Small molecule cognitive enhancer reverses age-related memory decline in mice.

With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma.

Mild repetitive traumatic brain injury (rTBI) induces chronic behavioral and cognitive alterations and increases the risk for dementia. Currently, there are no therapeutic strategies to prevent or mitigate chronic deficits associated with rTBI. Previously we developed an animal model of rTBI that recapitulates the cognitive and behavioral deficits observed in humans. We now report that rTBI results in an increase in risk-taking behavior in male but not female mice. This behavioral phenotype is associated with chronic activation of the integrated stress response and cell-specific synaptic alterations in the type A subtype of layer V pyramidal neurons in the medial prefrontal cortex. Strikingly, by briefly treating animals weeks after injury with ISRIB, a selective inhibitor of the integrated stress response (ISR), we (1) relieve ISR activation, (2) reverse the increased risk-taking behavioral phenotype and maintain this reversal, and (3) restore cell-specific synaptic function in the affected mice. Our results indicate that targeting the ISR even at late time points after injury can permanently reverse behavioral changes. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat rTBI-induced behavioral dysfunction.

Two-site recognition of Staphylococcus aureus peptidoglycan by lysostaphin SH3b.

Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore a therapeutic agent of choice to eradicate staphylococcal infections. The C-terminal SH3b domain of lysostaphin recognizes peptidoglycans containing a pentaglycine crossbridge and has been proposed to drive the preferential digestion of staphylococcal cell walls. Here we elucidate the molecular mechanism underpinning recognition of staphylococcal peptidoglycan by the lysostaphin SH3b domain. We show that the pentaglycine crossbridge and the peptide stem are recognized by two independent binding sites located on opposite sides of the SH3b domain, thereby inducing a clustering of SH3b domains. We propose that this unusual binding mechanism allows synergistic and structurally dynamic recognition of S. aureus peptidoglycan and underpins the potent bacteriolytic activity of this enzyme.

Food Safety through Natural Antimicrobials.

Microbial pathogens are the cause of many foodborne diseases after the ingestion of contaminated food. Several preservation methods have been developed to assure microbial food safety, as well as nutritional values and sensory characteristics of food. However, the demand for natural antimicrobial agents is increasing due to consumers' concern on health issues. Moreover, the use of antibiotics is leading to multidrug resistant microorganisms reinforcing the focus of researchers and the food industry on natural antimicrobials. Natural antimicrobial compounds from plants, animals, bacteria, viruses, algae and mushrooms are covered. Finally, new perspectives from researchers in the field and the interest of the food industry in innovations are reviewed. These new approaches should be useful for controlling foodborne bacterial pathogens; furthermore, the shelf-life of food would be extended.

Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinase δ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.

Effect of vacuum ageing on quality changes of lamb steaks from early fattening lambs during aerobic display.

The effects of vacuum ageing on the quality changes of lamb steaks during retail display were assessed. Biceps femoris and Quadriceps femoris muscles from thirty early fattening lambs fed barley straw and concentrate or alfalfa and concentrate were used. Half of the muscles were vacuum aged for three weeks (VA), and the other half were not aged (control). Control and VA muscles were sliced and aerobically displayed. Weight loss, pH, aldehyde contents, instrumental color characteristics and color acceptance were measured at display days 1, 3, 7 and 14. At day 1 redness was higher in VA lamb. However, redness of VA lamb decreases more rapidly during further storage. Redness and color acceptance decreased in VA lamb from day 3, whereas in not-aged lamb the decrease was observed from day 7 onwards. From days 7 to 14 a drop of color acceptance accompanied by an increase in pH and a decrease in lightness was observed in control and VA lamb.

Quality characteristics of a dry-cured lamb leg as affected by tumbling after dry-salting and processing time.

The aim of this study was to evaluate selected quality characteristics of a dry-cured lamb leg with different tumbling treatments after salting. The characteristics were measured at different processing times. Three batches of dry-cured lamb legs (nine legs per batch) were prepared with no-, short- and long-tumbling treatments, and microbial counts, NaCl, aw, proximate composition, pH, free fatty acids, water soluble nitrogen, volatile compounds, texture and colour were evaluated at days 1, 22 and 71 of processing. Furthermore, a descriptive sensory analysis (flavour and texture) was performed in the final product (day 71). Time-related changes were observed for most of the characteristics studied. The effect of tumbling was only observed for the sensory attribute pastiness that was higher in tumbled legs. Methyl-branched butanal was only detected in tumbled legs.

Neurogenesis in the adult goldfish cerebellum.

Neurogenesis was studied in the cerebellum of adult goldfish, to establish the phenomenon in this popular laboratory animal model. BrdU and proliferating cell nuclear antigen labeling revealed a high rate of cell proliferation within the molecular layer of the cerebellar corpus and valve. Most newborn cells expressed the neuronal marker beta-III-tubulin after 24 hr, supporting the goldfish cerebellum as an excellent paradigm to study vertebrate adult neurogenesis.

Nitric oxide amplifies the rat electroretinogram.

It is well established that nitric oxide (NO) participates in retinal signal processing through stimulation of its receptor enzyme, soluble guanylyl cyclase (sGC). However, under pathological conditions such as uveoretinitis, diabetic or ischemic retinopathy, elevated NO concentrations may cause protein S-nitrosation and peroxynitrite formation in the retina, promoting cellular injury and apoptosis. Previous electroretinogram (ERG) studies demonstrated deleterious effects of NO on the retinal light response, but showed no evidence for a role in normal signal processing. To better understand the function of NO in ocular physiology, we investigated the effects of exogenous NO, produced by NO donors with different release kinetics, on the flash ERG of the rat. Within a limited concentration range, NO strongly amplified ERG a- and b-waves, oscillatory potentials, and the scotopic threshold response. Amplification exceeded 100% under dark adaptation, whereas the photopic ERG and the isolated cone response were increased by less than 50%. Blocking photoreceptor-bipolar cell synapses by AP-4 demonstrated a significant increase of the isolated a-wave by NO, and modeling the ERG generator PIII supported photoreceptors as primary NO targets. The sGC inhibitors ODQ and NS2028 did not reduce NO-dependent ERG amplification, ruling out an involvement of the classical NO effector cyclic GMP. Using immunohistochemistry, we show that illumination and exogenous NO altered the S-nitrosation level of the photoreceptor layer, suggesting that direct protein modifications caused by elevated levels of NO may be responsible for the observed phenomenon.

GABA and glutamate immunoreactivity in tentacles of the sea anemone Phymactis papillosa (LESSON 1830).

Sea anemones have a structurally simple nervous system that controls behaviors like feeding, locomotion, aggression, and defense. Specific chemical and tactile stimuli are transduced by ectodermal sensory cells and transmitted via a neural network to cnidocytes and epithelio-muscular cells, but the nature of the neurotransmitters operating in these processes is still under discussion. Previous studies demonstrated an important role of peptidergic transmission in cnidarians, but during the last decade the contribution of conventional neurotransmitters became increasingly evident. Here, we used immunohistochemistry on light and electron microscopical preparations to investigate the localization of glutamate and GABA in tentacle cross-sections of the sea anemone Phymactis papillosa. Our results demonstrate strong glutamate immunoreactivity in the nerve plexus, while GABA labeling was most prominent in the underlying epithelio-muscular layer. Immunoreactivity for both molecules was also found in glandular epithelial cells, and putative sensory cells were GABA positive. Under electron microscopy, both glutamate and GABA immunogold labeling was found in putative neural processes within the neural plexus. These data support a function of glutamate and GABA as signaling molecules in the nervous system of sea anemones.

The GABAergic system in the retina of neonate and adult Octodon degus, studied by immunohistochemistry and electroretinography.

UNLABELLED: In the vertebrate retina, gamma-aminobutyric acid (GABA) mediates inhibitory processes that shape the visual response and is also thought to have neurotrophic functions during retinal development. To investigate the role of GABAergic signaling at the beginning of visual experience, we used immunohistochemistry to compare the distribution of GABA, the two isoforms of glutamic acid decarboxylase GAD65/67, and the GABA receptor types A, B, and C, in neonate versus adult Octodon degus, a native South American rodent with diurnal-crepuscular activity and a high cone-to-rod ratio. In parallel, we used electroretinography to evaluate retinal functionality and to test the contribution of fast GABAergic transmission to light responses at both developmental stages. Neonate O. degus opened their eyes on postnatal day (P)0 and displayed an adult-like retinal morphology at this time. GABA, its biosynthetic sources, and receptors had a similar cellular distribution in neonates and adults, but labeling of the outer plexiform layer and of certain amacrine and ganglion cells was more conspicuous at P0. In neonates, retinal sensitivity was 10 times lower than in adults, responses to ultraviolet light could not be detected, and oscillatory potentials were reduced or absent. Blockade of GABA(A/C) receptors by bicuculline and TPMPA had no noticeable effect in neonates, while it significantly altered the electroretinogram response in adults. CONCLUSION: In spite of modest differences regarding retinal morphology and GABAergic expression, overall light response properties and GABAergic signaling are undeveloped in neonate O. degus compared to adults, suggesting that full retinal functionality requires a period of neural refinement under visual experience.

Nivel de Ansiedad preoperatoria en los pacientes programados para cirugía / Anxiety level before surgery in patients scheduled for surgery

El presente estudio tiene como objetivo principal, establecer la relación entre el grado de información del procedimiento quirúrgico con el nivel de ansiedad preoperatoria en los pacientes programados para cirugía de la Fundación Mario Gaitan Yanguas en el periodo comprendido de octubre-noviembre del 2008. Se realizó un estudio cuantitativo, descriptivo, correlacional y de corte transversal. Para la recolección de la información se utilizó Escala De Valoración De La Ansiedad De Spielberger Idare-Estado. La población está conformada por los pacientes que acuden al servicio de cirugía. Las variables utilizadas son información acerca de la cirugía, nivel de ansiedad y causas de la ansiedad. Se concluye que el 59% de los pacientes tenían conocimiento acerca del procedimiento, 50.9 % presentaron un nivel de ansiedad moderada; los procedimientos con mayor nivel de ansiedad fue colecistectomía 67% y herniorrafia inguinal 50%. En cuanto a la relación entre el procedimiento y el nivel de ansiedad, la cesárea + pomeroy y la conización presentaron un nivel de ansiedad alto; y la relación entre el grado de información del procedimiento y el nivel de ansiedad, se encontró que, a pesar de que la mayoría de los pacientes manifiestan conocer el procedimiento, predomina el nivel de ansiedad moderada y baja

This study's main objective, establish the relationship between the degree of information from the surgical procedure with the level of anxiety in the preoperative patients scheduled for surgery the Fundación Mario Gaitan Yanguas during the period from October to November 2008. We performed a quantitative study, descriptive, correlational and cross. For the collection of information was used Scale From Anxiety Rating Spielberger Idar-State. The population is made up of the patients who come to the service of surgery. The variables used are about the surgery, anxiety level and cause of anxiety. It was concluded that 59% of patients had knowledge about the procedure, 50.9% had a moderate level of anxiety; procedures at a higher level of anxiety cholecystectomy was 67% and inguinal herniorrhaphy 50%. On the relationship between the procedure and the level of anxiety, cesarean + Pomeroy and conization showed a high level of anxiety, and the relationship between the degree of information of the procedure and the level of anxiety, it was found that despite that the majority of patients manifest the process, the prevailing level of anxiety moderate and low.

Immunohistochemical localization of GABA, GAD65, and the receptor subunits GABAAalpha1 and GABAB1 in the zebrafish cerebellum.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system. Its role is especially prominent in the cerebellum, where most neuron types are GABAergic. However, little is known about its function in the cerebellum of teleost fish, which is only partly homologous to its mammalian counterpart. Here, we investigated the expression and distribution of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase 65 (GAD65), and the receptor subunits GABA(Aalpha1) and GABA(B1) in the cerebellum of adult zebrafish. GABA and GAD65 presented a similar expression pattern that comprised the molecular layer, Purkinje cells and groups of presumed Golgi cells in the granular layer, both in the cerebellar corpus and valve. GABA(A) receptor subunits are principally found on fine radial fibers in the molecular layer, while GABA(B) receptor subunits localized prominently to the cell bodies of Purkinje cells in the ganglionic layer, and to their dendrites that span the molecular layer. These results are compared to the expression of the GABAergic system in the mammalian cerebellum.

The elusive crypt olfactory receptor neuron: evidence for its stimulation by amino acids and cAMP pathway agonists.

Crypt olfactory receptor neurons (ORNs) are a third type of chemosensory neuron along with ciliated and microvillous ORNs in the olfactory epithelium of fishes, but their functional role is still unknown. To investigate their odorant response properties and possible transduction pathways, we recorded crypt ORN activity with calcium imaging and the patch clamp technique in its cell-attached mode in combination with odorant and agonist stimulation. Bile salts and putative fish pheromones did not elicit responses with either method, but the cells frequently responded to amino acids, with excitation and intracellular calcium signals. 8Br-cAMP and IBMX plus forskolin stimulated over 40% of crypt ORNs and triggered calcium signals in a similar percentage. Furthermore, crypt ORNs were immunoreactive to an antiserum against adenylate cyclase III. Together, these data suggest the presence of a cAMP transduction pathway, which might transduce odorants such as amino acids.

Biocomplexity and conservation of biodiversity hotspots: three case studies from the Americas.

The perspective of 'biocomplexity' in the form of 'coupled natural and human systems' represents a resource for the future conservation of biodiversity hotspots in three direct ways: (i) modelling the impact on biodiversity of private land-use decisions and public land-use policies, (ii) indicating how the biocultural history of a biodiversity hotspot may be a resource for its future conservation, and (iii) identifying and deploying the nodes of both the material and psycho-spiritual connectivity between human and natural systems in service to conservation goals. Three biocomplexity case studies of areas notable for their biodiversity, selected for their variability along a latitudinal climate gradient and a human-impact gradient, are developed: the Big Thicket in southeast Texas, the Upper Botanamo River Basin in eastern Venezuela, and the Cape Horn Archipelago at the austral tip of Chile. More deeply, the biocomplexity perspective reveals alternative ways of understanding biodiversity itself, because it directs attention to the human concepts through which biodiversity is perceived and understood. The very meaning of biodiversity is contestable and varies according to the cognitive lenses through which it is perceived.

Relaciones alométricas y patrones de crecimiento para especies de árboles de la reserva forestal Imataca Venezuela / Allometric relations and growth patterns for tree species in the Imataca forest reserve Venezuela

Las relaciones alómetricas diámetro-altura fueron analizadas en 34 especies arbóreas de la Reserva Forestal Imataca, según la ecuación exponencial de Chapman y Richard, utilizada por los modelos de base individual ZELIG y FACET, que simulan la dinámica de crecimiento del bosque. Los coeficientes de la relación alométrica para cada especie fueron calculados por regresión lineal aplicada a la transformación logarítmica de la ecuación exponencial. Se determinó que la relación exponencial explica una proporción elevada de la variabilidad de altura para las especies estudiadas aunque se utilizaron datos de parcelas en localidades diferentes. Las relaciones resultantes serán incorporadas al modelo FACET en trabajos posteriores. Se evaluó la existencia de patrones alométricos, agrupando las especies según los requerimientos de luz (intolerantes o pioneras y tolerantes a la sombra) y por clases de altura (medianas con 10-30m, grandes de >30m), conformando cuatro grupos funcionales: pioneras medianas, pioneras grandes, tolerantes medianas y tolerantes grandes. Se encontraron diferencias entre las alometrías de los cuatro grupos utilizando análisis de varianza y análisis discriminante. Las diferencias en los coeficientes alométricos, tomados uno a la vez, son más significativas entre pioneras y tolerantes que entre las grandes y medianas. La combinación de ambos coeficientes, b2 y b3, permite diferenciar todos los grupos, especialmente usando una función discriminante, que además permitirá predecir la pertenencia de otras especies a cada grupo dados sus valores de coeficientes alométricos

Flúor contenido en la sal para consumo humano distribuida en la ciudad de México / Fluoride content of table salt in Mexico City

El objetivo de este estudio fue medir el contenido de flúor de una muestra de bolsas de sal a la venta en la ciudad de México, con objeto de estimar la proporción de sal comercializada que contiene la cantidad de flúor fijada por el Programa Nacional de Prevención de la Caries Dental Mediante el Consumo de Sal de Mesa Fluorada. Nunca se había evaluado la efectividad de este programa. En marzo de 1993, se adquirieron bolsas de sal en tiendas lozalizadas en 70 de las 3544 colonias que integran la ciudad de México. La selección se realizó por muestreo aleatorio simple. Asimismo, se compro sal en 20 por ciento de los 146 supermercados y tiendas de autoservicio de la ciudad, previamente seleccionados por muestreo aleatorio simple. A continuación, se midió a ciegas la cantidad de flúor presente en 221 bolsas de sal seleccionadas. El contenido real de este elemento se encontró frecuentemente por debajo de la cantidad señalada por la norma gubernamental. Además, la cantidad de flúor medida no coincidió con la anunciada en la etiqueta de las bolsas estudiadas, en contra de lo que estipula la ley

Patrón de consumo de refrescos en una población mexicana / Soft drink consumption patterns in a Mexican population

Para evaluar el patrón de consumo de los refrescos embotellados en el medio mexicano, se realizó una encuesta sobre el consumo de refrescos y bebidas refrescantes en usuarios (mayores de 10 años de edad) en la Ciudad de México (septiembre-octubre de 1993). Asimismo, se empleó una técnica estándar de laboratorio para establecer el pH de las bebidas. Los resultados mostraron que, en las 33 marcas de refrescos y 15 marcas de jugos y bebidas disponibles, los valores de pH fueron siempre marcadamente ácidos (entre 2.46 y 3.96). De los 2 008 respondentes (55.3 por ciento hombres, 44.7 por ciento mujeres; tasa de respuesta 90.1 por ciento), 1 657 (82.5 por ciento) afirmaron tomar refresco todos los días y 351 (17.5 por ciento) negaron su consumo. Aunque el alto consumo fue común en todos los grupos de edad, la ingestión referida pareció estar parcialmente asociada con la edad, siendo más considerable en los grupos más jóvenes. El número medio de refrescos bebidos por día fue 1.7, con una desviación estándar (DE) 1.3 y, por semana, fueron 9.3 (DE 9.9). El consumo informado de refresco pareció ser independiente de la escolaridad de los entrevistado. Si bien la proporción más alta de no consumidores de refresco se encontró en aquel grupo que consideró a los refrescos como un factor cariogénico muy importante, en general el grueso de los entrevistado indicó que el consumo de refrescos era un factor importante en la etiología de la caries. Asimismo, una mayor escolaridad estuvo más frecuentemente asociada a una atribución más preponderante de la importancia del papel de los refrescos en la caries

To evaluate soft drink consumption patterns in the Mexican population, the authors conducted a survey among people over 10 years of age in Mexico City (september-october 1993). Also, pH levels of commonly available beverages were measured using standard laboratory techniques. Results indicated that each one of the 33 soft drink brands and 15 brands of juices and beverages available, had markedly acidic pH values (between 2.46 and 3.96). Out of the 2 008 respondents (55.3% male, 44.7% female; response rate, 90.1%), 1 657 (82.5%) admitted drinking soft drinks daily, while 351 (17.5%) said they did not drink this type of beverages. Even though high consumption was frequent in all age groups, self-reported consumption was partially associated to age, being higher in the younger groups. The mean number of soft drinks ingested per day was reported to be 1.7, SD 1.3, and 9.3 per week SD 9.9. Self-reported consumption appeared to be independent of schooling level. Even though the largest proportion of non- consumers was found in the group that considered soft drinks to be a very important contributing factor to caries development, most interviewees agreed that soft drinks consumption was an important cariogenic factor. This attributed role was more prominent among interviewees with a higher level of schooling.

Flúor contenido en la sal para consumo humano distribuida en la ciudad de México / Fluoride content of table salt in Mexico City

El objetivo de este estudio fue medir el contenido de flúor de una muestra de bolsas de sal a la venta en la ciudad de México, con objeto de estimar la proporción de sal comercializada que contiene la cantidad de flúor fijada por el Programa Nacional de Prevención de la Caries Dental Mediante el Consumo de Sal de Mesa Fluorada. Nunca se había evaluado la efectividad de este programa. En marzo de 1993, se adquirieron bolsas de sal en tiendas lozalizadas en 70 de las 3544 colonias que integran la ciudad de México. La selección se realizó por muestreo aleatorio simple. Asimismo, se compro sal en 20 por ciento de los 146 supermercados y tiendas de autoservicio de la ciudad, previamente seleccionados por muestreo aleatorio simple. A continuación, se midió a ciegas la cantidad de flúor presente en 221 bolsas de sal seleccionadas. El contenido real de este elemento se encontró frecuentemente por debajo de la cantidad señalada por la norma gubernamental. Además, la cantidad de flúor medida no coincidió con la anunciada en la etiqueta de las bolsas estudiadas, en contra de lo que estipula la ley