602 research outputs found
Characterizing memory space: The neural representational structure of episodic and semantic memory
No full textMemories are not preserved in the past, they help us navigate the present and predict the future. Our representation of the world is constantly evolving as we experience time unfolding continuously, yet our past is made up of distinct episodes. In a series of three studies, I will look at how temporal and semantic information guide memory search in free recall.
In chapter one I will investigate how a continual inter-item distraction affects memory for a list of items from familiar categories. Retrieved-context theory states that context gradually drifts over time, making nearby items more similar than distant items. In lists of categorized stimuli, items can also be associated to one another by pre-experimental semantic representations. We created 'episodes' by presenting stimuli in triplets of same-category items, so that adjacent items tended to be semantically related. Our neuroimaging analyses show that semantic information is represented across the brain. This category-selective activation was attenuated by distraction in brain regions within core memory networks. Continual distraction decreased overall performance and semantic clustering at recall. Taken together, this suggests that successful encoding depends on the integration of category information within an event, and this process is disrupted by distraction. Chapter two implements a computational model to capture the organizational differences in recall for categorized lists. The best fit models point to an effect of distraction that disrupts neural information integration by altering the rate of contextual drift.
Finally, chapter three uses naturalistic stimuli to explore how meaning is derived from the interaction of temporal and semantic information. Studying memory for narratives allows us to exploit naturally occurring organizational structure. Recall is enhanced when an event is embedded within a structure of similar events that act as a retrieval cue for one another. Over time, and with consolidation into existing memories, the temporal structure of a narrative fades away. Memory for events gradually transforms as specific temporal order information is replaced by conceptual knowledge that can be generalized across episodes. These studies support a theory of human memory whereby meaningful experiences are created by adding a semantic interpretation to temporal event
Grasping at straws: a ratings downgrade for the emerging international financial architecture
No full textFollowing the Asia crisis of 1997-98, policymakers invested a great deal of energy in designing a new international financial architecture. However many of the policy proposals which have emerged from think tanks and the multilateral agencies have proven unworkable or politically unpalatable. The debate focuses on state-led initiatives. But the assumption that public policy is by definition an output of public institutions is difficult to sustain in an era of global change. This paper considers specialized forms of intelligence-gathering and judgment-determination which seem increasingly important as sources of governance in this era of financial market volatility. These agents - embedded knowledge networks (EKNs) - include the major bond rating agencies, Moody’s Investors Service and Standard and Poor’s, the focus of this paper. The Basel Committee has put forward a serious proposal to reform the existing capital adequacy framework which uses banks' own internal ratings and external bond ratings to calculate bank risk-weighted capital requirements. The paper shows that there are potentially unexpected consequences from using private rating agencies as a substitute for state-based regulation, due to the organizational incentives that shape the ratings industry. Cementing these organizational incentives into the emerging financial architecture will give rise to negative social and economic consequences
Letter to Benjamin Clark Cutler from Benjamin Stevens
No full textLetter dated April 14, 1863 to Assistant Adjutant General, Captain Benjamin Clark Cutler, Santa Fe, from First Lieutenant Benjamin Stevens, Fort Wingate, New Mexico, recommending John Murphy and Martin Quintana, in the First New Mexico Volunteers, for military promotion to Second Lieutenant. Letter also signed by First Lieutenant J. L. Barbey, joint author. Civil War. HL introduction page overlaid by document. Letter in English, handwritten, 1pp/fr
Accelerations for global optimization methods that use second derivative information
No full textTwo new improvements for the algorithm of Breiman & Cutler are presented. Better envelopes can be built up using positive definite quadratic forms. Better utilization of first and second derivative information is attained by combining both global aspects of curvature and local aspects nearthe global optimum. The basis of the results is the geometric viewpoint developed by the first author and can be applied to a number of covering type methods. Improvements in convergence rates are demonstrated empirically on standard test functions
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Modulation of ABA Receptor Function
No full textChapter 1Abscisic acid (ABA) is a phytohormone that plays important roles in plant development and environmental stress response. When bound to a family of star-related lipid-transfer (START) proteins, clade A subfamily of type II C protein phosphatases (PP2Cs) are negatively regulated leading to ABA response. It was only recently that the mechanism involved in ABA perception was identified. This was due in part to the success of bypassing this redundancy with the use of forward chemical genetics in Arabidopsis thaliana. Many biological findings utilizing forward chemical genetics have been limited to A. thaliana. Although a general insight has been gained from these studies, A. thaliana cannot fully address development and physiological phenomena in monocots. Here we describe a screening system in Panicum virgatum (Switchgrass) which we developed and used for a forward chemical genetics screen in search of an ABA agonist exclusive to monocots. Although a bonafide agonist was not isolated, our findings do illustrate the potential biological studies our screening system can be extended towards.Chapter 2Clade A subfamily of type II C protein phosphatases (PP2C) is negatively regulated by a family of star-related lipid-transfer (START) proteins called PYR/PYLs (pyrabactin resistance1/PYR1-like). In vivo, these proteins are activated when bound to Abscisic acid. This interaction stabilizes its conformation, leading to ABA signaling. Previous work done by Mosquna, et al.2011 were able to use that mimicked the agonist-bound conformation leading to the activations of signaling in vivo. Multiple yeast two-hybrid screens were performed to construct PYL2 receptors that inhibited PP2Cs in the absence of ABA. Here we compare the efficiencies of the constitutive active PYL2 receptors under drought stress in comparison to wildtype. Receptors were tested using the drought inducible promoter Rd29A. Our results reveal that conditional activation of constitutively active PYL2 is sufficient to elicit drought stress tolerance
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A Potent ABA Antagonist, Antabactin, as a Tool for Dormancy Research and a Germination Agrochemical
No full textAbscisic acid (ABA) is a plant hormone with regulatory roles spanning growth, development, and responses to abiotic and biotic stress. ABA is a key regulator of seed dormancy and ABA signaling is essential for dormancy. A number of studies have used genetic, omic and chemical approaches to dissect dormancy, with significant success. These approaches have led to better understanding of the genetic pathways involved including elucidation of the core ABA signaling pathway and the physiological responses, including ABA’s significant role in thermoinhibition. However, redundancy in the core ABA signaling pathway complicates genetic approaches, and chemical approaches are limited to compounds with herbicidal effects or lack of potency. To address these limitations, we developed antabactin (ANT), a potent ABA receptor antagonist, as a versatile research tool and agrochemical. The backbone of a potent ABA receptor agonist, Opabactin, was functionalized with a chemical library through click chemistry to generate a library of chemicals which were tested for antagonist activity and then optimized to produce ANT. ANT acts as a pan-receptor antagonist, effectively disrupting receptor-PP2C interactions. Our findings highlight ANT's efficacy in both in vitro and in planta. ANT application significantly speeds seed germination in barley, tomato, and Arabidopsis, and additionally it restores germination in thermoinhibited Arabidopsis, confirming ABA's role in thermoinhibition regulation. We also showed that, through ANT application, blocking ABA signaling fully restores germination in thermoinhibited lettuce and can be used in priming treatments to improve germination.
Beyond confirming ABA's role in thermoinhibition, we establish DELAY OF GERMINATION 1 (DOG1) as the primary regulator of dormancy and after-ripening. DOG1, a protein with unknown molecular function, is another key regulator of seed dormancy. By employing innovative seed germination phenotyping and image analysis techniques, we delineated the relative significance of these two key dormancy regulators in optimal conditions establishing DOG1 as the primary dormancy regulator over ABA in unstressed conditions. Lastly, we identified a germination-related locus in Arabidopsis through an association study, utilizing ANT to block ABA signaling.
This comprehensive exploration underscores Antabactin's potential as an agrochemical and as a tool for advancing our understanding of ABA’s role in dormancy regulation in plants. ANT's versatility offers promising avenues for future research and an increased understanding of plant growth and development
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Transcriptomic Profiling of Arabidopsis Abscisic Acid Sensitivity and Receptor Function
No full textAbscisic acid (ABA) is a plant hormone that regulates various responses to environmental stress and plant development. In the study, the transcriptional responses of Arabidopsis seedlings to ABA at concentrations ranging from 0.001 to 100 micromolar were analyzed. A total of 5749 ABA-responsive genes were identified, which can be grouped into nine clusters based on their dose-dependent response profiles. Approximately 20% of these genes showed atypical biphasic (bell-shaped or U-shaped) dose-response trends and were found to participate in specific biological processes including water transport. The sensitivity of ABA-responsive genes to ABA was also determined using effective dose (ED50) and benchmark dose (BMD) values. ABA receptors, which play a key role in ABA signaling, are encoded by 14 genes in three subfamilies with differing oligomeric states and ABA affinities. The transcriptional responses of mutant strains lacking each subfamily of ABA receptors were compared to the wild type using RNA sequencing. The results showed that the removal of subfamily III receptors had the largest effect on ABA-regulated gene expression, indicating the importance of these receptors in Arabidopsis seedlings. Additionally, the role of ABA signaling in osmotic stress was examined using an ABA receptor antagonist, antabactin (ANT), during osmotic stress caused by PEG treatment. The ABA dependency of genes under osmotic stress was quantitatively defined using a ?-value, which has a higher value when the effect of ANT increases. Motif analyses of cis-elements in the promoter regions of genes revealed a correlation between ABA dependency and the enrichment of ABA-related motifs. This study also reveals that the majority of osmotic-stress-responsive genes formerly classified as ABA-independent require ABA signaling for proper osmotic stress. Overall, this study provides insight into the complexity of the ABA signaling network and identifies a set of transcriptional markers for characterizing ABA sensitivity. It also highlights the importance of defining ABA responses using pharmacological methods and the role of ABA receptor affinity in the wide range of effects exerted by ABA
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Abscisic Acid (ABA) Transport, Sensitivity and Receptor Engineering in Arabidopsis
No full textAbscisic acid (ABA) is a phytohormone that regulates developmental processes and response to abiotic and biotic stresses. It mediates seed dormancy, inhibits seed germination and lateral root formation and controls seedling development. It also limits water loss in times of low water availability through stomatal closure. Core ABA signaling components consist of recently identified PYR/PYL/RCAR receptors that directly regulate clade A PP2C phosphatases. Inhibition of PP2C activity releases SnRK2 kinase inhibition, which enables phosphorylation of downstream targets. In Chapter 1, I identified four ABA transporters, which were identified by their ability to promote ABA uptake into S. cerevisiae cells, as indicated by measuring PYR1-PP2C interactions. For each protein identified, I cloned selected homologues and measured their ability to promote ABA transport in to S. cerevisiae by measuring 3H labeled ABA uptake. I also determined Kms for the two strongest ABA transporters identified (NRT1.2 and SUC7) and examined whether other substrates altered their ABA transport. Seed germination and root assay data showed that knockout mutants for a subset of the identified genes possessed altered sensitivity to ABA compared with wild type, which suggests that the genes AT1G69850, AT1G66570, AT1G09380 and AT4G22790 may function as ABA transporters in Arabidopsis. Collectively, the data suggest that there are likely many ABA transporters in Arabidopsis that function redundantly or in different tissues. In Chapter 2, I provided evidence for the existence and characteristics of ABA desensitization, measured at the transcriptional level. RNA-Seq analysis demonstrates that a large (~10%) subset of ABA responsive genes are less responsive to ABA for a period of hours after initial ABA exposure. I also present data describing the desensitization response based on transcriptomic and metabolomic profiles, which demonstrates the desensitization is not only restricted to several specific genes, but is genome wide and can be measured both in metabolic and transcriptional responses. In Chapter 3 I characterize engineered variants of the ABA receptor PYR1 that possess nanomolar sensitivity to the agrichemical mandipropamid. These were developed by others in my thesis lab to create a system for orthogonal control of ABA responses. My analyses of transcriptomic data show that the engineered receptor can induce an ABA-like response in transgenic Arabidopsis in response to mandipropamid and provide support for the functioning of the engineered receptor in vivo
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Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants
No full textLand plants respond to multiple abiotic stresses, including drought, through the signaling cascade induced by the phytohormone abscisic acid (ABA). Endogenous production, or externally applied ABA has a major function of eliciting guard cell closure, ultimately lowering transpiration and increasing drought tolerance in plants. Accordingly, the mechanisms of action in which ABA facilitates this response have been popular targets for agricultural research and applications. However, ABA has a multitude of responses aside from stomatal closure that are important for plant's survival to abiotic stress. In response to limited water availability, the phytohormone is known to maintain primary root growth while decreasing shoot growth, increase osmolyte accumulation, inhibit seed germination, and is involved in substantial crosstalk with other phytohormones. These responses are dependent on a core ABA signaling pathway comprised of three components: the ABA receptors known as the PYRABACTIN RESISTANT/PYRABACTIN RESISTANT-LIKE/REGULATORY COMPONENT OF ABA RECEPTORs (PYR/PYL/RCARs), the clade A protein phosphatase 2Cs (PP2Cs), and the sucrose nonfermenting related subfamily 2 (SnRK2s).The ABA receptors are the first interactors with ABA within the pathway, and cluster into three clades (I, II, III) based on sequence identity. Additionally, these clades can be further grouped based on oligomeric preference; clades I and II are preferentially monomeric, while clade III is preferentially dimeric. While some research has been done on non-redundant functions of the PYL proteins, many of the ABA responses remain uncharacterized with respect to the differential contributions of the different receptors. Additionally, most of the published ABA-receptor agonists are either direct ABA analogs displaying pan-agonist activity, or are primarily active only on the dimeric subgroup of the receptors. It would thus be potentially beneficial to develop agonists that show preferential activation of the monomeric receptors, allowing for temporal activation and subsequent analysis of their biological relevance.In order to identify compounds with novel selectivities, preferably on the monomeric receptors, I used high-throughput virtual screening to evaluate compounds unbiased to previous, active scaffolds. This resulted in a series of chemically similar hits which showed potent activity on the monomeric receptors, and translated to some in vivo responses. This potent, monomeric-specific scaffold was optimized using structure-aided design, improving the in vivo responses. Using this probe molecule I provide data that suggest that monomeric and dimeric ABA receptors may differentially control metabolomic and transcriptional responses, but are adequate in seed germination inhibition and primary root elongation
Codon MoE : a deep learning approach to predict codon sequences from Arabidopsis thaliana and Nicotiana benthamiana
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