#tdb nicolas

[danieyells]

Are you able to do height comparisons between the characters? I doubt their canon heights were released but one can infer from their models. I'm pretty sure Zenji is the tallest out of all them (besides the octopus).

I mean. Kind of? It seems like they're all set to the same idk plane/image size so they mostly look aligned.

Tumblr's probably not gonna like me using an image that's wider than they allow so idk i can try putting it somewhere else? I tried imgur but it won't open the folder for me after i uploaded it. in fact none of my imgur posts or folders are opening. cool. functional website.

Alan and Hyde are the tallest ones after Moby though, I can tell you that. Zenji is just barely below Hyde.

everyone else is under the cut

[catboy-beckett]

What better way to begin Tokyo Debunker posting than with a tierlist of the ghouls! I usually don't bother putting them in order within the tiers, but with this one I did! So the leftmost boy on each row is the one I liked most.

Obscuary really had no misses huh.

I know Ritsu has fans and I'm happy for you!!!! I am happy that you get joy out of him. Personally I think he has a pretty face but every time he speaks I desire strongly to kill him with a rock. I also know Leo has dedicated haters and yeah honestly fair.

Click "keep reading" if you wanna see my tierlist of specifically which characters I would fuck vvvv

This one includes the staff members (whom I thought it would be unfair to include in the original tierlist due to lack of screentime) and I threw in the little creatures since I had already made a "cute critter" tier for Lyca.

The Chancellor is not included.

Jin would be higher if they didn't make him a smoker. Wild that they put so much effort into positioning him as THE romance option and then added "by the way he smells absolutely fucking awful" lmao

[bioadvisers]

Bioadvisers shared on Biotech Advisers

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

In utero priming of highly functional effector T cell responses to human malaria

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat5916

[abbkine]

BioAdvisers said on Biotech Advisers

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

In utero priming of highly functional effector T cell responses to human malaria

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat5916

[cancersfakianakis1]

Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

Publication date: Available online 2 March 2017 Source:Cancer Cell Author(s): Ji Li, Nicola J. Stagg, Jennifer Johnston, Michael J. Harris, Sam A. Menzies, Danielle DiCara, Vanessa Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga, Rin Nakamura, Luke McCarty, Siddharth Sukumaran, Elizabeth Luis, Zhengmao Ye, Thomas D. Wu, Teiko Sumiyoshi, Dimitry Danilenko, Genee Y. Lee, Klara Totpal, Diego Ellerman, Isidro Hötzel, John R. James, Teemu T. Junttila The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.

Teaser

Li et al. report that the size and epitope location of the target play a key role in the efficiency of T cell activation induced by T cell-dependent bispecific antibodies (TDBs). They develop a TDB targeting FcRH5 expressed in all multiple myeloma tumor cells and show its potential in treating this disease. http://ift.tt/2lFGgS1

[danieyells]

I keep thinking of Ed(?) that vampire guy and thinking of mc trying to keep the relationship with him a secret, or at least on the down low, but after like, 2 check ups from Yuri and Jiro, they v quickly realize what's going on when they see their blood level is lower than usual after their first mission with obscuary..

and after the look of just being done with everything yuri is going on a rant about why they need to be more careful or wtv and 'why would you even do that??'

or even a walk of shame to the chancellors office when they get too silly and oops mc is a vampire now(assuming it can be easy to turn into one idk much about them LOL)

I wanna think of him in a hotter way but I just get too many silly thoughts of him lmao

(The vampire in Obscuary is Edward Hart, yes! Mostly just called Ed so far.)

Silly thoughts are the best tho lmao LBR THE GUY ALLEGEDLY CAN'T TIE HIS OWN SHOELACES, DOESN'T CLEAN UP AFTER HIMSELF, FALLS ASLEEP WHEREVER HE WANTS, IS KNOWN BY OTHER CAPTAINS TO BE A SLACKER, AND CARELESSLY TOUCHES RUI KNOWING IT'LL KILL HIM FOR A BIT; HE'S A MAGNET FOR SILLY THOUGHTS.

tbf we don't know how vampire lore is gonna work in tdb yet(Ed does have bitemarks on his neck, so biting is required to spread it presumably), so it's fair to not know how exactly it's spread or anything! I assume it won't be spread without intention to do so or without the target being near death or something(just so we can get that sweet feeding goodness), but it's also fun to imagine that the pc just like. . .offers to feed Ed and ends up a vampire because they just did not consider they'd catch vampirism. Why didn't anyone tell them! What do you mean they thought they knew!!! (on the other hand. . .would vampirism override their curse? Vampirism overrides Rui's curse when Edward touches him, it'd be a reasonable thing to try. . . .)

But lmaoooo going to Mortkranken and they're like. Why are you so anemic???? And the pc hadn't even considered it because hey blood comes back! And then it's even lower the second time. And they just. Figure it out right away like goddamn it your missions have been with Obscuary. And Yuri is so annoyed that they're doing something to jeopardize their wellbeing. Yes, he does need to feed daily if he's going on missions but he does not need to drink that much especially from the same person. Your blood comes back but it's still finite!

Yuri just scolds and fusses over them while Jiro prepares some iron supplements and like a list of food you should eat to help recover faster lolol

Another day they just got fed on by Ed and then get a text from Romeo saying to come to the VIP room and they're like "uh can i wait like. 20 minutes" "No. Come now." "I don't think that's a good idea." "Now."

and the second they step into Sinostra Taiga's sniffing them out because they've still got a partially bleeding wound and oh no he's hungry (and Romeo blames them anyway despite that they very specifically said they didn't think it's a good idea)

They pass out in class from the anemia and now Nicolas is worrying over them too(he's a lot nicer than Yuri at least) and now they're trying to figure out how they'll schedule with Ed to have a talk with him when Moby doesn't even wanna go to Obscuary(or Hotarubi!) despite being the dorm advisor

The pc gets turned and just. . .is Cornelius' office even open late? What do they even do about this!? They could go to Mortkraken, they're always up. . .they could find Hyde, he seems to be awake regardless of the time of day. And Ed is just so freespirited he doesn't even worry about it just pats them like oh don't worry about it you can spend as much time in Obscuary as you'd like!! Maybe this is what you needed! I'll teach you all about being a vampire, it'll be fun!!!

Of course when they eventually have to tell Cornelius or somebody it's a whole damn hassle. And they don't know how it'll effect the curse either. So now it's a mystery and things are up in the air and do they keep searching for a cure for something that may not even affect them anymore???? They aren't a ghoul but you're an anomaly now Obscuary is a ghoul-only dorm but do they place you there???? Do they keep you in containment??? It's just one problem after another!!! And what about keeping them fed!?