Specific therapy regimes could lead to long-term immunological control of HIV

We use mathematical models to study the relationship between HIV and the immune system during the natural course of infection and in the context of different antiviral treatment regimes. The models suggest that an efficient cytotoxic T lymphocyte (CTL) memory response is required to control the virus. We define CTL memory as long-term persistence of CTL precursors in the absence of antigen. Infection and depletion of CD4+ T helper cells interfere with CTL memory generation, resulting in persistent viral replication and disease progression. We find that antiviral drug therapy during primary infection can enable the development of CTL memory. In chronically infected patients, specific treatment schedules, either including deliberate drug holidays or antigenic boosts of the immune system, can lead to a re-establishment of CTL memory. Whether such treatment regimes would lead to long-term immunologic control deserves investigation under carefully controlled conditions.

Fibroblast Growth Factor (FGF) Soluble Receptor 1 Acts as a Natural Inhibitor of FGF2 Neurotrophic Activity during Retinal Degeneration

Fibroblast growth factors (FGF) 1 and 2 and their tyrosine kinase receptor (FGFR) are present throughout the adult retina. FGFs are potential mitogens, but adult retinal cells are maintained in a nonproliferative state unless the retina is damaged. Our work aims to find a modulator of FGF signaling in normal and pathological retina. We identified and sequenced a truncated FGFR1 form from rat retina generated by the use of selective polyadenylation sites. This 70-kDa form of soluble extracellular FGFR1 (SR1) was distributed mainly localized in the inner nuclear layer of the retina, whereas the full-length FGFR1 form was detected in the retinal Muller glial cells. FGF2 and FGFR1 mRNA levels greatly increased in light-induced retinal degeneration. FGFR1 was detected in the radial fibers of activated retinal Muller glial cells. In contrast, SR1 mRNA synthesis followed a biphasic pattern of down- and up-regulation, and anti-SR1 staining was intense in retinal pigmented epithelial cells. The synthesis of SR1 and FGFR1 specifically and independently regulated in normal and degenerating retina suggests that changes in the proportion of various FGFR forms may control the bioavailability of FGFs and thus their potential as neurotrophic factors. This was demonstrated in vivo during retinal degeneration when recombinant SR1 inhibited the neurotrophic activity of exogenous FGF2 and increased damaging effects of light by inhibiting endogenous FGF. This study highlights the significance of the generation of SR1 in normal and pathological conditions.

A modifier screen in the eye reveals control genes for Krüppel activity in the Drosophila embryo

Irregular facets (If) is a dominant mutation of Drosophila that results in small eyes with fused ommatidia. Previous results showed that the gene Krüppel (Kr), which is best known for its early segmentation function, is expressed ectopically in If mutant eye discs. However, it was not known whether ectopic Kr activity is either the cause or the result of the If mutation. Here, we show that If is a gain-of-function allele of Kr. We then used the If mutation in a genetic screen to identify dominant enhancers and suppressors of Kr activity on the third chromosome. Of 30 identified Kr-interacting loci, two were cloned, and we examined whether they also represent components of a natural Kr-dependent developmental pathway of the embryo. We show that the two genes, eyelid (eld) and extramacrochaetae (emc), which encode a Bright family-type DNA binding protein and a helix-loop-helix factor, respectively, are necessary to achieve the singling-out of a unique Kr-expressing cell during the development of the Malpighian tubules, the excretory organs of the fly. The results indicate that the Kr gain-of-function mutation If provides a tool to identify genes that are active during eye development and that a number of them function also in the control of Kr-dependent developmental processes.

Disfacilitation and active inhibition in the neocortex during the natural sleep-wake cycle: An intracellular study

Earlier extracellular recordings during natural sleep have shown that, during slow-wave sleep (SWS), neocortical neurons display long-lasting periods of silence, whereas they are tonically active and discharge at higher rates during waking and sleep with rapid eye movements (REMs). We analyzed the nature of long-lasting periods of neuronal silence in SWS and the changes in firing rates related to ocular movements during REM sleep and waking using intracellular recordings from electrophysiologically identified neocortical neurons in nonanesthetized and nonparalyzed cats. We found that the silent periods during SWS are associated with neuronal hyperpolarizations, which are due to a mixture of K+ currents and disfacilitation processes. Conventional fast-spiking neurons (presumably local inhibitory interneurons) increased their firing rates during REMs and eye movements in waking. During REMs, the firing rates of regular-spiking neurons from associative areas decreased and intracellular traces revealed numerous, short-lasting, low-amplitude inhibitory postsynaptic potentials (IPSPs), that were reversed after intracellular chloride infusion. In awake cats, regular-spiking neurons could either increase or decrease their firing rates during eye movements. The short-lasting IPSPs associated with eye movements were still present in waking; they preceded the spikes and affected their timing. We propose that there are two different forms of firing rate control: disfacilitation induces long-lasting periods of silence that occur spontaneously during SWS, whereas active inhibition, consisting of low-amplitude, short-lasting IPSPs, is prevalent during REMs and precisely controls the timing of action potentials in waking.

Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity

Certain HLA-B antigens have been associated with lack of progression to AIDS. HLA-B alleles can be divided into two mutually exclusive groups based on the expression of the molecular epitopes HLA-Bw4 and HLA-Bw6. Notably, in addition to its role in presenting viral peptides for immune recognition, the HLA-Bw4, but not HLA-Bw6, motif functions as a ligand for a natural killer cell inhibitory receptor (KIR). Here, we show that profound suppression of HIV-1 viremia is significantly associated with homozygosity for HLA-B alleles that share the HLA-Bw4 epitope. Furthermore, homozygosity for HLA-Bw4 alleles was also significantly associated with the ability to remain AIDS free and to maintain a normal CD4 T cell count in a second cohort of HIV-1-infected individuals with well defined dates of seroconversion. This association was independent of the presence of a mutation in CC chemokine receptor 5 (CCR5) associated with resistance to HIV-1 infection, and it was independent of the presence of HLA alleles that could potentially confound the results. We conclude that homozygosity for HLA-Bw4-bearing B alleles is associated with a significant advantage and that the HLA-Bw4 motif is important in AIDS pathogenesis.

Commitment to natural killer cells requires the helix–loop–helix inhibitor Id2

We have previously described how T and natural killer (NK) lineage commitment proceeds from common T/NK progenitors (p-T/NK) in the murine fetal thymus (FT), with the use of a clonal assay system capable of discriminating p-T/NK from unipotent T or NK lineage-committed progenitors (p-T and p-NK, respectively). The molecular mechanisms controlling the commitment processes, however, are yet to be defined. In this study, we investigated the progenitor activity of FT cells from Id2−/− mice that exhibit defective NK cell development. In the Id2−/− FT, NK cells were greatly reduced, and a cell population that exclusively contains p-NK in the wild-type thymus was completely missing. Id2−/− FT progenitors were unable to differentiate into NK cells in IL-2-supplemented-FT organ culture. Single progenitor analysis demonstrated that all Id2−/− fetal thymic progenitors are destined for the T cell lineage, whereas progenitors for T/NK, T, and NK cell lineages were found in the control. Interestingly, the total progenitor number was similar between Id2−/− and Id2+/+ embryos analyzed. Expression of Id2 was correlated with p-NK activity. Our results suggest that Id2 is indispensable in thymic NK cell development, where it most probably restricts bipotent T/NK progenitors to the NK cell lineage.

Piperonylic Acid, a Selective, Mechanism-Based Inactivator of the trans-Cinnamate 4-Hydroxylase: A New Tool to Control the Flux of Metabolites in the Phenylpropanoid Pathway1

Piperonylic acid (PA) is a natural molecule bearing a methylenedioxy function that closely mimics the structure of trans-cinnamic acid. The CYP73A subfamily of plant P450s catalyzes trans-cinnamic acid 4-hydroxylation, the second step of the general phenylpropanoid pathway. We show that when incubated in vitro with yeast-expressed CYP73A1, PA behaves as a potent mechanism-based and quasi-irreversible inactivator of trans-cinnamate 4-hydroxylase. Inactivation requires NADPH, is time dependent and saturable (KI = 17 μm, kinact = 0.064 min−1), and results from the formation of a stable metabolite-P450 complex absorbing at 427 nm. The formation of this complex is reversible with substrate or other strong ligands of the enzyme. In plant microsomes PA seems to selectively inactivate the CYP73A P450 subpopulation. It does not form detectable complexes with other recombinant plant P450 enzymes. In vivo PA induces a sharp decrease in 4-coumaric acid concomitant to cinnamic acid accumulation in an elicited tobacco (Nicotiana tabacum) cell suspension. It also strongly decreases the formation of scopoletin in tobacco leaves infected with tobacco mosaic virus.

Normal human serum contains a natural IgM antibody cytotoxic for human neuroblastoma cells.

Neuroblastoma (NB) is characterized by the second highest spontaneous regression of any human malignant disorder, a phenomenon that remains to be elucidated. In this study, a survey of 94 normal human adult sera revealed a considerable natural humoral cytotoxicity against human NB cell lines in approximately one-third of the tested sera of both genders. Specific cell killing by these sera was in the range of 40% to 95%. Serum cytotoxicity was dependent on an intact classical pathway of complement. By several lines of evidence, IgM antibodies were identified as the cytotoxic factor in the sera. Further analyses revealed that a 260-kDa protein was recognized by natural IgM of cytotoxic sera in Western blots of NB cell extracts. The antigen was expressed on the surface of seven human NB cell lines but not on human melanoma or other control tumor cell lines derived from kidney, pancreas, colon, bone, skeletal muscle, lymphatic system, and bone marrow. Furthermore, no reactivity was observed with normal human fibroblasts, melanocytes, and epidermal keratinocytes. The antigen was expressed in vivo as detected by immunohistochemistry in both the tumor of a NB patient and NB tumors established in nude rats from human NB cell lines. Most interestingly, the IgM anti-NB antibody was absent from the sera of 11 human NB patients with active disease. The anti-NB IgM also could not be detected in tumor tissue obtained from a NB patient. Collectively, our data suggest the existence of a natural humoral immunological tumor defense mechanism, which could account for the in vivo phenomenon of spontaneous NB tumor regression.

Invasion, Proliferation and Control of Invasive Aquatic Plants in Colorado State Parks

Nonnative aquatic species are invasive worldwide. These species adversely affect natural aquatic ecosystems in a variety of ways and can negatively affect agriculture, recreation and industry. This study addresses identification and control of aquatic plant species of concern in Colorado State Parks. Seventeen species identified as potential threats to the parks and safe, effective chemical control methodologies were determined for each species. A matrix was developed to include the plants, appropriate chemical controls and the type of aquatic habitat where chemical use would be safe and effective. The matrix and recommendations for its use will be provided to the Colorado Division of Parks and Outdoor Recreation to develop a management plan under Section 1204 of the National Invasive Species Act.

Climate Change Policy & the Natural Gas Transmission Sector

Various emission reduction strategies are proposed to manage climate change in the U.S. This applied capstone evaluates the most likely policy options considering impacts and benefits to the natural gas transmission sector (NGT). It examines a case-study including a comparison of policy options to recommend the most beneficial program to the NGT sector. Two conclusions of major importance are: a federally preempted cap-and-trade program would be the most cost-effective for the NGT sector and the NGT sector should not be the point of regulation of any climate policy. Recommendations, strategies, and costs for implementation of a compliance plan for a federally preempted cap-and-trade program were developed as a tool for NGT companies as part of this applied capstone project.

Abundancia y distribución de especies depredadoras sometidas a control en gestión cinegética: estudio de caso representativo de la urraca (Pica pica) en la comarca de la Marina Baja

El presente estudio tiene como objeto analizar la abundancia y distribución de la urraca en función de las diferentes matrices de usos del suelo y gradientes ambientales. Este trabajo se ha centrado en la Comarca de la Marina Baja (Alicante), una región con 578,8 Km² de superficie. La zona cuenta con una vegetación climática de carrascal de termotipo mesomediterráneo y ombrotipo seco y subhúmedo. Se han realizado un total de 396 transectos para estimar la abundancia de la urraca durante los años 2006-2008, en diferentes matrices del paisaje: natural, abandono, regadío y secano. Las abundancias relativas, la evolución de la especie, el efecto sobre otras especies de caza y el efecto que tiene el control poblacional de las urracas se ha obtenido de 21 encuestas realizadas a los gestores de los terrenos cinegéticos. El análisis de los resultados, muestra una mayor abundancia de los individuos en zonas de cultivo de secano (IKA=0.76 aves/km) y cultivos abandonados (IKA=0.73 aves/km), siendo los valores medios anuales cada vez mayores desde el inicio del muestreo. El análisis múltiple de regresión lineal de la abundancia de urraca con la matriz de usos del suelo muestra una relación significativa y positiva con el abandono antiguo (p<0.01), el frutal de secano y las zonas húmedas (p<0.05), mientras que no hay relación significativa (p>0.05) con los índices del paisaje. El análisis ANOVA muestra que las variables significativas influyentes sobre el número de urracas son: matriz de usos del suelo, latitud/ombroclima, continentalidad y la interacción usos del suelo:continentalidad (p<0.05). La urraca ha experimentado un aumento en sus poblaciones desde principios de la primera década del actual siglo. Los cotos que realizan un control sobre la población de urracas tienen un efecto positivo que se ve reflejado en la menor afección sobre otras especies cinegéticas.

Radiactividad natural de los materiales de construcción. Aplicación al hormigón. Parte I. Radiación externa: índice de riesgo radiactivo

El presente artículo analiza aspectos relacionados con el concepto de radiactividad natural, profundizando en los tipos de radiactividad existente en los materiales naturales radiactivos NORM (“Naturally Occurring Radioactive Materials”) utilizados en la construcción, así como sus fuentes e infl uencias. Este es un artículo que se presenta como la primera parte de un trabajo sobre la radiactividad natural de los materiales de construcción, cuya segunda parte hace referencia a la radiación interna debida al gas radón emitido de manera natural por dichos materiales y se publica por los mismos autores, en esta misma revista. Se aborda la necesidad de establecer criterios de control en este tipo de materiales y se analiza el establecimiento de diferentes índices de riesgo según los distintos países. Al mismo tiempo, se realiza un recorrido por el marco normativo, tanto internacional como nacional, relativo a estos materiales NORM. El presente trabajo es parte de la tesis doctoral de la primera autora del mismo, Beatriz Piedecausa García, a quien el resto de autores agradece su esfuerzo para preparar el texto que ahora se publica y la autorización y las facilidades ofrecidas para acceder a su trabajo.

Augmented Reality for preschoolers: an experience around Natural Sciences educational contents

Early education is a key element for the future success of students in the education system. This work analyzes the feasibility of using augmented reality contents with preschool students (four and five years old) as a tool for improving their learning process. A quasi experimental design based on a nonequivalent groups posttest-only design was used. A didactic unit has been developed around the topic “animals” by the participant teachers. The control group followed all the didactic activities defined in the developed didactic materials, while the experimental group was provided in addition with some augmented reality contents. Results show improved learning outcomes in the experimental group with respect to the control group.

Coverage and invariance for the biological control of pests in mediterranean greenhouses

A major problem related to the treatment of ecosystems is that they have no available mathematical formalization. This implies that many of their properties are not presented as short, rigorous modalities, but rather as long expressions which, from a biological standpoint, totally capture the significance of the property, but which have the disadvantage of not being sufficiently manageable, from a mathematical standpoint. The interpretation of ecosystems through networks allows us to employ the concepts of coverage and invariance alongside other related concepts. The latter will allow us to present the two most important relations in an ecosystem – predator–prey and competition – in a different way. Biological control, defined as “the use of living organisms, their resources or their products to prevent or reduce loss or damage caused by pests”, is now considered the environmentally safest and most economically advantageous method of pest control (van Lenteren, 2011). A guild includes all those organisms that share a common food resource (Polis et al., 1989), which in the context of biological control means all the natural enemies of a given pest. There are several types of intraguild interactions, but the one that has received most research attention is intraguild predation, which occurs when two organisms share the same prey while at the same time participating in some kind of trophic interaction. However, this is not the only intraguild relationship possible, and studies are now being conducted on others, such as oviposition deterrence. In this article, we apply the developed concepts of structural functions, coverage, invariant sets, etc. (Lloret et al., 1998, Esteve and Lloret, 2006a, Esteve and Lloret, 2006b and Esteve and Lloret, 2007) to a tritrophic system that includes aphids, one of the most damaging pests and a current bottleneck for the success of biological control in Mediterranean greenhouses.