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## The SORL1 Gene and Convergent Neural Risk for Alzheimer's Disease Across the Human Lifespan

Felsky, Daniel; Szeszko, Philip; Yu, Lei; Honer, William G; De Jager, Philip L; Schneider, Julie A; Malhotra, Anil K; Lencz, Todd; Ikuta, Toshikazu; Pipitone, Jon; Chakravarty, M Mallar; Lobaugh, Nancy J; Mulsant, Benoit H; Pollock, Bruce G; Kennedy, Jame
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
EN_US
Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: 1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86, and n=68, age 8-40); 2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92); and 3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI), and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner, in fronto-temporal white matter tracts in both samples at 5% FWE-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression...

## Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence

Wang, A-L; Elman, I; Lowen, S B; Blady, S J; Lynch, K G; Hyatt, J M; O'Brien, C P; Langleben, D D
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN_US
Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its use is hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0–3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use...

## Children's Understanding Of The Relationship Between Addition and Subtraction

Spelke, Elizabeth S.; Gilmore, Camilla K.
Tipo: Artigo de Revista Científica
EN_US
In learning mathematics, children must master fundamental logical relationships, including the inverse relationship between addition and subtraction. At the start of elementary school, children lack generalized understanding of this relationship in the context of exact arithmetic problems: they fail to judge, for example, that 12 + 9 − 9 yields 12. Here, we investigate whether preschool children’s approximate number knowledge nevertheless supports understanding of this relationship. Five-year-old children were more accurate on approximate large-number arithmetic problems that involved an inverse transformation than those that did not, when problems were presented in either non-symbolic or symbolic form. In contrast they showed no advantage for problems involving an inverse transformation when exact arithmetic was involved. Prior to formal schooling, children therefore show generalized understanding of at least one logical principle of arithmetic. The teaching of mathematics may be enhanced by building on this understanding.; Psychology

## Does large-sized cities' urbanisation predominantly degrade environmental resources in China? Relationships between urbanisation and resources in Changjiang Delta Region

Kim, Saehoon; Rowe, Peter G.
Fonte: Taylor & Francis Publicador: Taylor & Francis
Tipo: Artigo de Revista Científica
EN_US
Outward expansion of urban lands in the developing nations is often associated with a substantial loss of environmental resources such as forests, wetlands, freshwater and cash crop fields. Yet, determining how different aspects of urbanisation – such as city population size and spread pattern of built-up lands – contribute to the cumulative loss of resources remains controversial. In this study, data sets were constructed describing changes to land cover across 65,200 grid cells at 1 km2 spatial resolution for China’s Changjiang Delta Region over the past 60 years. The results showed that the region lost 12.2% of total resource sites. The distribution of resource degradation showed a highly dispersed pattern and was not confined to a few intense areas associated with large cities. No empirical evidence was found that city population size alone accurately predicts the distribution of resource loss. Very large cities (N = 4) contributed 35% to the total loss, demonstrating impacts similar to those of much more scattered towns (N = 230). Urban expansion of large cities may lead to extensive resource loss; however, a set of non-linear mechanisms, such as the diminishing effects of per-unit area urban spread on resources and interactions between urban patterns and the size of urban spread...

## "I’ll Have One of Each": How Separating Rewards into (Meaningless) Categories Increases Motivation

Wiltermuth, Scott S.; Gino, Francesca
Fonte: American Psychological Association Publicador: American Psychological Association
Tipo: Artigo de Revista Científica
EN_US
We propose that separating rewards into categories can increase motivation, even when those categories are meaningless. Across six experiments, people were more motivated to obtain one reward from one category and another reward from another category than they were to obtain two rewards from a pool that included all items from either reward category. As a result, they worked longer when potential rewards for their work were separated into meaningless categories. This categorization effect persisted regardless of whether the rewards were presented using a gain or loss frame. Using both moderation and mediation analyses, we found that categorizing rewards had these positive effects on motivation by increasing the degree to which people felt they would "miss out" if they did not obtain the second reward. We discuss implications for research on motivation and incentives.

## From Mashtots' to Nga'ara

Russell, James R.
Fonte: Harvard University Publicador: Harvard University
Tipo: Conference Paper
EN_US
Near Eastern Languages and Civilizations

## Development and Deployment of Optical Instruments to Measure Trace Atmospheric Species: I. Water Isotopologues; II. Glyoxal; III. Iodine Monoxide

O'Brien, Anthony
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
EN_US
Understanding future climate requires observations of trace species that can significantly influence the chemical or radiative properties of the atmosphere. The development of optical instruments, utilizing laser-systems as high-resolution light sources, for making in situ observations of trace species from either airborne- or ground-based platforms and results from field campaigns are presented. Glyoxal, the smallest $$\alpha$$-dicarbonyl, is a common product during the oxidation of volatile organic compounds. An instrument using the technique of laser-induced phosphorescence was developed to measure glyoxal at the part per trillion by volume (pptv) level from a tower in a forest canopy. The instrument was deployed as part of the Community Atmosphere-Biosphere INteractions EXperiment. The instrumental limit of detection is 3 pptv with a 1-minute acquisition time. Nearly continuous measurements of glyoxal ranging between 5 – 75 pptv were acquired throughout the campaign and vertical gradients in the forest canopy were found to be driven by elevated temperature. A sensitive instrument using laser-induced fluorescence detection was developed and deployed into remote marine environments to measure iodine monoxide (IO) where the mixing ratio is on the order of 1 – 5 pptv. The challenges and solutions of operating in this environment and results from the field and laboratory are discussed. Laboratory experiments show that IO can be generated from Laminaria digitata...

## Nabokov's Details: Making Sense of Irrational Standards

Horgan, Pelagia
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
EN_US
Vladimir Nabokov's passion for detail is well-known, central to our very idea of the "Nabokovian." Yet Nabokov's most important claims for detail pose a challenge for the reader who would take them seriously. Startlingly extreme and deliberately counterintuitive -- Nabokov called them his "irrational standards" -- these claims push the very limits of reason and belief. Nabokov's critics have tended to treat his more extravagant claims for detail -- including his assertion that the "capacity to wonder at trifles" is the highest form of consciousness there is -- as just a manner of speaking, a form of italics, a bit of wishful thinking, a mandarin's glib performance, or an aesthete's flight of fancy. This dissertation, by contrast, asserts that Nabokov meant what he said, and sets out to understand what he meant. Nabokov's passion for detail, I argue, represents more than a stylistic preference or prescription for good noticing. Rather, it reflects and advocates for a special way of being in the world, of disposing or orienting oneself to things, and for this reason is best understood as part of a broad program of detailphilic habits, attitudes, practices and attunements Nabokov adhered to throughout his life. In making this argument...

## Getting Told and Being Believed

Moran, Richard A.
Fonte: University of Michigan Publicador: University of Michigan
Tipo: Artigo de Revista Científica
EN_US
The paper argues for the centrality of believing the speaker (as distinct from believing the statement) in the epistemology of testimony, and develops a line of thought from Angus Ross which claims that in telling someone something, the kind of reason for belief that a speaker presents is of an essentially different kind from ordinary evidence. Investigating the nature of the audience's dependence on the speaker's free assurance leads to a discussion of Grice's formulation of non-natural meaning in an epistemological light, concentrating on just how the recognition of the speaker's self-reflexive intention is supposed to count for his audience as a reason to believe P. This is understood as the speaker's explicitly assuming responsibility for the truth of his statement, and thereby constituting his utterance as a reason to believe.; Philosophy

## Study on Bacterial Protein Synthesis System toward the Incorporation of D-Amino Acid & Synthesis of 2'-deoxy-3'-mercapto-tRNA

Huang, Po-Yi
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
EN_US
Life is anti-entropic and highly organized phenomenon with two characteristics reinforcing each other: homochirality and the stereospecific catalysis of chemical reactions. The exclusive presence of L-amino acids and R-sugars in living world well depict this. Hypothetically, the amino acids and sugars of reverse chirality could form a parallel kingdom which is highly orthogonal to the present world. The components from this mirror kingdom, such as protein or nucleic acid, will be much more resistant to the defensive mechanism of present living system, which could be of great value. Therefore, by gradually rewiring the present bio-machineries, we look to build a bridge leading us to the space of mirror-imaged biomolecules. We begin by investigating protein synthesis with mirror amino acid since most amino acids contain one chiral center to be inversed comparing to sugars. In this work, we analyzed three stages critical for the incorporation of D-amino acid into ribosomal protein synthesis: amino acylation, EF-Tu binding of amino acyl-tRNA and delivery bias, and ribosome catalyzed peptidyl transfer. We have demonstrated that the affinity between EF-Tu and amino acyl-tRNA plays critical role on D-amino acid incorporation, and built a platform aimed to select for ribosome tolerating D-amino acid better.; Chemistry and Chemical Biology

## The Impact of Corporate Social Responsibility on Investment Recommendations: Analysts' Perceptions and Shifting Institutional Logics

Ioannou; Serafeim, Georgios
Tipo: Artigo de Revista Científica
EN_US
We explore the impact of corporate social responsibility (CSR) ratings on sell-side analysts' assessments of firms' future financial performance. We suggest that when analysts perceive CSR as an agency cost, due to the prevalence of an agency logic, they produce pessimistic recommendations for firms with high CSR ratings. Moreover, we theorize that over time, the emergence of a stakeholder focus, and the gradual weakening of the agency logic, shifts the analysts' perceptions of CSR ratings and results in increasingly less pessimistic recommendations for firms with high CSR ratings. Using a large sample of publicly traded U.S. firms over 15 years, we confirm that in the early 1990s, analysts issue more pessimistic recommendations for firms with high CSR ratings. However, in more recent years analysts progressively assess these firms less pessimistically, and eventually they assess them optimistically. Furthermore, we find that more experienced analysts and analysts at higher-status brokerage houses are the first to shift the relation between CSR ratings and investment recommendation optimism. We find no significant link between firms' CSR ratings and analysts' forecast errors, indicating that learning is unlikely to account for the observed shifts in recommendations.

## Real-Time Increased Detection of Neoplastic Tissue in Barrett’s Esophagus with Probe-Based Confocal Laser Endomicroscopy: Final Results of an International Multicenter, Prospective, Randomized, Controlled Trial

Sharma, Prateek; Meining, Alexander R.; Coron, Emmanuel; Lightdale, Charles J.; Wolfsen, Herbert C.; Bansal, Ajay; Bajbouj, Monther; Galmiche, Jean-Paul; Abrams, Julian A.; Rastogi, Amit; Gupta, Neil; Michalek, Joel E.; Lauwers, Gregory Y.; Wallace, Micha
Fonte: Elsevier BV Publicador: Elsevier BV
Tipo: Artigo de Revista Científica
EN_US
BACKGROUND: Probe-based confocal laser endomicroscopy (pCLE) allows real-time detection of neoplastic Barrett's esophagus (BE) tissue. However, the accuracy of pCLE in real time has not yet been extensively evaluated. OBJECTIVE: To compare the sensitivity and specificity of pCLE in addition to high-definition white-light endoscopy (HD-WLE) with HD-WLE alone for the detection of high-grade dysplasia (HGD) and early carcinoma (EC) in BE. DESIGN: International, prospective, multicenter, randomized, controlled trial. SETTING: Five tertiary referral centers. PATIENTS: A total of 101 consecutive BE patients presenting for surveillance or endoscopic treatment of HGD/EC. INTERVENTIONS: All patients were examined by HD-WLE, narrow-band imaging (NBI), and pCLE, and the findings were recorded before biopsy samples were obtained. The order of HD-WLE and NBI was randomized and performed by 2 independent, blinded endoscopists. All suspicious lesions on HD-WLE or NBI and 4-quadrant random locations were documented. These locations were examined by pCLE, and a presumptive diagnosis of benign or neoplastic (HGD/EC) tissue was made in real time. Finally, biopsies were taken from all locations and were reviewed by a central pathologist, blinded to endoscopic and pCLE data. MAIN OUTCOME MEASUREMENTS: Diagnostic characteristics of pCLE. RESULTS: The sensitivity and specificity for HD-WLE were 34.2% and 92.7%...

## Comments on ‘Alternative Models of Political Business Cycles’ by W.D. Nordhaus

Alesina, Alberto Francesco
Fonte: Brookings Institution Press Publicador: Brookings Institution Press
Tipo: Commentary or Review
EN_US
Economics

## Comments on "When Do Policy Reforms Work?' by Daron Acemoglu et al.

Alesina, Alberto Francesco
Fonte: Brookings Institution Press Publicador: Brookings Institution Press
Tipo: Commentary or Review
EN_US
Questions of the effectiveness of economic policy reform are inseparable from the political economy factors responsible for distortionary policies in the first place. Distortionary policies are more likely to be adopted where politicians face fewer constraints. Hence reform should have modest effects in societies where the political system already imposes strong constraints, and in societies with weak constraints, because it does not alter the underlying political economy. Reform should be most effective in societies with intermediate constraints. Furthermore, effective reform in one dimension may lead to deterioration in others, as politicians address the underlying demands through other means—a phenomenon we call the seesaw effect. We report evidence that central bank reforms reduced inflation in countries with intermediate constraints but had no or little effect where constraints were strong or weak. We also present evidence consistent with the seesaw effect: in countries where central bank reform reduces inflation, government expenditure tends to increase.; Economics

## Comments on 'Europe's Gamble' by M. Obstfeld

Alesina, Alberto Francesco
Fonte: Brookings Institution Press Publicador: Brookings Institution Press
Tipo: Commentary or Review
EN_US
Economics

## A highly sensitive novel immunoassay specifically detects low levels of soluble Aβ oligomers in human cerebrospinal fluid

Yang, Ting; O’Malley, Tiernan T; Kanmert, Daniel; Jerecic, Jasna; Zieske, Lynn R; Zetterberg, Henrik; Hyman, Bradley T; Walsh, Dominic M; Selkoe, Dennis J
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Introduction: Amyloid β-protein oligomers play a key role in Alzheimer’s disease (AD), but well-validated assays that routinely detect them in cerebrospinal fluid (CSF) are just emerging. We sought to confirm and extend a recent study using the Singulex Erenna platform that reported increased mean CSF oligomer levels in AD. Methods: We tested four antibody pairs and chose one pair that was particularly sensitive, using 1C22, our new oligomer-selective monoclonal antibody, for capture. We applied this new assay to extracts of human brain and CSF. Results: A combination of 1C22 for capture and 3D6 for detection yielded an Erenna immunoassay with a lower limit of quantification of approximately 0.15 pg/ml that was highly selective for oligomers over monomers and detected a wide size-range of oligomers. Most CSFs we tested had detectable oligomer levels but with a large overlap between AD and controls and a trend for higher mean levels in mild cognitive impairment (MCI) than controls. Conclusion: Aβ oligomers are detectable in most human CSFs, but AD and controls overlap. MCI CSFs may have a modest elevation in mean value by this assay. Electronic supplementary material The online version of this article (doi:10.1186/s13195-015-0100-y) contains supplementary material...

## Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy

Lin, Alexander P; Ramadan, Saadallah; Stern, Robert A; Box, Hayden C; Nowinski, Christopher J; Ross, Brian D; Mountford, Carolyn E
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Introduction: The goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY). Methods: To achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil. Results: The variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P ≤0.05), between healthy controls and those athletes with RBT. Men with RBT showed higher levels of glutamine/glutamate (31%)...

## Helicobacter pylori cag Pathogenicity Island's Role in B7-H1 Induction and Immune Evasion

Lina, Taslima T.; Alzahrani, Shatha; House, Jennifer; Yamaoka, Yoshio; Sharpe, Arlene H.; Rampy, Bill A.; Pinchuk, Irina V.; Reyes, Victor E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
During Helicobacter pylori (H. pylori) infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation, effector function, and induce Treg cells in vitro. In this study, we investigated the underlying mechanisms and the functional relevance of B7-H1 induction by H. pylori infection to chronic infection. Using H. pylori wild type (WT), cag pathogenicity island (cag PAI-) and cagA- isogenic mutant strains we demonstrated that H. pylori requires its type 4 secretion system (T4SS) as well as its effector protein CagA and peptidoglycan (PG) fragments for B7-H1 upregulation on GEC. Our study also showed that H. pylori uses the p38 MAPK pathway to upregulate B7-H1 expression in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, which has a functional T4SS delivery system, but not with H. pylori SS1 strain lacking a functional T4SS, led to a strong upregulation of B7-H1 expression in the gastric mucosa, increased bacterial load, induction of Treg cells in the stomach, increased IL-10 in the serum. Interestingly...

## Alzheimery's disease pathology is associated with early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

De Jager, PL; Srivastava, G; Lunnon, K; Burgess, J; Schalkwyk, LC; Yu, L; Eaton, ML; Keenan, BT; Ernst, J; McCabe, C; Tang, A; Raj, T; Replogle, J; Brodeur, W; Gabriel, S; Chai, HS; Younkin, C; Younkin, SG; Zou, F; Szyf, M; Epstein, CB; Schneider, JA; Ber
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
EN_US
Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validate 11 of the differentially methylated regions in an independent set of 117 subjects. Further, we functionally validate these CpG associations and identify the nearby genes whose RNA expression is altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

## Scholars' Briefs and the Vocation of the Law Professor

Fallon, Richard Henry
Fonte: Harvard University Publicador: Harvard University
Tipo: Outros
EN_US