Intervention of carbohydrate recognition by proteins and nucleic acids.

Carbohydrates in biological systems are often associated with specific recognition and signaling processes leading to important biological functions and diseases. Considerable efforts have been directed toward understanding and mimicking the recognition processes and developing effective agents to control the processes. The pace of discovery research in glycobiology and development of carbohydrate-based therapeutics, however, has been relatively slow due to the lack of appropriate strategies and methods available for carbohydrate-related research. This review summarizes some of the most recent developments in the field, with particular emphasis on work from our laboratories regarding the use of chemoenzymatic strategies to tackle the carbohydrate recognition problem. Highlights include the study of selectin-carbohydrate and aminoglycoside-RNA interactions and development of agents for the intervention of these recognition processes.

Cloning of an arylalkylamine N-acetyltransferase (aaNAT1) from Drosophila melanogaster expressed in the nervous system and the gut.

In insects, neurotransmitter catabolism, melatonin precursor formation, and sclerotization involve arylalkylamine N-acetyltransferase (aaNAT, EC 2.3.1.87) activity. It is not known if one or multiple aaNAT enzymes are responsible for these activities. We recently have purified an aaNAT from Drosophila melanogaster. Here, we report the cloning of the corresponding aaNAT cDNA (aaNAT1) that upon COS cell expression acetylates dopamine, tryptamine, and the immediate melatonin precursor serotonin. aaNAT1 represents a novel gene family unrelated to known acetyl-transferases, except in two weakly conserved amino acid motifs. In situ hybridization studies of aaNAT1 mRNA in embryos reveal hybridization signals in the brain, the ventral cord, the gut, and probably in oenocytes, indicating a broad tissue distribution of aaNAT1 transcripts. Moreover, in day/ night studies we demonstrate a diurnal rhythm of melatonin concentration without a clear-cut change in aaNAT1 mRNA levels. The data suggest that tissue-specific regulation of aaNAT1 may be associated with different enzymatic functions and do not exclude the possibility of additional aaNAT genes.

Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.

Patients suffering from schizophrenia display subtle cognitive abnormalities that may reflect a difficulty in rapidly coordinating the steps that occur in a variety of mental activities. Working interactively with the prefrontal cortex, the cerebellum may play a role in coordinating both motor and cognitive performance. This positron-emission tomography study suggests the presence of a prefrontal-thalamic-cerebellar network that is activated when normal subjects recall complex narrative material, but is dysfunctional in schizophrenic patients when they perform the same task. These results support a role for the cerebellum in cognitive functions and suggest that patients with schizophrenia may suffer from a "cognitive dysmetria" due to dysfunctional prefrontal-thalamic-cerebellar circuitry.

A circadian clock regulates rod and cone input to fish retinal cone horizontal cells.

In the vertebrate retina, the light responses of post-receptor neurons depend on the ambient or background illumination. Using intracellular recording, we have found that a circadian clock regulates the light responses of dark-adapted fish cone horizontal cells. Goldfish were maintained on a 12-hr light/12-hr dark cycle. At different times of the day or night, retinas were superfused in darkness for 90 min ("prolonged darkness"), following which horizontal cells were impaled without the aid of any light flashes. In some of the experiments, fish were kept in constant darkness for 3-48 hr prior to surgery. After prolonged darkness during the night, but not during the day, the light responses of L-type cone horizontal cells resembled those of rod horizontal cells with respect to threshold, waveform, intensity-response functions, and spectral sensitivity. Following light sensitization during the night and day, the light responses of rod and cone horizontal cells were clearly different with respect to threshold, waveform, intensity-response functions, and spectral sensitivity. Under conditions of constant darkness for two full light/dark cycles, average responses of cone horizontal cells to a bright light stimulus during the subjective day were greater than during the subjective night. Prior reversal of the light/dark cycle reversed the 24-hr rhythm of cone horizontal cell responses to bright lights. In addition, following one full cycle of constant darkness, average cone horizontal cell spectral sensitivity during the subjective night closely matched that of rod horizontal cells, whereas average cone horizontal cell spectral sensitivity during the subjective day was similar to that of red (625 nm) cones. These results indicate that the effects of dark adaptation depend on the time of day and are regulated by a circadian clock so that cone input to cone horizontal cells predominates in the day and rod input predominates in the night.

Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain.

The hypothesis that age-associated impairment of cognitive and motor functions is due to oxidative molecular damage was tested in the mouse. In a blind study, senescent mice (aged 22 months) were subjected to a battery of behavioral tests for motor and cognitive functions and subsequently assayed for oxidative molecular damage as assessed by protein carbonyl concentration in different regions of the brain. The degree of age-related impairment in each mouse was determined by comparison to a reference group of young mice (aged 4 months) tested concurrently on the behavioral battery. The age-related loss of ability to perform a spatial swim maze task was found to be positively correlated with oxidative molecular damage in the cerebral cortex, whereas age-related loss of motor coordination was correlated with oxidative molecular damage within the cerebellum. These results support the view that oxidative stress is a causal factor in brain senescence. Furthermore, the findings suggest that age-related declines of cognitive and motor performance progress independently, and involve oxidative molecular damage within different regions of the brain.

Sequence similarity analysis of Escherichia coli proteins: functional and evolutionary implications.

A computer analysis of 2328 protein sequences comprising about 60% of the Escherichia coli gene products was performed using methods for database screening with individual sequences and alignment blocks. A high fraction of E. coli proteins--86%--shows significant sequence similarity to other proteins in current databases; about 70% show conservation at least at the level of distantly related bacteria, and about 40% contain ancient conserved regions (ACRs) shared with eukaryotic or Archaeal proteins. For > 90% of the E. coli proteins, either functional information or sequence similarity, or both, are available. Forty-six percent of the E. coli proteins belong to 299 clusters of paralogs (intraspecies homologs) defined on the basis of pairwise similarity. Another 10% could be included in 70 superclusters using motif detection methods. The majority of the clusters contain only two to four members. In contrast, nearly 25% of all E. coli proteins belong to the four largest superclusters--namely, permeases, ATPases and GTPases with the conserved "Walker-type" motif, helix-turn-helix regulatory proteins, and NAD(FAD)-binding proteins. We conclude that bacterial protein sequences generally are highly conserved in evolution, with about 50% of all ACR-containing protein families represented among the E. coli gene products. With the current sequence databases and methods of their screening, computer analysis yields useful information on the functions and evolutionary relationships of the vast majority of genes in a bacterial genome. Sequence similarity with E. coli proteins allows the prediction of functions for a number of important eukaryotic genes, including several whose products are implicated in human diseases.

Persistent infection of rhesus macaques with T-cell-line-tropic and macrophage-tropic clones of simian/human immunodeficiency viruses (SHIV).

To elucidate the functions of human immunodeficiency virus type 1 (HIV-1) genes in a nonhuman primate model, we have constructed infectious recombinant viruses (chimeras) between the pathogenic molecular clone of simian immunodeficiency virus (SIV) SIVmac239 and molecular clones of HIV-1 that differ in phenotypic properties controlled by the env gene. HIV-1SF33 is a T-cell-line-tropic virus which induces syncytia, and HIV-1SF162 is a macrophage-tropic virus that does not induce syncytia. A DNA fragment encoding tat, rev, and env (gp160) of SIVmac239 has been replaced with the counterpart genetic region of HIV-1SF33 and HIV-1SF162 to derive chimeric recombinant simian/human immunodeficiency virus (SHIV) strains SHIVSF33 and SHIVSF162, respectively. In the acute infection stage, macaques inoculated with SHIVSF33 had levels of viremia similar to macaques infected with SIVmac239, whereas virus loads were 1/10th to 1/100th those in macaques infected with SHIVSF162. Of note is the relatively small amount of virus detected in lymph nodes of SHIVSF162-infected macaques. In the chronic infection stage, macaques infected with SHIVSF33 also showed higher virus loads than macaques infected with SHIVSF162. Virus persists for over 1 year, as demonstrated by PCR for amplification of viral DNA in all animals and by virus isolation in some animals. Antiviral antibodies, including antibodies to the HIV-1 env glycoprotein (gp160), were detected; titers of antiviral antibodies were higher in macaques infected with SHIVSF33 than in macaques infected with SHIVSF162. Although virus has persisted for over 1 year after inoculation, these animals have remained healthy with no signs of immunodeficiency. These findings demonstrate the utility of the SHIV/macaque model for analyzing HIV-1 env gene functions and for evaluating vaccines based on HIV-1 env antigens.

Life-span, T-cell responses, and incidence of lymphomas in congenic mice.

Survival, T-cell functions, and postmortem histopathology were studied in H-2 congenic strains of mice bearing H-2b, H-2k, and H-2d haplotypes. Males lived longer than females in all homozygous and heterozygous combinations except for H-2d homozygotes, which showed no differences between males and females. Association of heterozygosity with longer survival was observed only with H-2b/H-2b and H-2b/H-2d mice. Analysis using classification and regression trees (CART) showed that both males and females of H-2b homozygous and H-2k/H-2b mice had the shortest life-span of the strains studied. In histopathological analyses, lymphomas were noted to be more frequent in females, while hemangiosarcomas and hepatomas were more frequent in males. Lymphomas appeared earlier than hepatomas or hemangiosarcomas. The incidence of lymphomas was associated with the H-2 haplotype--e.g., H-2b homozygous mice had more lymphomas than did mice of the H-2d haplotype. More vigorous T-cell function was maintained with age (27 months) in H-2d, H-2b/H-2d, and H-2d/H-2k mice as compared with H-2b, H-2k, and H-2b/H-2k mice, which showed a decline of T-cell responses with age.

VAR models and methods for monetary and health economics

Negli ultimi anni i modelli VAR sono diventati il principale strumento econometrico per verificare se può esistere una relazione tra le variabili e per valutare gli effetti delle politiche economiche. Questa tesi studia tre diversi approcci di identificazione a partire dai modelli VAR in forma ridotta (tra cui periodo di campionamento, set di variabili endogene, termini deterministici). Usiamo nel caso di modelli VAR il test di Causalità di Granger per verificare la capacità di una variabile di prevedere un altra, nel caso di cointegrazione usiamo modelli VECM per stimare congiuntamente i coefficienti di lungo periodo ed i coefficienti di breve periodo e nel caso di piccoli set di dati e problemi di overfitting usiamo modelli VAR bayesiani con funzioni di risposta di impulso e decomposizione della varianza, per analizzare l'effetto degli shock sulle variabili macroeconomiche. A tale scopo, gli studi empirici sono effettuati utilizzando serie storiche di dati specifici e formulando diverse ipotesi. Sono stati utilizzati tre modelli VAR: in primis per studiare le decisioni di politica monetaria e discriminare tra le varie teorie post-keynesiane sulla politica monetaria ed in particolare sulla cosiddetta "regola di solvibilità" (Brancaccio e Fontana 2013, 2015) e regola del GDP nominale in Area Euro (paper 1); secondo per estendere l'evidenza dell'ipotesi di endogeneità della moneta valutando gli effetti della cartolarizzazione delle banche sul meccanismo di trasmissione della politica monetaria negli Stati Uniti (paper 2); terzo per valutare gli effetti dell'invecchiamento sulla spesa sanitaria in Italia in termini di implicazioni di politiche economiche (paper 3). La tesi è introdotta dal capitolo 1 in cui si delinea il contesto, la motivazione e lo scopo di questa ricerca, mentre la struttura e la sintesi, così come i principali risultati, sono descritti nei rimanenti capitoli. Nel capitolo 2 sono esaminati, utilizzando un modello VAR in differenze prime con dati trimestrali della zona Euro, se le decisioni in materia di politica monetaria possono essere interpretate in termini di una "regola di politica monetaria", con specifico riferimento alla cosiddetta "nominal GDP targeting rule" (McCallum 1988 Hall e Mankiw 1994; Woodford 2012). I risultati evidenziano una relazione causale che va dallo scostamento tra i tassi di crescita del PIL nominale e PIL obiettivo alle variazioni dei tassi di interesse di mercato a tre mesi. La stessa analisi non sembra confermare l'esistenza di una relazione causale significativa inversa dalla variazione del tasso di interesse di mercato allo scostamento tra i tassi di crescita del PIL nominale e PIL obiettivo. Risultati simili sono stati ottenuti sostituendo il tasso di interesse di mercato con il tasso di interesse di rifinanziamento della BCE. Questa conferma di una sola delle due direzioni di causalità non supporta un'interpretazione della politica monetaria basata sulla nominal GDP targeting rule e dà adito a dubbi in termini più generali per l'applicabilità della regola di Taylor e tutte le regole convenzionali della politica monetaria per il caso in questione. I risultati appaiono invece essere più in linea con altri approcci possibili, come quelli basati su alcune analisi post-keynesiane e marxiste della teoria monetaria e più in particolare la cosiddetta "regola di solvibilità" (Brancaccio e Fontana 2013, 2015). Queste linee di ricerca contestano la tesi semplicistica che l'ambito della politica monetaria consiste nella stabilizzazione dell'inflazione, del PIL reale o del reddito nominale intorno ad un livello "naturale equilibrio". Piuttosto, essi suggeriscono che le banche centrali in realtà seguono uno scopo più complesso, che è il regolamento del sistema finanziario, con particolare riferimento ai rapporti tra creditori e debitori e la relativa solvibilità delle unità economiche. Il capitolo 3 analizza l’offerta di prestiti considerando l’endogeneità della moneta derivante dall'attività di cartolarizzazione delle banche nel corso del periodo 1999-2012. Anche se gran parte della letteratura indaga sulla endogenità dell'offerta di moneta, questo approccio è stato adottato raramente per indagare la endogeneità della moneta nel breve e lungo termine con uno studio degli Stati Uniti durante le due crisi principali: scoppio della bolla dot-com (1998-1999) e la crisi dei mutui sub-prime (2008-2009). In particolare, si considerano gli effetti dell'innovazione finanziaria sul canale dei prestiti utilizzando la serie dei prestiti aggiustata per la cartolarizzazione al fine di verificare se il sistema bancario americano è stimolato a ricercare fonti più economiche di finanziamento come la cartolarizzazione, in caso di politica monetaria restrittiva (Altunbas et al., 2009). L'analisi si basa sull'aggregato monetario M1 ed M2. Utilizzando modelli VECM, esaminiamo una relazione di lungo periodo tra le variabili in livello e valutiamo gli effetti dell’offerta di moneta analizzando quanto la politica monetaria influisce sulle deviazioni di breve periodo dalla relazione di lungo periodo. I risultati mostrano che la cartolarizzazione influenza l'impatto dei prestiti su M1 ed M2. Ciò implica che l'offerta di moneta è endogena confermando l'approccio strutturalista ed evidenziando che gli agenti economici sono motivati ad aumentare la cartolarizzazione per una preventiva copertura contro shock di politica monetaria. Il capitolo 4 indaga il rapporto tra spesa pro capite sanitaria, PIL pro capite, indice di vecchiaia ed aspettativa di vita in Italia nel periodo 1990-2013, utilizzando i modelli VAR bayesiani e dati annuali estratti dalla banca dati OCSE ed Eurostat. Le funzioni di risposta d'impulso e la scomposizione della varianza evidenziano una relazione positiva: dal PIL pro capite alla spesa pro capite sanitaria, dalla speranza di vita alla spesa sanitaria, e dall'indice di invecchiamento alla spesa pro capite sanitaria. L'impatto dell'invecchiamento sulla spesa sanitaria è più significativo rispetto alle altre variabili. Nel complesso, i nostri risultati suggeriscono che le disabilità strettamente connesse all'invecchiamento possono essere il driver principale della spesa sanitaria nel breve-medio periodo. Una buona gestione della sanità contribuisce a migliorare il benessere del paziente, senza aumentare la spesa sanitaria totale. Tuttavia, le politiche che migliorano lo stato di salute delle persone anziane potrebbe essere necessarie per una più bassa domanda pro capite dei servizi sanitari e sociali.

Nonequilibrium spin glass dynamics with Janus

The out of equilibrium evolution for an Edwards‐Anderson spin glass is followed for a tenth of a second, a long enough time to let us make safe predictions about the behaviour at experimental scales. This work has been made possible by Janus, an FPGA based special purpose computer. We have thoroughly studied the spin glass correlation functions and the growth of the coherence length for L = 80 lattices in 3D. Our main conclusion is that these spin glasses follow noncoarsening dynamics, at least up to the experimentally relevant time scales.

On the uniform approximation of Cauchy continuous functions

In the context of real-valued functions defined on metric spaces, it is known that the locally Lipschitz functions are uniformly dense in the continuous functions and that the Lipschitz in the small functions - the locally Lipschitz functions where both the local Lipschitz constant and the size of the neighborhood can be chosen independent of the point - are uniformly dense in the uniformly continuous functions. Between these two basic classes of continuous functions lies the class of Cauchy continuous functions, i.e., the functions that map Cauchy sequences in the domain to Cauchy sequences in the target space. Here, we exhibit an intermediate class of Cauchy continuous locally Lipschitz functions that is uniformly dense in the real-valued Cauchy continuous functions. In fact, our result is valid when our target space is an arbitrary Banach space.

Comment Letter: The NYSE and the End of the Structural Separation between Regulatory and Commercial Interests of the Exchange

The NYSE transformed into a for profit entity in 2006. As part of the approval process, the NYSE agreed to structurally separate the regulatory function from the business function. In doing so, the NYSE created NYSE Regulation, a non-profit with an independent board, to handle most regulatory matters. During the comment period, a spirited debate arose over the ability of a for profit company to carry out a regulatory mission. Some suggested that the regulatory function was incompatible with a "for profit" motive and that NYSE Regulation should be spun off. Others accepted the proposed structure but called for additional changes designed to reduce the possible influence of the public holding company over the regulatory function. In the end, the SEC approved the structure but with a number of prophylactic safeguards including the requirement that NYSE Regulation have a board consisting of all independent directors (save the CEO) and that directors from the for profit holding company could not make up a majority of the board. More recently, however, the NYSE has proposed to end the structural separation of the two functions and instead put in place a functional separation. The proposal would result in the termination of the delegation agreement between the Exchange and NYSE Regulation and the creation of both a Regulatory Oversight Committee of the Board of Directors of the Exchange and the creation of a Chief Regulatory Officer. This letter examines the history of the separation of the two functions and critiques the NYSE's proposal.

False anglicisms in the Spanish language of fashion and beauty

Many works have already dealt with anglicisms in Spanish, especially in science and information technologies. However, despite the high and growing number of English terms incorporated daily by the language of fashion, it has received comparative less attention in lexicographic and terminological studies than that of other areas, such as science or business. For several reasons, which include prestige or peer pressure, Spanish has not only adopted English words with new meanings and usage, but also contains other forms based on English patterns which users seem to consider more accurate or expressive. This paper concentrates on false anglicisms as indicators of some of the special relationships and influences between languages arising from the pervasive presence of English. We shall look at the Spanish language of fashion, which, in addition to genuine anglicisms, has for some time been using English words with different meanings, or even created items of its own (or imported them from other languages) with the appearance of English words. These false anglicisms, which have proven extremely popular in receiving languages (not only in Spanish) have frequently been disseminated by youth magazines and the new digital media, both in general spheres and in fashion-specific contexts.

Analyzing the commercial activities of a street network by ranking their nodes: a case study in Murcia, Spain

Urban researchers and planners are often interested in understanding how economic activities are distributed in urban regions, what forces influence their special pattern and how urban structure and functions are mutually dependent. In this paper, we want to show how an algorithm for ranking the nodes in a network can be used to understand and visualize certain commercial activities of a city. The first part of the method consists of collecting real information about different types of commercial activities at each location in the urban network of the city of Murcia, Spain. Four clearly differentiated commercial activities are studied, such as restaurants and bars, shops, banks and supermarkets or department stores, but obviously we can study other. The information collected is then quantified by means of a data matrix, which is used as the basis for the implementation of a PageRank algorithm which produces a ranking of all the nodes in the network, according to their significance within it. Finally, we visualize the resulting classification using a colour scale that helps us to represent the business network.

A Quantile-Based Probabilistic Mean Value Theorem

For non-negative random variables with finite means we introduce an analogous of the equilibrium residual-lifetime distribution based on the quantile function. This allows us to construct new distributions with support (0, 1), and to obtain a new quantile-based version of the probabilistic generalization of Taylor's theorem. Similarly, for pairs of stochastically ordered random variables we come to a new quantile-based form of the probabilistic mean value theorem. The latter involves a distribution that generalizes the Lorenz curve. We investigate the special case of proportional quantile functions and apply the given results to various models based on classes of distributions and measures of risk theory. Motivated by some stochastic comparisons, we also introduce the “expected reversed proportional shortfall order”, and a new characterization of random lifetimes involving the reversed hazard rate function.