#xBB; &#xE0; se r&#xE9;pandre dans les g&#xE9;nomes de m&#xE9;tazoaires. Au moins 50 pour cent du g&#xE9;nome humain est d&#xE9;riv&#xE9; de r&#xE9;trotransposons, avec trois familles actives (L1, Alu et SVA) associ&#xE9;s &#xE0; la mutagen&#xE8;se insertionnelle et la maladie. Epig&#xE9;n&#xE9;tique et post-transcriptionnelle r&#xE9;trotransposition bloc de suppression dans les cellules somatiques, &#xE0; l&#x26;#39;exclusion du d&#xE9;veloppement embryonnaire pr&#xE9;coce et de certaines tumeurs malignes. Des rapports r&#xE9;cents d&#x26;#39;expression L1 et de la variation du nombre de copies dans le cerveau humain sugg&#xE8;rent que la mobilisation L1 peut &#xE9;galement se produire au cours du d&#xE9;veloppement ult&#xE9;rieur. Cependant, les sites d&#x26;#39;int&#xE9;gration correspondants n&#x26;#39;ont pas &#xE9;t&#xE9; cartographi&#xE9;es. Ici, nous appliquons une m&#xE9;thode &#xE0; haut d&#xE9;bit pour identifier de nombreuses L1, Alu et SVA des mutations germinales, ainsi que 7,743 putatifs insertions L1 somatiques, dans l&#x26;#39;hippocampe et le noyau caud&#xE9; de trois personnes. &#xC9;tonnamment, nous avons aussi trouv&#xE9; 13,692 somatiques insertions Alu et 1350 insertions SVA. Nos r&#xE9;sultats d&#xE9;montrent que les r&#xE9;trotransposons mobiliser pour codant pour des prot&#xE9;ines des g&#xE8;nes diff&#xE9;rentiellement exprim&#xE9;s et active dans le cerveau. Ainsi, somatique g&#xE9;nome mosa&#xEF;que entra&#xEE;n&#xE9;e par r&#xE9;trotransposition peut remodeler le circuit g&#xE9;n&#xE9;tique qui sous-tend normaux et anormaux processus neurobiologiques.

R&#xE9;trotransposition somatique modifie le paysage g&#xE9;n&#xE9;tique du cerveau humain

Retrotransposons sind mobile genetische Elemente, mit denen einen Germline &#39;Copy-and-Paste&#39; Mechanismus indem Genome ausgebreitet. Mindestens ist 50 Prozent des menschlichen Genoms abgeleitet Retrotransposons, mit drei aktive Familien (L1, Alu und SVA) muss Mutagenese und Krankheit zugeordnet. Epigenetische und Posttranskriptionale Unterdr&uuml;ckung Block Retrotransposition somatischer Zellen, ohne fr&uuml;hen Embryonalentwicklung und einige Krebserkrankungen. J&uuml;ngste Berichte &uuml;ber L1 Ausdruck und Copy Number variants im menschlichen Gehirn schlagen vor, da&szlig; L1 Mobilisierung auch w&auml;hrend der sp&auml;teren Entwicklung auftreten kann. Jedoch haben die entsprechenden Seiten der Integration nicht zugeordnet wurde. Hier wenden wir eine Hochdurchsatz-Methode um zahlreiche L1, Alu und SVA Keimbahn-Mutationen, sowie 7.743 vermeintliche somatische L1 Einf&uuml;gungen in den Hippocampus und Nucleus caudatus drei Personen zu identifizieren. &Uuml;berraschenderweise fanden wir auch 13.692 somatische Alu Einf&uuml;gungen und 1.350 SVA Einf&uuml;gungen. Unsere Ergebnisse zeigen, dass Retrotransposons auf Protein-kodierenden Gene differentiell exprimierten und aktiv im Gehirn mobilisieren. Somatische Genom-Mosaik, getrieben von Retrotransposition kann so die genetische Schaltung neu gestalten, die normale und anormale neurobiologische Prozessen zugrunde liegt.

Somatische Retrotransposition &auml;ndert die genetische Landschaft des menschlichen Gehirns.

Retrotrasposoni sono elementi genetici mobili che utilizzano un meccanismo di &#39;copia e incolla&#39; germinale a diffondersi in tutta genomi metazoi. Almeno il 50 per cento del genoma umano &egrave; derivato da retrotrasposoni, con tre famiglie attive (L1, Alu e SVA) associati con la malattia e la mutagenesi inserzionale. Soppressione epigenetici ed espresione blocco retrotrasposizione nelle cellule somatiche, escluso lo sviluppo dell&#39;embrione precoce e alcuni tumori maligni. Rapporti recenti di L1 espressione e copia numero variazione nel cervello umano suggeriscono che la mobilitazione L1 pu&ograve; verificarsi anche durante il successivo sviluppo. Tuttavia, non sono stati mappati i corrispondenti siti di integrazione. Qui si applica un metodo di alto-rendimento per identificare mutazioni germinali numerosi L1, Alu e SVA, come pure 7.743 putativi somatici L1 inserimenti, nell&#39;ippocampo e nucleo caudato di tre individui. Sorprendentemente, abbiamo anche trovato 13.692 somatici Inserzioni Alu e 1.350 inserimenti SVA. I nostri risultati dimostrano che i retrotrasposoni mobilitare per geni codificanti proteine differenzialmente espressi e attivi nel cervello. Cos&igrave;, un mosaicismo somatico genoma guidato da retrotrasposizione pu&ograve; rimodellare la circuiteria genetica che &egrave; alla base dei processi neurobiologici normali e anormali.

Somatico retrotrasposizione altera il paesaggio genetico del cervello umano.

&#x30EC;&#x30C8;&#x30ED;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30BE;&#x30F3;&#x306F;&#x3001;&#x5F8C;&#x751F;&#x52D5;&#x7269;&#x306E;&#x30B2;&#x30CE;&#x30E0;&#x5168;&#x4F53;&#x306B;&#x5E83;&#x304C;&#x308B;&#x3088;&#x3046;&#x306B;&#x751F;&#x6B96;&#x7D30;&#x80DE; &#x26;quot;&#x30B3;&#x30D4;&#x30FC;&#x30A2;&#x30F3;&#x30C9;&#x30DA;&#x30FC;&#x30B9;&#x30C8;&#x26;quot;&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x4F7F;&#x7528;&#x3059;&#x308B;&#x30E2;&#x30D0;&#x30A4;&#x30EB;&#x907A;&#x4F1D;&#x7684;&#x8981;&#x7D20;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x30D2;&#x30C8;&#x30B2;&#x30CE;&#x30E0;&#x306E;&#x5C11;&#x306A;&#x304F;&#x3068;&#x3082;50&#x30D1;&#x30FC;&#x30BB;&#x30F3;&#x30C8;&#x304C;&#x633F;&#x5165;&#x7A81;&#x7136;&#x5909;&#x7570;&#x3068;&#x75BE;&#x60A3;&#x306B;&#x95A2;&#x9023;&#x3059;&#x308B;3&#x3064;&#x306E;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x306A;&#x5BB6;&#x65CF;&#xFF08;L1&#x3001;ALU&#x3068;SVA&#xFF09;&#x3068;&#x3001;&#x30EC;&#x30C8;&#x30ED;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30BE;&#x30F3;&#x306B;&#x7531;&#x6765;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x521D;&#x671F;&#x80DA;&#x306E;&#x958B;&#x767A;&#x3068;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x60AA;&#x6027;&#x816B;&#x760D;&#x3092;&#x9664;&#x304F;&#x4F53;&#x7D30;&#x80DE;&#x306E;&#x30A8;&#x30D4;&#x30B8;&#x30A7;&#x30CD;&#x30C6;&#x30A3;&#x30C3;&#x30AF;&#x3068;&#x8EE2;&#x5199;&#x5F8C;&#x6291;&#x5236;&#x30D6;&#x30ED;&#x30C3;&#x30AF;&#x30EC;&#x30C8;&#x30ED;&#x8EE2;&#x4F4D;&#x3001;&#x3002;&#x4EBA;&#x9593;&#x306E;&#x8133;&#x306B;&#x304A;&#x3051;&#x308B;L1&#x306E;&#x767A;&#x73FE;&#x304A;&#x3088;&#x3073;&#x30B3;&#x30D4;&#x30FC;&#x6570;&#x5909;&#x5316;&#x306E;&#x6700;&#x8FD1;&#x306E;&#x5831;&#x544A;&#x3067;&#x306F;&#x3001;L1&#x306E;&#x52D5;&#x54E1;&#x3082;&#x3001;&#x5F8C;&#x306E;&#x958B;&#x767A;&#x4E2D;&#x306B;&#x767A;&#x751F;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x793A;&#x5506;&#x3055;&#x308C;&#x305F;&#x3002;&#x305F;&#x3060;&#x3057;&#x3001;&#x5BFE;&#x5FDC;&#x3059;&#x308B;&#x7D71;&#x5408;&#x30B5;&#x30A4;&#x30C8;&#x304C;&#x30DE;&#x30C3;&#x30D7;&#x3055;&#x308C;&#x3066;&#x3044;&#x306A;&#x3044;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;3&#x4EBA;&#x306E;&#x6D77;&#x99AC;&#x3068;&#x5C3E;&#x72B6;&#x6838;&#x3067;&#x306F;&#x3001;&#x591A;&#x6570;&#x306E;L1&#x3001;ALU&#x3068;SVA&#x751F;&#x6B96;&#x7D30;&#x80DE;&#x306E;&#x5909;&#x7570;&#x3068;&#x540C;&#x69D8;&#x306B;&#x3001;7743&#x306E;&#x63A8;&#x5B9A;&#x4F53;L1&#x306E;&#x633F;&#x5165;&#x3092;&#x8B58;&#x5225;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x30CF;&#x30A4;&#x30B9;&#x30EB;&#x30FC;&#x30D7;&#x30C3;&#x30C8;&#x6CD5;&#x3092;&#x9069;&#x7528;&#x3057;&#x307E;&#x3059;&#x3002;&#x9A5A;&#x304F;&#x3079;&#x304D;&#x3053;&#x3068;&#x306B;&#x3001;&#x6211;&#x3005;&#x306F;&#x307E;&#x305F;&#x3001;13692&#x4F53;&#x306E;ALU&#x306E;&#x633F;&#x5165;&#x304A;&#x3088;&#x3073;1350 SVA&#x633F;&#x5165;&#x3092;&#x767A;&#x898B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;&#x30EC;&#x30C8;&#x30ED;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30BE;&#x30F3;&#x306F;&#x3001;&#x793A;&#x5DEE;&#x7684;&#x306B;&#x767A;&#x73FE;&#x3057;&#x3001;&#x8133;&#x5185;&#x306E;&#x6D3B;&#x6027;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x3092;&#x30B3;&#x30FC;&#x30C9;&#x3059;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x306B;&#x52D5;&#x54E1;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x30EC;&#x30C8;&#x30ED;&#x8EE2;&#x4F4D;&#x306B;&#x3088;&#x3063;&#x3066;&#x99C6;&#x52D5;&#x3055;&#x308C;&#x308B;&#x4F53;&#x7D30;&#x80DE;&#x30B2;&#x30CE;&#x30E0;&#x306E;&#x30E2;&#x30B6;&#x30A4;&#x30AF;&#x306F;&#x3001;&#x907A;&#x4F1D;&#x5B50;&#x56DE;&#x8DEF;&#x3092;&#x652F;&#x3048;&#x308B;&#x6B63;&#x5E38;&#x3068;&#x7570;&#x5E38;&#x795E;&#x7D4C;&#x751F;&#x7269;&#x5B66;&#x7684;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x3092;&#x518D;&#x69CB;&#x7BC9;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;

&#x4F53;&#x30EC;&#x30C8;&#x30ED;&#x8EE2;&#x4F4D;&#x306F;&#x3001;&#x4EBA;&#x9593;&#x306E;&#x8133;&#x306E;&#x907A;&#x4F1D;&#x7684;&#x666F;&#x89B3;&#x3092;&#x5909;&#x66F4;&#x3057;&#x307E;&#x3059;&#x3002;

Retrotransposons&#xB294; metazoan &#xC720;&#xC804;&#xC790;&#xC5D0; &#xAC78;&#xCCD0; &#xD655;&#xC0B0; &#xBC88;&#xC9F8; &#39; &#xBCF5;&#xC0AC;-&#xBD99;&#xC5EC;&#xB123;&#xAE30; &#39; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC0AC;&#xC6A9; &#xD558;&#xB294; &#xBAA8;&#xBC14;&#xC77C; &#xC720;&#xC804; &#xC694;&#xC18C;&#xC785;&#xB2C8;&#xB2E4;. &#xC801;&#xC5B4;&#xB3C4; &#xC778;&#xAC04; &#xAC8C;&#xB188;&#xC758; 50 %&#xB294; retrotransposons, &#xC138; &#xBA85; &#xAC00;&#xC871; (L1, Alu&#xC640; SVA)&#xC640; insertional mutagenesis &#xBC0F; &#xC9C8;&#xBCD1;&#xACFC; &#xAD00;&#xB828; &#xB41C;&#xC5D0;&#xC11C; &#xD30C;&#xC0DD; &#xB429;&#xB2C8;&#xB2E4;. &#xCD08;&#xAE30; &#xBC30;&#xC544; &#xBC1C;&#xB2EC; &#xBC0F; &#xC77C;&#xBD80; &#xC545;&#xC131; &#xC885;&#xC591;&#xC744; &#xC81C;&#xC678;&#xD55C; &#xCCB4;&#xC138;&#xD3EC;&#xC5D0; epigenetic&#xACFC; post-transcriptional &#xC5B5;&#xC81C; &#xBE14;&#xB85D; retrotransposition. &#xC778;&#xAC04;&#xC758; &#xB450;&#xB1CC;&#xC5D0; L1 &#xD45C;&#xD604;&#xACFC; &#xBCF5;&#xC0AC;&#xBCF8; &#xBC88;&#xD638; &#xBCC0;&#xC774;&#xC758; &#xCD5C;&#xADFC; &#xBCF4;&#xACE0;&#xC11C; L1 &#xB3D9;&#xC6D0; &#xC774;&#xD6C4; &#xAC1C;&#xBC1C; &#xC911;&#xC5D0; &#xBC1C;&#xC0DD;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xD574;&#xB2F9; &#xD558;&#xB294; &#xD1B5;&#xD569; &#xC0AC;&#xC774;&#xD2B8; &#xB9E4;&#xD551; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4; &#xC5C6;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xAC00; &#xB192; &#xCC98;&#xB9AC;&#xB7C9; &#xBC29;&#xBC95;&#xC740; &#xC218;&#xB9CE;&#xC740; L1, Alu&#xC640; SVA &#xBC88;&#xC9F8; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; 7743 putative &#xCCB4;&#xC138;&#xD3EC; L1 &#xC0BD;&#xC785;, &#xD574; &#xB9C8; &#xBC0F; caudate &#xD575; 3 &#xAC1C;&#xC778;&#xC758; &#xC2DD;&#xBCC4;&#xC744; &#xC801;&#xC6A9; &#xD569;&#xB2C8;&#xB2E4;. &#xB180;&#xB78D;&#xAC8C;&#xB3C4;, &#xC6B0;&#xB9AC;&#xB294; &#xB610;&#xD55C; 13,692 &#xCCB4;&#xC138;&#xD3EC; Alu &#xC0BD;&#xC785; &#xBC0F; 1350 SVA &#xC0BD;&#xC785; &#xBC1C;&#xACAC;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; retrotransposons &#xB2E8;&#xBC31;&#xC9C8; &#xCF54;&#xB529; &#xC720;&#xC804;&#xC790; &#xCC28;&#xB3D9; &#xD45C;&#xD604; &#xD558; &#xACE0; &#xC801;&#xADF9;&#xC801;&#xC778; &#xB450;&#xB1CC;&#xC5D0; &#xB3D9;&#xC6D0; &#xC785;&#xC99D;. &#xB530;&#xB77C;&#xC11C;, &#xCCB4;&#xC138;&#xD3EC; &#xAC8C;&#xB188; mosaicism retrotransposition&#xC5D0; &#xC758;&#xD574; &#xAD6C;&#xB3D9; &#xC815;&#xC0C1; &#xBC0F; &#xBE44;&#xC815;&#xC0C1;&#xC801;&#xC778; neurobiological &#xD504;&#xB85C;&#xC138;&#xC2A4; underpins &#xC720;&#xC804;&#xC790; &#xD68C;&#xB85C; &#xBC14;&#xAFC0; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xCCB4;&#xC138;&#xD3EC; retrotransposition &#xC778;&#xAC04;&#xC758; &#xB1CC;&#xC758; &#xC720;&#xC804;&#xC790; &#xD48D;&#xACBD;&#xC744; &#xBCC0;&#xACBD;&#xD569;&#xB2C8;&#xB2E4;.

Los retrotransposones son elementos gen&#xE9;ticos m&#xF3;viles que utilizan un mecanismo de l&#xED;nea germinal &#x26;#39;copiar y pegar&#x26;#39; a extenderse por todo genomas metazoos. Al menos el 50 por ciento del genoma humano se deriva de retrotransposones, con tres familias activas (L1, aluminio y SVA) asociados con la mutag&#xE9;nesis de inserci&#xF3;n y la enfermedad. Supresi&#xF3;n de Epigen&#xE9;tica y post-transcripcional retrotransposition bloque en las c&#xE9;lulas som&#xE1;ticas, con exclusi&#xF3;n del desarrollo embrionario temprano y tumores malignos algunos. Informes recientes de la expresi&#xF3;n de L1 y la variaci&#xF3;n del n&#xFA;mero de copias en el cerebro humano sugieren que la movilizaci&#xF3;n de L1 tambi&#xE9;n puede ocurrir durante el desarrollo posterior. Sin embargo, los sitios de integraci&#xF3;n correspondientes no han sido asignadas. Aqu&#xED; aplicamos un m&#xE9;todo de alto rendimiento para identificar los numerosos L1, Alu y las mutaciones en l&#xED;nea germinal SVA, as&#xED; como 7.743 inserciones supuestas L1 som&#xE1;ticos, en el hipocampo y el n&#xFA;cleo caudado de tres personas. Sorprendentemente, tambi&#xE9;n se encontr&#xF3; 13,692 som&#xE1;ticas inserciones Alu y 1.350 inserciones SVA. Nuestros resultados demuestran que los retrotransposones se movilizan para genes que codifican prote&#xED;nas expresadas diferencialmente y activa en el cerebro. Por lo tanto, mosaicismo som&#xE1;tico genoma impulsado por retrotransposition puede remodelar el circuito gen&#xE9;tico que subyace a los procesos neurobiol&#xF3;gicos normales y anormales.

Retrotransposition som&#xE1;ticas altera el paisaje gen&#xE9;tico del cerebro humano

Proposal for a British neurosurgical trainee research collaborative.

The authors present an unusual case of a healthy young male who developed a spontaneous subdural haematoma. Headache was followed by blurring of vision and left upper limb symptoms. The diagnosis was made from a CT scan. Symptoms resolved with surgical decompression. The authors explore the risk factors and pathophysiology implicated in this condition. The authors demonstrate that apparently 'healthy' pursuits can have significant consequences, but the physician must also exclude serious underlying risk factors for bleeding, which the authors discuss.

Spontaneous subdural haematoma in a healthy young male.

Clinical research, which is essential for improving patient outcomes, is increasingly carried out in the context of networks established between multiple institutions. Research is also considered an important component of training curricula. The recent successful completion of a randomised trial (ROSSINI), which was led by general surgical trainees of the West Midlands Research Collaborative, has established the feasibility of trainee collaborative research networks. A research network for neurosurgical trainees in the UK and Ireland was, therefore, established following the meeting of the British Neurosurgical Trainee Association (BNTA) in Aberdeen on 19 April 2012. This BNTA initiative quickly gained the full support from the Society of British Neurological Surgeons and the UK Neurosurgical Research Network. The inaugural meeting of the British Neurosurgical Trainee Research Collaborative took place at the Royal College of Surgeons of England, London, on 19 October 2012. The purpose of this report is both to record progress to date and to promote this concept.

A report from the inaugural meeting of the British Neurosurgical Trainee Research Collaborative held in the Royal College of Surgeons of England, 19 October 2012.

LINE-1 (L1) retrotransposons are mobile genetic elements comprising ~17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.

Interfacing neurons with silicon semiconductors is a challenge being tackled through various bioengineering approaches. Such constructs inform our understanding of neuronal coding and learning and ultimately guide us toward creating intelligent neuroprostheses. A fundamental prerequisite is to dictate the spatial organization of neuronal cells. We sought to pattern neurons using photolithographically defined arrays of polymer parylene-C, activated with fetal calf serum. We used a purified human neuronal cell line [Lund human mesencephalic (LUHMES)] to establish whether neurons remain viable when isolated on-chip or whether they require a supporting cell substrate. When cultured in isolation, LUHMES neurons failed to pattern and did not show any morphological signs of differentiation. We therefore sought a cell type with which to prepattern parylene regions, hypothesizing that this cellular template would enable secondary neuronal adhesion and network formation. From a range of cell lines tested, human embryonal kidney (HEK) 293 cells patterned with highest accuracy. LUHMES neurons adhered to pre-established HEK 293 cell clusters and this coculture environment promoted morphological differentiation of neurons. Neurites extended between islands of adherent cell somata, creating an orthogonally arranged neuronal network. HEK 293 cells appear to fulfill a role analogous to glia, dictating cell adhesion, and generating an environment conducive to neuronal survival. We next replaced HEK 293 cells with slower growing glioma-derived precursors. These primary human cells patterned accurately on parylene and provided a similarly effective scaffold for neuronal adhesion. These findings advance the use of this microfabrication-compatible platform for neuronal patterning. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

Patterning human neuronal networks on photolithographically engineered silicon dioxide substrates functionalized with glial analogues.

Ensuring a bright future for clinical research in surgery with trainee led research networks.

Background. Chronic subdural haematoma (CSDH) is a common condition that increases in incidence with rising age. Evacuation of a CSDH is one of the commonest neurosurgical procedures; however the optimal peri-operative management, surgical technique, post-operative care and the role of adjuvant therapies remain controversial. Aim. We propose a prospective multi-centre audit in order to establish current practices, outcomes and national benchmarks for future studies. Methods. Neurosurgical units (NSU) in the United Kingdom and Ireland will be invited to enrol patients to this audit. All adult patients aged 16 years and over with a primary or recurrent CSDH will be eligible for inclusion. Outcome measures and analysis. The proposed outcome measures are (1) clinical recurrence requiring re-operation within 60 days; (2) modified Rankin scale (mRS) score at discharge from NSU; (3) morbidity and mortality in the NSU; (4) destination at discharge from NSU and (5) length of stay in the NSU. Audit standards have been derived from published systematic reviews and a recent randomised trial. The proposed standards are clinical recurrence rate < 20%; unfavourable mRS (4-6) at discharge from NSU < 30%; mortality rate in NSU < 5%; morbidity rate in NSU < 10%. Data will be submitted directly into a secure online database and analysed by the study's management group. Conclusions. The audit will determine the contemporary management and outcomes of patients with CSDH in the United Kingdom and Ireland. It will inform national guidelines, clinical practice and future studies in order to improve the outcome of patients with CSDH.

Proposal for a prospective multi-centre audit of chronic subdural haematoma management in the United Kingdom and Ireland.

Background. The increasing utilisation of decompressive craniectomy for traumatic brain injury and stroke has led to an increase in the number of cranioplasties undertaken. Cranioplasty is also undertaken following excision of tumours originating from or invading the skull vault, removal of bone flaps due to post-operative infection, and decompressive craniectomy for the management of rarer causes of brain oedema and/or refractory intracranial hypertension. The existing literature which mainly consists of single-centre, retrospective studies, shows a significant variation in practice patterns and a wide range of morbidity. There also exists a need to measure the outcome as perceived by the patients themselves with patient reported outcome measures (PROMs; functional outcome, quality of life, satisfaction with cosmesis). In the UK, the concept of long-term surveillance of neurosurgical implants is well established with the UK shunt registry. Based on this background, we propose to establish the UK Cranial Reconstruction Registry (UKCRR). Aim. The overarching aim of the UKCRR is to collect high-quality data about cranioplasties undertaken across the UK and Ireland in order to improve outcomes for patients. Methods. Any patient undergoing reconstruction of the skull vault with autologous bone, titanium, or synthetic material in participating units will be eligible for inclusion. Data will be submitted directly by participating units to the Outcome Registry Intervention and Operation Network secure platform. A Steering Committee will be responsible for overseeing the strategic direction and running of the UKCRR. Outcome measures. These will include re-operation due to a cranioplasty-related issue, surgical site infection, re-admission due to a cranioplasty-related issue, unplanned post-operative escalation of care, adverse events, length of stay in admitting unit, destination at discharge from admitting unit, mortality at discharge from admitting unit, neurological status and PROMs during routine follow-up. Conclusion. The UKCRR will be an important pillar in the ongoing efforts to optimise the outcomes of patients undergoing cranioplasty.

Article	Year
Prion protein accumulation and neuroprotection in hypoxic brain damage. The American journal of pathology\| PubMed ID: 15215178	2004
Multiple schwannomatosis caused by the recently described INI1 gene--molecular pathology, and implications for prognosis. British journal of neurosurgery\| PubMed ID: 20854059	2011
Mislocalization of the E3 ligase, β-transducin repeat-containing protein 1 (β-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat p... The Journal of biological chemistry\| PubMed ID: 21454620	2011
The Internet for neurosurgeons: current resources and future challenges. British journal of neurosurgery\| PubMed ID: 21501057	2011
Somatic retrotransposition alters the genetic landscape of the human brain. Nature\| PubMed ID: 22037309	2011
Proposal for a British neurosurgical trainee research collaborative. British journal of neurosurgery\| PubMed ID: 22583319	2012
Spontaneous subdural haematoma in a healthy young male. BMJ case reports\| PubMed ID: 22689720	2011
A report from the inaugural meeting of the British Neurosurgical Trainee Research Collaborative held in the Royal College of Surgeons of England, 19 October 2012. British journal of neurosurgery\| PubMed ID: 23530715	2013
Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell\| PubMed ID: 23540693	2013
Patterning human neuronal networks on photolithographically engineered silicon dioxide substrates functionalized with glial analogues. Journal of biomedical materials research. Part A\| PubMed ID: 23733444	2013
Ensuring a bright future for clinical research in surgery with trainee led research networks. BMJ (Clinical research ed.)\| PubMed ID: 23965517	2013
Proposal for a prospective multi-centre audit of chronic subdural haematoma management in the United Kingdom and Ireland. British journal of neurosurgery\| PubMed ID: 24053314	2013
Proposal for establishment of the UK Cranial Reconstruction Registry (UKCRR). British journal of neurosurgery\| PubMed ID: 24237069	2013
Chronic subdural haematoma: How can we improve patient care and outcomes? British journal of neurosurgery\| PubMed ID: 24325139	2014

Paul M. Brennan

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