Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson’s disease in rats

A recombinant adeno-associated virus (rAAV) vector capable of infecting cells and expressing rat glial cell line-derived neurotrophic factor (rGDNF), a putative central nervous system dopaminergic survival factor, under the control of a potent cytomegalovirus (CMV) immediate/early promoter (AAV-MD-rGDNF) was constructed. Two experiments were performed to evaluate the time course of expression of rAAV-mediated GDNF protein expression and to test the vector in an animal model of Parkinson’s disease. To evaluate the ability of rAAV-rGDNF to protect nigral dopaminergic neurons in the progressive Sauer and Oertel 6-hydroxydopamine (6-OHDA) lesion model, rats received perinigral injections of either rAAV-rGDNF virus or rAAV-lacZ control virus 3 weeks prior to a striatal 6-OHDA lesion and were sacrificed 4 weeks after 6-OHDA. Cell counts of back-labeled fluorogold-positive neurons in the substantia nigra revealed that rAAV-MD-rGDNF protected a significant number of cells when compared with cell counts of rAAV-CMV-lacZ-injected rats (94% vs. 51%, respectively). In close agreement, 85% of tyrosine hydroxylase-positive cells remained in the nigral rAAV-MD-rGDNF group vs. only 49% in the lacZ group. A separate group of rats were given identical perinigral virus injections and were sacrificed at 3 and 10 weeks after surgery. Nigral GDNF protein expression remained relatively stable over the 10 weeks investigated. These data indicate that the use of rAAV, a noncytopathic viral vector, can promote delivery of functional levels of GDNF in a degenerative model of Parkinson’s disease.

Protein Changes in Response to Progressive Water Deficit in Maize1 : Quantitative Variation and Polypeptide Identification

Three-week-old plants of two unrelated lines of maize (Zea mays L.) and their hybrid were submitted to progressive water stress for 10 d. Changes induced in leaf proteins were studied by two-dimensional electrophoresis and quantitatively analyzed using image analysis. Seventy-eight proteins out of a total of 413 showed a significant quantitative variation (increase or decrease), with 38 of them exhibiting a different expression in the two genotypes. Eleven proteins that increased by a factor of 1.3 to 5 in stressed plants and 8 proteins detected only in stressed plants were selected for internal amino acid microsequencing, and by similarity search 16 were found to be closely related to previously reported proteins. In addition to proteins already known to be involved in the response to water stress (e.g. RAB17 [Responsive to ABA]), several enzymes involved in basic metabolic cellular pathways such as glycolysis and the Krebs cycle (e.g. enolase and triose phosphate isomerase) were identified, as well as several others, including caffeate O-methyltransferase, the induction of which could be related to lignification.

Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress

Stress early in postnatal life may result in long-term memory deficits and selective loss of hippocampal neurons. The mechanisms involved are poorly understood, but they may involve molecules and processes in the immature limbic system that are activated by stressful challenges. We report that administration of corticotropin-releasing hormone (CRH), the key limbic stress modulator, to the brains of immature rats reproduced the consequences of early-life stress, reducing memory functions throughout life. These deficits were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation of hippocampal CRH expression. Importantly, they did not require the presence of stress levels of glucocorticoids. These findings indicate a critical role for CRH in the mechanisms underlying the long-term effects of early-life stress on hippocampal integrity and function.

The treatment of chronic progressive multiple sclerosis with cladribine.

A 2-year, placebo-controlled, double-blind, crossover study was started in 1992 to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic progressive multiple sclerosis. In the first year patients were given cladribine 0.10 mg/kg per day for 7 days as four monthly courses for a total of 2.8 mg/kg or placebo. During the second year patients treated with placebo during the first year were given i.v. infusions of 0.10 mg, 0.05 mg, and 0.05 mg of cladribine per kg of body weight per day for 7 consecutive days in three successive monthly courses, for a total dose of 1.4 mg/kg. Patients who had been treated previously with cladribine were crossed over to placebo. Analysis of the results revealed a favorable influence on the neurological performance scores, both in the Kurtze extended disability status and the Scripps neurological rating scale, and on MRI findings in patients treated with cladribine. In the first year the most striking finding was that while clinical deterioration continued in the placebo-treated patients, the condition of patients who received cladribine stabilized or even improved slightly. Toxicity and therapeutic response were dose-related.

An n-allele model for progressive amplification in the FMR1 locus.

An n-allele model is developed for the FMR1 locus, which causes the fragile X syndrome, where n is the number of triplet repeats in the first exon. Frequencies in the general population and in index families are used to generate an n to n + delta transition matrix that predicts specific risks in satisfactory agreement with observation. However, until sequencing distinguishes between stable and unstable alleles with the same value of n, it is premature to infer whether allelic frequencies at the FMR1 locus are at equilibrium or, as some have suggested, are evolving toward higher frequencies of the pathogenic allele.

Private (Brown) Eyes: Ethnicity, Genre and Gender in Crime Fiction in the Gloria Damasco novels and the Chicanos Comic Series

The representation of women in crime fiction has traditionally been a complicated one. Consistently forced into secondary characters (assistants, girlfriends, or damsels in distress) the most active role a female character could aspire to was that of the femme fatale, a pit of perdition, an unwelcome distraction for a man looking for truth and justice. This traditional approach to the genre has been challenged in the last decades by women acting as detectives, trusted with solving their cases in a hostile male world. Similarly, the traditional white male protagonist has been contested by fictions where ethnic minorities are not just consigned to the criminal world, but where detectives are members of ethnic groups, and can use their knowledge of the community to solve the case. This essay focuses on the crossroads of ethnic and women’s detective fiction, specifically the Gloria Damasco series by Chicana writer Lucha Corpi and the graphic novel Chicanos (Trillo and Risso, 1996). Both protagonists (Gloria Damasco, a Chicana clairvoyant detective, and “poor, ugly, and a detective” Alejandrina Yolanda Jalisco) must face both the dangers of investigating criminal cases and discrimination in their professional surroundings due to their gender and ethnicity. By contrasting these texts, the essay elucidates the importance of specific cultural products, their connection to (and defiance of) canonical forms of the genre, and their rejection of generic and gender expectations.

The Lie That Tells the Truth: Creating Truth in Fiction and the Novel Delivering Hope

What makes fiction believable is the truth behind the words. This Capstone Project explores the ways in which authors put the truth on the page while simultaneously fabricating stories. The Reflective Paper examines writing techniques used to make the reader trust the story and the storyteller. The Creative Capstone is the result of applying these craft skills to Delivering Hope, a novel in progress about a critically ill baby bringing a dysfunctional family back together. The author relies on her personal experience of high- risk pregnancy and preterm birth to help create truth in her fiction.

Is Progressive Discipline Effective?

Progressive discipline has been utilized as a management tool to improve employee behavior since the 1930s. Research throughout the years has failed to determine if progressive discipline is actually successful in modifying employee behavior. This capstone addresses this issue and includes a review of literature on the subject of progressive discipline in the workplace, and a survey of human resources professionals determining the presence and success of progressive discipline in several organizations in Colorado. The results indicate that employee behavior modification may not be as strongly correlated to the type of discipline used, but that other factors related to disciplinary practices have more influence on employee behavior modification.

Nostalgic representation of reality in television fiction: an empirical study based on the analysis of the Spanish television series Cuéntame cómo pasó

The Spanish transition from dictatorship to democracy is often described as an example of negotiation or agreement between the elites (Sánchez Cuenca and Aguilar, 2009: 433). Journalistic and political elites, aware of their important historical role, agreed a consensus on certain issues (democracy, constitution, amnesty) or characters (King Juan Carlos I), in order to ensure the stability of the democratic process (Zugasti, 2007, 2008). Television, which articulates the discourse of the masses, has been one of the basic means used to illustrate the development. Among the highlights of recent major audiovisual content, Cuéntame cómo pasó (2001-present) -a TV-series designed to explain changes with a nostalgic tone in Spanish society since 1968 until today- stands out. By choosing a random sample of episodes for this research we propose to verify the validity of the representation of the political process which contextualizes the series. By analyzing many elements, such as the opinions of the main characters, their personal, political and geographical situations, we try to show the construction of a focal point that sanctifies the official version. We also stress the pacifying and nostalgic tone, which constructs stereotypes and taboos about the process and which characterizes this series as a symbolic culmination of the democratization undertaken by the elites.

Conformational changes of dissolved humic and fulvic superstructures with progressive iron complexation

Conformational changes of a humic acid (HA) and a fulvic acid (FA) induced by iron complexation were followed by high-performance size exclusion chromatography (HPSEC) with both UV–vis and refractive index (RI) detectors. Molecular size distribution was reduced for HA and increased for FA with progressive iron complexation. Since interactions of Fe with humic components are electrostatic, it is likely that the triple-charged Fe ions formed stronger complexes with the more acidic hydrophilic and hydrated FA than with the less acidic and more hydrophobic HA. The large content of ionized carboxyl groups in FA, thus favored the formation of intra- or intermolecular bridges between the negatively charged fulvic acid molecules, and led to more compact and larger size network than for HA. Conversely, iron complexation with HA disrupted the humic conformational arrangements stabilized by only weak hydrophobic bonds into smaller-size aggregates of greater conformational stability due to formation of strong metal complexes. These results confirmed that humic molecules in solution were organized in supramolecular associations of relatively small molecules loosely bound together by dispersive interactions and hydrogen bonds, and they specifically responded to chemical changes brought about by metal additions. The present study revealed the molecular changes occurring in superstructures of natural organic matter when in metal complexes and contributed to understand and predict the environmental behavior in waters and soil of metal complexes with natural organic matter.

Ultrasonic and X-ray computed tomography characterization of progressive fracture damage in low-porous carbonate rocks

This paper studies the fracturing process in low-porous rocks during uniaxial compressive tests considering the original defects and the new mechanical cracks in the material. For this purpose, five different kinds of rocks have been chosen with carbonate mineralogy and low porosity (lower than 2%). The characterization of the fracture damage is carried out using three different techniques: ultrasounds, mercury porosimetry and X-ray computed tomography. The proposed methodology allows quantifying the evolution of the porous system as well as studying the location of new cracks in the rock samples. Intercrystalline porosity (the smallest pores with pore radius < 1 μm) shows a limited development during loading, disappearing rapidly from the porosimetry curves and it is directly related to the initial plastic behaviour in the stress–strain patterns. However, the biggest pores (corresponding to the cracks) suffer a continuous enlargement until the unstable propagation of fractures. The measured crack initiation stress varies between 0.25 σp and 0.50 σp for marbles and between 0.50 σp and 0.85 σp for micrite limestone. The unstable propagation of cracks is assumed to occur very close to the peak strength. Crack propagation through the sample is completely independent of pre-existing defects (porous bands, stylolites, fractures and veins). The ultrasonic response in the time-domain is less sensitive to the fracture damage than the frequency-domain. P-wave velocity increases during loading test until the beginning of the unstable crack propagation. This increase is higher for marbles (between 15% and 30% from initial vp values) and lower for micrite limestones (between 5% and 10%). When the mechanical cracks propagate unstably, the velocity stops to increase and decreases only when rock damage is very high. Frequency analysis of the ultrasonic signals shows clear changes during the loading process. The spectrum of treated waveforms shows two main frequency peaks centred at low (~ 20 kHz) and high (~ 35 kHz) values. When new fractures appear and grow the amplitude of the high-frequency peak decreases, while that of the low-frequency peak increases. Besides, a slight frequency shift is observed towards higher frequencies.

Fleshing Out and Losing Flesh: The Decomposing Corpse as Narrative Object in American Hardboiled Detective Fiction

This dissertation examines the corpse as an object in and of American hardboiled detective fiction written between 1920 and 1950. I deploy several theoretical frames, including narratology, body-as-text theory, object relations theory, and genre theory, in order to demonstrate the significance of objects, symbols, and things primarily in the clever and crafty work of Dashiell Hammett (1894-1961) and Raymond Chandler (1888-1959), but also touching on the writings of their lesser known accomplices. I construct a literary genealogy of American hardboiled detective fiction originating in the writings of Edgar Allan Poe, compare the contributions of classic or Golden Age detective fiction in England, and describe the socio-economic contexts, particularly the predominance of the “pulps,” that gave birth to the realism of the Hardboiled School. Taking seriously Chandler’s obsession with the art of murder, I engage with how authors pre-empt their readers’ knowledge of the tricks of the trade and manipulate their expectations, as well as discuss the characteristics and effect of the inimitable hardboiled style, its sharpshooting language and deadpan humour. Critical scholarship has rarely addressed the body and figure of the corpse, preferring to focus instead on the machinations of the femme fatale, the performance of masculinity, or the prevalence of violence. I cast new light on the world of hardboiled detective fiction by dissecting the corpse as the object that both motivates and de-composes (or rots away from) the narrative that makes it signify. I treat the corpse as an inanimate object, indifferent to representation, that destabilizes the integrity and self-possession, as well as the ratiocination, of the detective who authors the narrative of how the corpse came to be. The corpse is all deceptive and dangerous surface rather than the container of hidden depths of life and meaning that the detective hopes to uncover and reconstruct. I conclude with a chapter that is both critical denouement and creative writing experiment to reveal the self-reflexive (and at times metafictional) dimensions of hardboiled fiction. My dissertation, too, in the manner of hardboiled fiction, hopes to incriminate my readers as much as enlighten them.

The future imagined: Exploring fiction as a means of reflecting on today’s Grand Societal Challenges and tomorrow’s options

European science policy (so-called Horizon 2020) is guided by Grand Societal Challenges (GSCs) with the explicit aim of shaping the future. In this paper we propose an innovative approach to the analysis and critique of Europe’s GSCs. The aim is to explore how speculative and creative fiction offer ways of embodying, telling, imagining, and symbolising ‘futures’, that can provide alternative frames and understandings to enrich the grand challenges of the 21st century, and the related rationale and agendas for ERA and H2020. We identify six ways in which filmic and literary representations can be considered creative foresight methods (i.e. through: creative input, detail, warning, reflection, critique, involvement) and can provide alternative perspectives on these central challenges, and warning signals for the science policy they inform. The inquiry involved the selection of 64 novels and movies engaging with notions of the future, produced over the last 150 years. Content analysis based on a standardised matrix of major themes and sub-domains, allows to build a hierarchy of themes and to identify major patterns of long-lasting concerns about humanity’s future. The study highlights how fiction sees oppression, inequality and a range of ethical issues linked to human and nature’s dignity as central to, and inseparable from innovation, technology and science. It concludes identifying warning signals in four major domains, arguing that these signals are compelling, and ought to be heard, not least because elements of such future have already escaped the imaginary world to make part of today’s experience. It identifies areas poorly defined or absent from Europe's science agenda, and argues for the need to increase research into human, social, political and cultural processes involved in techno-science endeavours.