Contributions Of the Human Medial Prefrontal Cortex To Associative Recognition Memory: Evidence From Functional Neuroimaging

Neuroimaging studies of episodic memory, or memory of events from our personal past, have predominantly focused their attention on medial temporal lobe (MTL). There is growing acknowledgement however, from the cognitive neuroscience of memory literature, that regions outside the MTL can support episodic memory processes. The medial prefrontal cortex is one such region garnering increasing interest from researchers. Using behavioral and functional magnetic resonance imaging measures, over two studies, this thesis provides evidence of a mnemonic role of the medial PFC. In the first study, participants were scanned while judging the extent to which they agreed or disagreed with the sociopolitical views of unfamiliar individuals. Behavioral tests of associative recognition revealed that participants remembered with high confidence viewpoints previously linked with judgments of strong agreement/disagreement. Neurally, the medial PFC mediated the interaction between high-confidence associative recognition memory and beliefs associated with strong agree/disagree judgments. In an effort to generalize this finding to well-established associative information, in the second study, we investigated associative recognition memory for real-world concepts. Object-scene pairs congruent or incongruent with a preexisting schema were presented to participants in a cued-recall paradigm. Behavioral tests of conceptual and perceptual recognition revealed memory enhancements arising from strong resonance between presented pairs and preexisting schemas. Neurally, the medial PFC tracked increases in visual recall of schema-congruent pairs whereas the MTL tracked increases in visual recall of schema-incongruent pairs. Additionally, ventral areas of the medial PFC tracked conceptual components of visual recall specifically for schema-congruent pairs. These findings are consistent with a recent theoretical proposal of medial PFC contributions to memory for schema-related content. Collectively, these studies provide evidence of a role for the medial PFC in associative recognition memory persisting for associative information deployed in our daily social interactions and for those associations formed over multiple learning episodes. Additionally, this set of findings advance our understanding of the cognitive contributions of the medial PFC beyond its canonical role in processes underlying social cognition.

Eyewitness Memory: Balancing the Accuracy, Precision, and Quantity of Information through Metacognitive Monitoring and Control

Historically, memory has been evaluated by examining how much is remembered, however a more recent conception of memory focuses on the accuracy of memories. When using this accuracy-oriented conception of memory, unlike with the quantity-oriented approach, memory does not always deteriorate over time. A possible explanation for this seemingly surprising finding lies in the metacognitive processes of monitoring and control. Use of these processes allows people to withhold responses of which they are unsure, or to adjust the precision of responses to a level that is broad enough to be correct. The ability to accurately report memories has implications for investigators who interview witnesses to crimes, and those who evaluate witness testimony. This research examined the amount of information provided, accuracy, and precision of responses provided during immediate and delayed interviews about a videotaped mock crime. The interview format was manipulated such that a single free narrative response was elicited, or a series of either yes/no or cued questions were asked. Instructions provided by the interviewer indicated to the participants that they should either stress being informative, or being accurate. The interviews were then transcribed and scored. Results indicate that accuracy rates remained stable and high after a one week delay. Compared to those interviewed immediately, after a delay participants provided less information and responses that were less precise. Participants in the free narrative condition were the most accurate. Participants in the cued questions condition provided the most precise responses. Participants in the yes/no questions condition were most likely to say “I don’t know”. The results indicate that people are able to monitor their memories and modify their reports to maintain high accuracy. When control over precision was not possible, such as in the yes/no condition, people said “I don’t know” to maintain accuracy. However when withholding responses and adjusting precision were both possible, people utilized both methods. It seems that concerns that memories reported after a long retention interval might be inaccurate are unfounded.

On the Threshold of Paradise and Present: Memory in Contemporary Cuban – American Literature

The exile leaving his or her homeland for new and unknown territory travels with much more than just luggage and the clothes on his or her back. He or she carries a weighty collection of memories. Available for the exile in times when the harmony of the past is far removed from the difficult circumstances present during the process of cultural assimilation, these memories present an opportunity for the exile to fashion for him or herself an identity that mimics the realities of life in the home left behind. In this creative endeavor, I seek to examine the powerful potential of memory as it is exercised by a collection of Cubans and Cuban-Americans in different corners of the United States. Analyzing Achy Obejas’ Memory Mambo, Cristina García’s Dreaming in Cuban, Ana Menéndez’s In Cuba I Was a German Shepherd, and Elías Miguel Muñoz’s Brand New Memory, I aim to trace the suggestive potential of memory as it is used by each of the characters in these works in an effort to reconcile their Cuban identities with the ones that are in the process of creation in the U.S. I will borrow from a collection of literature dealing with identity and exile, relevant graduate-level theses on Cuban-American literature, as well as theoretical perspectives on memory formation and nostalgia in order to trace the various ways in which memory is relied on in the process of cultural assimilation and emotional coping. Being presented in Miami, which hosts the largest concentration of Cuban immigrants, this thesis aims to present itself as a reflective tool for Cubans and Cuban-Americans who may find value in seeing their personal sentiments portrayed in literature, thus allowing for a potential reevaluation of identity. If the existing literature on my topic of analysis reveals anything, it is that the scope of my project is one that has not been inspected previously, thus making my analytical contribution a new one that will add a new interpretive set of lens through which readers of contemporary Cuban-American literature can examine the works.

On the Threshold of Paradise and Present: Memory in Contemporary Cuban‐American Literature

The exile leaving his or her homeland for new and unknown territory travels with much more than just luggage and the clothes on his or her back. He or she carries a weighty collection of memories. Available for the exile in times when the harmony of the past is far removed from the difficult circumstances present during the process of cultural assimilation, these memories present an opportunity for the exile to fashion for him or herself an identity that mimics the realities of life in the home left behind. In this creative endeavor, I seek to examine the powerful potential of memory as it is exercised by a collection of Cubans and Cuban-Americans in different corners of the United States. Analyzing Achy Obejas’ Memory Mambo, Cristina García’s Dreaming in Cuban, Ana Menéndez’s In Cuba I Was a German Shepherd, and Elías Miguel Muñoz’s Brand New Memory, I aim to trace the suggestive potential of memory as it is used by each of the characters in these works in an effort to reconcile their Cuban identities with the ones that are in the process of creation in the U.S. I will borrow from a collection of literature dealing with identity and exile, relevant graduate-level theses on Cuban-American literature, as well as theoretical perspectives on memory formation and nostalgia in order to trace the various ways in which memory is relied on in the process of cultural assimilation and emotional coping. Being presented in Miami, which hosts the largest concentration of Cuban immigrants, this thesis aims to present itself as a reflective tool for Cubans and Cuban-Americans who may find value in seeing their personal sentiments portrayed in literature, thus allowing for a potential reevaluation of identity. If the existing literature on my topic of analysis reveals anything, it is that the scope of my project is one that has not been inspected previously, thus making my analytical contribution a new one that will add a new interpretive set of lens through which readers of contemporary Cuban-American literature can examine the works.

Stories from the Inside:The Prisons Memory Archive

A close textual reading of the online-available recording of ex-prison officer, John Heatherington, who is filmed as he returns to the site of the Maze and Long Kesh Prison, which was the largest prison oeperating during the Troubles in Northern Ireland. Using the empty site as stimulant for his memory, John recalls the tension, violence and dark humour of the period, while also showing exceptional empathy for all those, including prisoners, who passed through the prison system.The interview is taken from the Prisons Memory Archive (www.prisonsmemoryarchive.com) and, as director of the PMA, I have a particular insight to the recording process and John's special contribution to it.

The Multidirectional Memory of Charlie Hebdo

This article will discuss notions and concepts of remembering in the aftermath of the Charlie Hebdo attacks. Much has been written about the immediate response to the attacks, both commending the collective spirit of unity that defined the ‘marche républicaine’ of 11 January 2015, and criticising the alleged hypocrisy and cynicism of, most notably, the political figures that took to the streets that day, hand in hand. I will consider a selection of the memory practices that have emerged since then, notably on the anniversary of the event. This demonstration of memory provides key insights into the form and manner of remembering within a particular cultural group, but also reflects how the present moment is integral to our understanding of memory. The purpose of this article is to consider how official and non-official remembering of Charlie Hebdo can intertwine as well as pull in separate directions. A focus on the politics, the language, the aesthetics and the geography of commemorative activities in this article will enable an appreciation of the multidirectional character of remembering Charlie Hebdo.

How task format affects cognitive performance: a memory test with two species of New World monkeys

In cognitive tests, animals are often given a choice between two options and obtain a reward if they choose correctly. We investigated whether task format affects subjects' performance in a physical cognition test. In experiment 1, a two-choice memory test, 15 marmosets, Callithrix jacchus, had to remember the location of a food reward over time delays of increasing duration. We predicted that their performance would decline with increasing delay, but this was not found. One possible explanation was that the subjects were not sufficiently motivated to choose correctly when presented with only two options because in each trial they had a 50% chance of being rewarded. In experiment 2, we explored this possibility by testing eight naïve marmosets and seven squirrel monkeys, Saimiri sciureus, with both the traditional two-choice and a new nine-choice version of the memory test that increased the cost of a wrong choice. We found that task format affected the monkeys' performance. When choosing between nine options, both species performed better and their performance declined as delays became longer. Our results suggest that the two-choice format compromises the assessment of physical cognition, at least in memory tests with these New World monkeys, whereas providing more options, which decreases the probability of obtaining a reward when making a random guess, improves both performance and measurement validity of memory. Our findings suggest that two-choice tasks should be used with caution in comparisons within and across species because they are prone to motivational biases.

Development of site-specific sediment quality guidelines for North and South Atlantic littoral zones: Comparison against national and international sediment quality benchmarks

We aimed to develop site-specific sediment quality guidelines (SQGs) for two estuarine and port zones in Southeastern Brazil (Santos Estuarine System and Paranagua Estuarine System) and three in Southern Spain (Ria of Huelva, Bay of Cadiz, and Bay of Algeciras), and compare these values against national and traditionally used international benchmark values. Site-specific SQGs were derived based on sediment physical-chemical, toxicological, and benthic community data integrated through multivariate analysis. This technique allowed the identification of chemicals of concern and the establishment of effects range correlatively to individual concentrations of contaminants for each site of study. The results revealed that sediments from Santos channel, as well as inner portions of the SES, are considered highly polluted (exceeding SQGs-high) by metals, PAHs and PCBs. High pollution by PAHs and some metals was found in Sao Vicente channel. In PES, sediments from inner portions (proximities of the Ponta do Mix port's terminal and the Port of Paranagua) are highly polluted by metals and PAHs, including one zone inside the limits of an environmental protection area. In Gulf of Cadiz, SQGs exceedences were found in Ria of Huelva (all analysed metals and PAHs), in the surroundings of the Port of CAdiz (Bay of CAdiz) (metals), and in Bay of Algeciras (Ni and PAHs). The site-specific SQGs derived in this study are more restricted than national SQGs applied in Brazil and Spain, as well as international guidelines. This finding confirms the importance of the development of site-specific SQGs to support the characterisation of sediments and dredged material. The use of the same methodology to derive SQGs in Brazilian and Spanish port zones confirmed the applicability of this technique with an international scope and provided a harmonised methodology for site-specific SQGs derivation. (C) 2009 Elsevier B.V. All rights reserved.

RGS14 (414)-mediated prevention of an episodic memory loss: a study of molecular mechanism

A large proportion of human populations suffer memory impairments either caused by normal aging or afflicted by diverse neurological and neurodegenerative diseases. Memory enhancers and other drugs tested so far against memory loss have failed to produce therapeutic efficacy in clinical trials and thus, there is a need to find remedy for this mental disorder. In search for cure of memory loss, our laboratory discovered a robust memory enhancer called RGS14(414). A treatment in brain with its gene produces an enduring effect on memory that lasts for lifetime of rats. Therefore, current thesis work was designed to investigate whether RGS14(414) treatment can prevent memory loss and furthermore, explore through biological processes responsible for RGS-mediated memory enhancement. We found that RGS14(414) gene treatment prevented episodic memory loss in rodent models of normal aging and Alzheimer´s disease. A memory loss was observed in normal rats at 18 months of age; however, when they were treated with RGS14(414) gene at 3 months of age, they abrogated this deficit and their memory remained intact till the age of 22 months. In addition to normal aging rats, effect of memory enhancer treatment in mice model of Alzheimer´s disease (AD-mice) produced a similar effect. AD-mice subjected to treatment with RGS14(414) gene at the age of 2 months, a period when memory was intact, showed not only a prevention in memory loss observed at 4 months of age but also they were able to maintain normal memory after 6 months of the treatment. We posit that long-lasting effect on memory enhancement and prevention of memory loss mediated through RGS14(414) might be due to a permanent structural change caused by a surge in neuronal connections and enhanced neuronal remodeling, key processes for long-term memory formation. A neuronal arborization analysis of both pyramidal and non-pyramidal neurons in brain of RGS14(414)-treated rats exhibited robust rise in neurites outgrowth of both kind of cells, and an increment in number of branching from the apical dendrite of pyramidal neurons, reaching to almost three times of the control animals. To further understand of underlying mechanism by which RGS14(414) induces neuronal arborization, we investigated into neurotrophic factors. We observed that RGS14 treatment induces a selective increase in BDNF. Role of BDNF in neuronal arborization, as well as its implication in learning and memory processes is well described. In addition, our results showing a dynamic expression pattern of BDNF during ORM processing that overlapped with memory consolidation further support the idea of the implication of this neurotrophin in formation of long-term memory in RGS-animals. On the other hand, in studies of expression profiling of RGS-treated animals, we have demonstrated that 14-3-3ζ protein displays a coherent relationship to RGS-mediated ORM enhancement. Recent studies have demonstrated that the interaction of receptor for activated protein kinase 1 (RACK1) with 14-3-3ζ is essential for its nuclear translocation, where RACK1-14-3-3ζ complex binds at promotor IV region of BDNF and promotes an increase in BDNF gene transcription. These observations suggest that 14-3-3ζ might regulate the elevated level of BDNF seen in RGS14(414) gene treated animals. Therefore, it seems that RGS-mediated surge in 14-3-3ζ causes elevated BDNF synthesis needed for neuronal arborization and enhanced ORM. The prevention of memory loss might be mediated through a restoration in BDNF and 14-3-3ζ protein levels, which are significantly decreased in aging and Alzheimer’s disease. Additionally, our results demonstrate that RGS14(414) treatment could be a viable strategy against episodic memory loss.

Cancers of unknown primary site (CUPs) as a model of metastatic process.

Cancers of unknown primary site (CUPs) are a rare group of metastatic tumours, with a frequency of 3-5%, with an overall survival of 6-10 month. The identification of tumour primary site is usually reached by a combination of diagnostic investigations and immunohistochemical testing of the tumour tissue. In CUP patients, these investigations are inconclusive. Since international guidelines for treatment are based on primary site indication, CUP treatment requires a blind approach. As a consequence, CUPs are usually empiric treated with poorly effective. In this study, we applied a set of microRNAs using EvaGreen-based Droplet Digital PCR in a retrospective and prospective collection of formalin-fixed paraffin-embedded tissue samples. We assessed miRNA expression of 155 samples including primary tumours (N=94), metastases of known origin (N=10) and metastases of unknown origin (N=50). Then, we applied the shrunken centroids predictive algorithm to obtain the CUP’s site(s)-of-origin. The molecular test was successfully applied to all CUP samples and provided a site-of-origin identification for all samples, potentially within a one-week time frame from sample inclusion. In the second part of the study we derived two CUP cell lines, and corresponding patient-derived xenografts (PDXs). CUP cell lines and PDXs underwent histological, molecular, and genomic characterization confirming the features of the original tumour. Tissues-of-origin prediction was obtained from the tumour microRNA expression profile and confirmed by single cell RNA sequencing. Genomic testing analysis identified FGFR2 amplification in both models. Drug-screening assays were performed to test the activity of FGFR2-targeting drug and the combination treatment with the MEK inhibitor trametinib, which proved to be synergic and exceptionally active, both in vitro and in vivo. In conclusion, our study demonstrated that miRNA expression profiling could be employed as diagnostic test. Then we successfully derived two CUP models from patients, used for therapy tests, bringing personalized therapy closer to CUP patients.

Molecular And Biochemical Characterization Of Caffeine Synthase And Purine Alkaloid Concentration In Guarana Fruit.

Guarana seeds have the highest caffeine concentration among plants accumulating purine alkaloids, but in contrast with coffee and tea, practically nothing is known about caffeine metabolism in this Amazonian plant. In this study, the levels of purine alkaloids in tissues of five guarana cultivars were determined. Theobromine was the main alkaloid that accumulated in leaves, stems, inflorescences and pericarps of fruit, while caffeine accumulated in the seeds and reached levels from 3.3% to 5.8%. In all tissues analysed, the alkaloid concentration, whether theobromine or caffeine, was higher in young/immature tissues, then decreasing with plant development/maturation. Caffeine synthase activity was highest in seeds of immature fruit. A nucleotide sequence (PcCS) was assembled with sequences retrieved from the EST database REALGENE using sequences of caffeine synthase from coffee and tea, whose expression was also highest in seeds from immature fruit. The PcCS has 1083bp and the protein sequence has greater similarity and identity with the caffeine synthase from cocoa (BTS1) and tea (TCS1). A recombinant PcCS allowed functional characterization of the enzyme as a bifunctional CS, able to catalyse the methylation of 7-methylxanthine to theobromine (3,7-dimethylxanthine), and theobromine to caffeine (1,3,7-trimethylxanthine), respectively. Among several substrates tested, PcCS showed higher affinity for theobromine, differing from all other caffeine synthases described so far, which have higher affinity for paraxanthine. When compared to previous knowledge on the protein structure of coffee caffeine synthase, the unique substrate affinity of PcCS is probably explained by the amino acid residues found in the active site of the predicted protein.

Design And Synthesis Of N-acylated Aza-goniothalamin Derivatives And Evaluation Of Their In Vitro And In Vivo Antitumor Activity.

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N-Acylation of aza-goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1-(E)-But-2-enoyl-6-styryl-5,6-dihydropyridin-2(1H)-one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC-3 cells, which was probably a signal for caspase-dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7-aminoactinomycin D double staining, which indicated apoptosis, and also led to G2 /M cell-cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza-goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.

Fracture Of Distal Humerus: Mipo Technique With Visualization Of The Radial Nerve.

To evaluate the outcomes in patients treated for humerus distal third fractures with MIPO technique and visualization of the radial nerve by an accessory approach, in those without radial palsy before surgery. The patients were treated with MIPO technique. The visualization and isolation of the radial nerve was done by an approach between the brachialis and the brachiorradialis, with an oblique incision, in the lateral side of the arm. MEPS was used to evaluate the elbow function. Seven patients were evaluated with a mean age of 29.8 years old. The average follow up was 29.85 months. The radial neuropraxis after surgery occurred in three patients. The sensorial recovery occurred after 3.16 months on average and also of the motor function, after 5.33 months on average, in all patients. We achieved fracture consolidation in all patients (M=4.22 months). The averages for flexion-extension and prono-supination were 112.85° and 145°, respectively. The MEPS average score was 86.42. There was no case of infection. This approach allowed excluding a radial nerve interposition on site of the fracture and/or under the plate, showing a high level of consolidation of the fracture and a good evolution of the range of movement of the elbow. Level of Evidence IV, Case Series.

Kinase Inhibitor Profile For Human Nek1, Nek6, And Nek7 And Analysis Of The Structural Basis For Inhibitor Specificity.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.

In vitro Microfluidic Model For The Study Of Vaso-occlusive Processes.

Vaso-occlusion, responsible for much of the morbidity of sickle-cell disease, is a complex multicellular process, apparently triggered by leukocyte adhesion to the vessel wall. The microcirculation represents a major site of leukocyte-endothelial interactions and vaso-occlusive processes. We have developed a biochip with subdividing interconnecting microchannels that decrease in size (40 μm to 10 μm in width), for use in conjunction with a precise microfluidic device, to mimic cell flow and adhesion through channels of sizes that approach those of the microcirculation. The biochips were utilized to observe the dynamics of the passage of neutrophils and red blood cells, isolated from healthy and sickle-cell anemia (SCA) individuals, through laminin or endothelial adhesion molecule-coated microchannels at physiologically relevant rates of flow and shear stress. Obstruction of E-selectin/intercellular adhesion molecule 1-coated biochip microchannels by SCA neutrophils was significantly greater than that observed for healthy neutrophils, particularly in the microchannels of 40-15 μm in width. Whereas SCA red blood cells alone did not significantly adhere to, or obstruct, microchannels, mixed suspensions of SCA neutrophils and red blood cells significantly adhered to and obstructed laminin-coated channels. Results from this in vitro microfluidic model support a primary role for leukocytes in the initiation of SCA occlusive processes in the microcirculation. This assay represents an easy-to-use and reproducible in vitro technique for understanding molecular mechanisms and cellular interactions occurring in subdividing microchannels of widths approaching those observed in the microvasculature. The assay could hold potential for testing drugs developed to inhibit occlusive mechanisms such as those observed in SCA and thrombotic diseases.