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"James, Jaime"
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The totality
\"The League was forced to make an impossible decision ... and now its time to face the consequences! The returning Martian Manhunter struggles to protect the team from an incoming threat that will shatter the world as they know it, while a familiar face strikes out on a dark path... Spinning out of the cataclysmic events of Dark Nights: Metal and the universe-defining No Justice, the core members of the Justice League--Superman, Batman, Wonder Woman, Aquaman, The Flash and more--are finally reunited for an adventure for the ages!\"-- Provided by publisher.
Book
Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive
Congenital neutropenia is characterized by low absolute neutrophil numbers in blood, leading to recurrent bacterial infections, and patients often require life-long granulocyte CSF (G-CSF) support. X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich syndrome protein (WASp). To understand the pathophysiology in XLN and the role of WASp in neutrophils, we here examined XLN patients and 2 XLN mouse models. XLN patients had reduced myelopoiesis and extremely low blood neutrophil number. However, their neutrophils had a hyperactive phenotype and were present in normal numbers in XLN patient saliva. Murine XLN neutrophils were hyperactivated, with increased actin dynamics and migration into tissues. We provide molecular evidence that the hyperactivity of XLN neutrophils is caused by WASp in a constitutively open conformation due to contingent phosphorylation of the critical tyrosine-293 and plasma membrane localization. This renders WASp activity less dependent on regulation by PI3K. Our data show that the amplitude of WASp activity inside a cell could be enhanced by cell-surface receptor signaling even in the context in which WASp is already in an active conformation. Moreover, these data categorize XLN as an atypical congenital neutropenia in which constitutive activation of WASp in tissue neutrophils compensates for reduced myelopoiesis.
Journal Article
Fall of the batmen
\"Red Robin has returned, resuming his work in Gotham City as well as his romance with Stephanie Brown, the Spoiler. These two, along with Batwoman, Clayface, Batwing, Azrael and Orphan, help Batman reduce the threat of crime to the citizenry. But their success comes with a horrible price. The First Victim and his Victim Syndicate want one thing: to make Batman pay. They have turned the whole city against the Batmen in protest, abducted Clayface and threatened to release all of Arkham Asylum's most dangerous villains if Batman doesn't unmask on live television. Everything Red Robin has built to ensure a new future for the team could crumble if the Victim Syndicate triumphs...or if one member of the team makes a detrimental decision that could tear them apart. Plus, a full-length look at Basil Karlo's tortured life, from being the son of a distant man-of-a-thousand-faces father to the accident that turned the rising celebrity into the shape-changing Clayface.\"-- Provided by publisher.
Book
Redox regulation of PTPN22 affects the severity of T-cell-dependent autoimmune inflammation
Chronic autoimmune diseases are associated with mutations in PTPN22, a modifier of T cell receptor (TCR) signaling. As with all protein tyrosine phosphatases, the activity of PTPN22 is redox regulated, but if or how such regulation can modulate inflammatory pathways in vivo is not known. To determine this, we created a mouse with a cysteine-to-serine mutation at position 129 in PTPN22 (C129S), a residue proposed to alter the redox regulatory properties of PTPN22 by forming a disulfide with the catalytic C227 residue. The C129S mutant mouse showed a stronger T-cell-dependent inflammatory response and development of T-cell-dependent autoimmune arthritis due to enhanced TCR signaling and activation of T cells, an effect neutralized by a mutation in Ncf1, a component of the NOX2 complex. Activity assays with purified proteins suggest that the functional results can be explained by an increased sensitivity to oxidation of the C129S mutated PTPN22 protein. We also observed that the disulfide of native PTPN22 can be directly reduced by the thioredoxin system, while the C129S mutant lacking this disulfide was less amenable to reductive reactivation. In conclusion, we show that PTPN22 functionally interacts with Ncf1 and is regulated by oxidation via the noncatalytic C129 residue and oxidation-prone PTPN22 leads to increased severity in the development of T-cell-dependent autoimmunity.
Journal Article
The best American science & nature writing. 2023
\"Twenty science and nature essays that represent the best examples of the form published in 2022.\" -- Provided by publisher.
Book
Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation
The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the
SH3gl1
gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of
SH3gl1
affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that
SH3GL1
regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.
The autoimmune disorder, rheumatoid arthritis (RA), has been associated with multiple pathophysiological factors. Here the authors show that deficiency in endophilin A2 in rodents protects them from experimental arthritis by altering T cell activation threshold and effector functions, thereby hinting a potential target for RA therapy.
Journal Article
Redox Regulation of LAT Enhances T Cell-Mediated Inflammation
The positional cloning of single nucleotide polymorphisms (SNPs) of the neutrophil cytosolic factor 1 (Ncf1) gene, advocating that a low oxidative burst drives autoimmune disease, demands an understanding of the underlying molecular causes. A cellular target could be T cells, which have been shown to be regulated by reactive oxygen species (ROS). However, the pathways by which ROS mediate T cell signaling remain unclear. The adaptor molecule linker for activation of T cells (LAT) is essential for coupling T cell receptor-mediated antigen recognition to downstream responses, and it contains several cysteine residues that have previously been suggested to be involved in redox regulation. To address the possibility that ROS regulate T cell-dependent inflammation through LAT, we established a mouse strain with cysteine-to-serine mutations at positions 120 and 172 (LATSS). We found that redox regulation of LAT through C120 and C172 mediate its localization and phosphorylation. LATSS mice had reduced numbers of double-positive thymocytes and naïve peripheral T cells. Importantly, redox insensitivity of LAT enhanced T cell-dependent autoimmune inflammation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). This effect was reversed on an NCF1-mutated (NCF1m1j), ROS-deficient, background. Overall, our data show that LAT is redox-regulated, acts to repress T cell activation, and is targeted by ROS induced by NCF1 in antigen-presenting cells (APCs).
Journal Article
Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases
It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.
Journal Article
Redox Regulation of T Cells in Autoimmunity
Autoimmune disorders affect a significant part of the population and therefore present a serious health and economic burden. One of the most common autoimmune diseases is rheumatoid arthritis (RA), affecting 0.5-1% of the population which is mediated by both genetic and environmental risk factors. A common thread throughout this thesis is the impact of various proteins on T cell signaling and how this affects autoimmune inflammation in rodents.Studies I and II investigate the role of redox regulation on two major players in TCR signaling: PTPN22 and LAT. We targeted known redox-sensitive cysteine residues in these proteins and could thereby investigate their importance in vivo. Study I shows that PTPN22 function can be regulated by its non-catalytic cysteine 129 (C129) residue by forming a disulfide bond which protects the active site from irreversible oxidation; impaired redox regulation leads to enhanced T cell and inflammatory responses. In a similar vein, we found in Study II that cysteines 120 and 172 mediate redox regulation of LAT by affecting its phosphorylation and localization. Redox insensitivity of the LAT protein worsens T-cell dependent inflammation.In the last two studies we have used a forward genetics approach to identify genetic determinants of RA susceptibility: In Study III we were the first to identify that loss of Sh3gl1 leads to protection from autoimmunity due to alterations in the T cell signaling pathway, thereby providing an attractive new therapeutic target. Study IV shows that polymorphisms regulating vitamin D receptor expression affect T cell activation and T cell mediated inflammation.Collectively, our results show the importance of physiological redox effects and expand the knowledge on RA genetics.
Dissertation