CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses

The humoral immune response is mediated by antigen activated B cells thathave terminally differentiated into antibody secreting cells (ASCs). The ASC pool iscomposed of short-lived plasma cells (SLPCs) and long-lived plasma cells (LLPCs) thatsecrete antigen-specific antibodies to clear an infection and maintain long-termprotective antibody titers to prevent subsequent reinfections. SLPCs have generallybeen viewed to be formed from T cell-independent immune responses and localized inthe spleen. LLPCs have been viewed to be formed from T cell-dependent immuneresponses and localized in the bone marrow. However, regardless of the type ofstimulating antigen, ASCs of varying lifespans, both SLPCs and LLPCs are found in thespleen and bone marrow. Currently, it remains unclear as to what factors and pathwaysregulate PC longevity.Our laboratory previously identified the CREB coactivator CRTC2 as a regulatorof ASC differentiation. DNA double strand breaks associated with class switchrecombination activates a signaling pathway in human germinal center (GC) B cells thatresults in the phosphorylation and inactivation of CRTC2. Phosphorylated CRTC2 is relocalizedto the cytoplasm and CRTC2 target genes are down-regulated. Dysregulationof CRTC2 activity through over-expression of a nucleus-localized and constitutivelyactive form of CRTC2 (CRTC2-AA) in human tonsillar B cells, prevented GC B cellsfrom exiting the GC reaction and inhibited ASC differentiation. However, it remainedunclear whether the function of CRTC2 in this in vitro differentiation system would berecapitulated in vivo and whether CRTC2 played any other roles in an in vivo humoralimmune response.To evaluate these questions, we generated a transgenic (TG) mouse modelwhich expresses CRTC2-AA at all stages of B cell development. Using these TG mice,we demonstrate that Crtc2 repression in PCs is an intrinsic requirement for PCmetabolic fitness. Sustained CRTC2 activity shortened the survival of splenic and bonemarrow PCs which resulted in the reduction of long-lived PCs and antibody deficits inresponse to immunizations and acute viral infection. We further demonstrated that TGPCs adopt characteristics associated with SLPCs which include reduced antibodysecretion, glycolysis, oxidative metabolism, and spare respiratory capacity.Mechanistically, Crtc2 repression is necessary for the fidelity of PC gene expressionand mRNA alternative-splicing programs, with both programs altered in TG PCs.Combined, our results show that Crtc2 repression in PCs must occur to support PCmetabolism and extend PC survival and lifespan during a humoral immune response.We hypothesize that the level of Crtc2 repression in differentiated ASCs determinesmetabolic fitness and ultimately PC survival and longevity in the bone marrow

Negative Differential Resistance in the Scanning Tunneling Spectroscopy of Organic molecules

The conductance-voltage spectrum of molecular nanostructures measured by scanning tunneling spectroscopy (STS) is generally assumed to reflect the local density of states of the molecule. This excludes the possibility of observing negative differential resistance (NDR). We report here the observation of NDR in the scanning tunneling microscope (STM) current-voltage (I-V) characteristics of self-assembled monolayer (SAM) of 4-p-Terphenylthiol molecules on gold substrate measured using a platinum probe. We argue that the NDR arises from narrow structures in the local density of states at the tip apex atom and show that depending on the electrostatic potential profile across the system, NDR could be observed in one or both bias directions.Comment: 13 Pages, 4 figures, submitted to Phys. Rev. B Rapid Communicatio

Experimental Evidence for Using a TTM Stages of Change Model in Boosting Progress Toward 2FA Adoption

Behavior change ideas from health psychology can also help boost end user compliance with security recommendations, such as adopting two-factor authentication (2FA). Our research adapts the Transtheoretical Model Stages of Change from health and wellness research to a cybersecurity context. We first create and validate an assessment to identify workers on Amazon Mechanical Turk who have not enabled 2FA for their accounts as being in Stage 1 (no intention to adopt 2FA) or Stages 2-3 (some intention to adopt 2FA). We randomly assigned participants to receive an informational intervention with varied content (highlighting process, norms, or both) or not. After three days, we again surveyed workers for Stage of Amazon 2FA adoption. We found that those in the intervention group showed more progress toward action/maintenance (Stages 4-5) than those in the control group, and those who received content highlighting the process of enabling 2FA were significantly more likely to progress toward 2FA adoption. Our work contributes support for applying a Stages of Change Model in usable security.Comment: 41 pages, including the stage algorithm programmed on Mturk, the survey flow and specific items used, and a link to download the five informational handouts used for the control condition and the 2FA intervention condition

User expectations for media sharing practices in open display networks

Open Display Networks have the potential to allow many content creators to publish their media to an open-ended set of screen displays. However, this raises the issue of how to match that content to the right displays. In this study, we aim to understand how the perceived utility of particular media sharing scenarios is affected by three independent variables, more specifically: (a) the locativeness of the content being shared; (b) how personal that content is and (c) the scope in which it is being shared. To assess these effects, we composed a set of 24 media sharing scenarios embedded with different treatments of our three independent variables. We then asked 100 participants to express their perception of the relevance of those scenarios. The results suggest a clear preference for scenarios where content is both local and directly related to the person that is publishing it. This is in stark contrast to the types of content that are commonly found in public displays, and confirms the opportunity that open displays networks may represent a new media for self-expression. This novel understanding may inform the design of new publication paradigms that will enable people to share media across the display networks.This research has received funding from FCT under the Carnegie Mellon—Portugal agreement. Project Wesp (Grant CMU-PT/SE/028/2008)