Environmental Cycles, Melatonin, and Circadian Control of Stress Response in Fish

Fish have evolved a biological clock to cope with environmental cycles, so they display circadian rhythms in most physiological functions including stress response. Photoperiodic information is transduced by the pineal organ into a rhythmic secretion of melatonin, which is released into the blood circulation with high concentrations at night and low during the day. The melatonin rhythmic profile is under the control of circadian clocks in most fish (except salmonids), and it is considered as an important output of the circadian system, thus modulating most daily behavioral and physiological rhythms. Lighting conditions (intensity and spectrum) change in the underwater environment and affect fish embryo and larvae development: constant light/darkness or red lights can lead to increased malformations and mortality, whereas blue light usually results in best hatching rates and growth performance in marine fish. Many factors display daily rhythms along the hypothalamus-pituitary-interrenal (HPI) axis that controls stress response in fish, including corticotropin-releasing hormone (Crh) and its binding protein (Crhbp), proopiomelanocortin A and B (Pomca and Pomcb), and plasma cortisol, glucose, and lactate. Many of these circadian rhythms are under the control of endogenous molecular clocks, which consist of self-sustained transcriptional-translational feedback loops involving the cyclic expression of circadian clock genes (clock, bmal, per, and cry) which persists under constant light or darkness. Exposing fish to a stressor can result in altered rhythms of most stress indicators, such as cortisol, glucose, and lactate among others, as well as daily rhythms of most behavioral and physiological functions. In addition, crh and pomca expression profiles can be affected by other factors such as light spectrum, which strongly influence the expression profile of growth-related (igf1a, igf2a) genes. Additionally, the daily cycle of water temperature (warmer at day and cooler at night) is another factor that has to be considered. The response to any acute stressor is not only species dependent, but also depends on the time of the day when the stress occurs: nocturnal species show higher responses when stressed during day time, whereas diurnal fish respond stronger at night. Melatonin administration in fish has sedative effects with a reduction in locomotor activity and cortisol levels, as well as reduced liver glycogen and dopaminergic and serotonergic activities within the hypothalamus. In this paper, we are reviewing the role of environmental cycles and biological clocks on the entrainment of daily rhythms in the HPI axis and stress responses in fish

A New Porphyrin for the Preparation of Functionalized Water-Soluble Gold Nanoparticles with Low Intrinsic Toxicity

A potential new photosensitizer based on a dissymmetric porphyrin derivative bearing a thiol group was synthesized. 5-[4-(11-Mercaptoundecyloxy)-phenyl-10,15,20-triphenylporphyrin (PR-SH) was used to functionalize gold nanoparticles in order to obtain a potential drug delivery system. Water-soluble multifunctional gold nanoparticles GNP-PR/PEG were prepared using the Brust-Schiffrin methodology, by immobilization of both a thiolated polyethylene glycol (PEG) and the porphyrin thiol compound (PR-SH). The nanoparticles were fully characterized by transmission electron microscopy and 1H nuclear magnetic resonance spectroscopy, UV/Vis absorption spectroscopy, and X-ray photoelectron spectroscopy. Furthermore, the ability of GNP-PR/PEGs to induce singlet oxygen production was analyzed to demonstrate the activity of the photosensitizer. Cytotoxicity experiments showed the nanoparticles are nontoxic. Finally, cellular uptake experiments demonstrated that the functionalized gold nanoparticles are internalized. Therefore, this colloid can be considered to be a novel nanosystem that could potentially be suitable as an intracellular drug delivery system of photosensitizers for photodynamic therapy. Keywords: drug delivery, gold nanoparticles, photodynamic therapy, photosensitizers, porphyrin

MODELAMIENTO MATEMÁTICO DEL PROBLEMA DE OCUPACIÓN DE QUIRÓFANOS

En este artículo se plantea un modelo matemático lineal entero cuyo objetivo es maximizar la utilización de quirófanos en instituciones hospitalarias. El modelo matemático surge después de aplicar una técnica que se propone con el enfoque de Six Sigma DMAIC que permite revisar procesos para identificar situaciones que deben ser mejoradas. Con base en ello surgen diferentes problemáticas pero aparece como punto neurálgico el nivel de ocupación de la sala de quirófanos, allí se identifican los elementos vulnerables en el proceso y con base en herramientas estadísticas se determinan los valores de los parámetros que se deben considerar para plantear el modelo matemático. La técnica de solución utilizada para resolver el modelo es el algoritmo de Branch and Bound con el solver CPLEX

A beam-beam monitoring detector for the MPD experiment at NICA

The Multi-Purpose Detector (MPD) is to be installed at the Nuclotron Ion Collider fAcility (NICA) of the Joint Institute for Nuclear Research (JINR). Its main goal is to study the phase diagram of the strongly interacting matter produced in heavy-ion collisions. These studies, while providing insight into the physics of heavy-ion collisions, are relevant for improving our understanding of the evolution of the early Universe and the formation of neutron stars. In order to extend the MPD trigger capabilities, we propose to include a high granularity beam-beam monitoring detector (BE-BE) to provide a level-0 trigger signal with an expected time resolution of 30 ps. This new detector will improve the determination of the reaction plane by the MPD experiment, a key measurement for flow studies that provides physics insight into the early stages of the reaction. In this work, we use simulated Au+Au collisions at NICA energies to show the potential of such a detector to determine the event plane resolution, providing further redundancy to the detectors originally considered for this purpose namely, the Fast Forward Detector (FFD) and the Hadron Calorimeter (HCAL). We also show our results for the time resolution studies of two prototype cells carried out at the T10 beam line at the CERN PS complex.Comment: 16 pages, 12 figures. Updated to published version with added comments and correction

The Connor-Davidson Resilience Scale (CD-RISC) amongst Young Spanish Adults

The interest in resilience has grown over the last few decades due to its relationships with health, well-being, and quality of life. Several instruments have been developed to measure resilience, with one of the most common being the Connor-Davidson Resilience Scale (CD-RISC). This scale has been validated in many cultures with divergent results. This paper investigates the factor structure of the CD-RISC. Participants were 3,214 students (62.1% female, mean age = 21.01, SD = 2.86) who were randomly divided into two equal subsamples (n = 1,607). One subsample was used to explore which models best fit the data and these models were fitted using the other subsample. Confirmatory factor analysis did not support the original 5-factor CD-RISC. The analyses supported unidimensional scale structures for both the 22-item and 10-item versions of the scale. The shorter instrument reduces the time needed to answer the questionnaire, allows it to be combined with other instruments, and does not require large sample sizes

Wnt signaling and Loxl2 promote aggressive osteosarcoma

Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less (Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 coexpression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS

Viscoelastic properties of plasma-agarose hydrogels dictate favorable fibroblast responses for skin tissue engineering applications

Dermal wound healing relies on the properties of the extracellular matrix (ECM). Thus, hydrogels that replicate skin ECM have reached clinical application. After a dermal injury, a transient, biodegradable fibrin clot is instrumental in wound healing. Human plasma, and its main constituent, fibrin would make a suitable biomaterial for improving wound healing and processed as hydrogels albeit with limited mechanical strength. To overcome this, plasma-agarose (PA) composite hydrogels have been developed and used to prepare diverse bioengineered tissues. To date, little is known about the influence of variable agarose concentrations on the viscoelastic properties of PA hydrogels and their correlation to cell biology. This study reports the characterization of the viscoelastic properties of different concentrations of agarose in PA hydrogels: 0 %, 0.5 %, 1 %, 1.5 %, and 2 % (w/v), and their influence on the cell number and mitochondrial activity of human dermal fibroblasts. Results show that agarose addition increased the stiffness, relaxation time constants 1 (τ1) and 2 (τ2), and fiber diameter, whereas the porosity decreased. Changes in cell metabolism occurred at the early stages of culturing and correlated to the displacement of fast (τ1) and intermediate (τ2) Maxwell elements. Fibroblasts seeded in low PA concentrations spread faster during 14 d than cells cultured in higher agarose concentrations. Collectively, these results confirm that PA viscoelasticity and hydrogel architecture strongly influenced cell behavior. Therefore, viscoelasticity is a key parameter in the design of PA-based implants

Effects of trans fatty acid-enriched bubaline milk intake in hepatic fat degeneration induced by cholesterol in rabbits

Este trabajo comparó los efectos del consumo de dos leches bubalinas, con baja y alta relación de AGt/AGS, sobre la lipemia y el desarrollo de degeneración grasa hepática inducido por colesterol en conejos. Veinte conejos neozelandeses, machos, fueron aleatoriamente separados en un grupo control (n=10) que recibió leche con baja relación AGt/AGS (5,3% de AGt y 67,12 % de AGS) obtenida de búfalas en sistema pastoril; y un grupo alto trans (n=10) que recibió leche con alta relación AGt/AGS (25,84% de AGt y 45,89% de AGS) obtenida de búfalas con suplementación lipídica en su dieta. La leche fue administrada durante 75 días y su consumo fue registrado diariamente. A partir del día 15 todos los conejos recibieron 0,93 g de colesterol/día, vía oral, para inducir degeneración grasa hepática. Se evaluó el lipidograma sérico y los niveles de ALT y AST. En hígado se midió el contenido de lípidos y, en muestras histológicas, se evaluó el área sudanofílica, la fibrosis e infiltración de macrófagos. Los conejos consumieron 9293,13 ml y 9930 ml de leche con baja y alta relación AGt/AGS, respectivamente, sin diferencia entre grupos (p 0,404). El grupo alto trans registró mayores niveles séricos de colesterol total que el control (6,08 vs. 5,58 g/l, p 0,049). Los valores de ALT fueron significativamente (p <0,0001) mayores en el grupo alto trans. El hígado registró un significativo (p 0,0437) incremento de lípidos en el grupo alto trans (10,62 % de lípidos) cuando se comparó con el control (8,68 % de lípidos). El grupo alto trans registró en el parénquima hepático mayor extensión del área sudanofílica (37,05 % vs. 26,42 %, p 0,0338), mayor frecuencia de fibrosis (8 vs. 3 hígados, p 0,0247) y mayor infiltración de macrófagos (94,20 vs. 48 macrófagos, p 0,0190) que el grupo control. En conclusión, la leche con alta relación AGt/AGS contribuyó a incrementar la colesterolemia y a incrementar el efecto hepatotóxico del colesterol, cuando se comparó con la leche con baja relación de AGt/AGS. Dichos efectos estén, posiblemente, relacionados con el contenido de AGt de esta leche.This work compared the effects of the two bubaline milk consumption, with low and high ratio of tFA/SFA, on lipemia and the development of hepatic fat degeneration induced by cholesterol in rabbits. Twenty New Zealand males rabbits were randomly separated into a control group (n=10) that received milk with low trans/saturated FA ratio (5.3% tFA and 67.12% SFA) obtained from grazing buffalos; and a high trans group (n=10) that received milk with high tFA/SFA ratio (25.84% tFA and 45.89% SFA) obtained from buffalos with lipid supplementation in their diet. The milk was administered for 75 days and its intake was recorded daily. From day 15, all rabbits were challenged with 0.93 g of cholesterol/day, orally, in order to induce hepatic fat degeneration. The serum lipidogram, ALT and AST were recorded. On the liver, lipid content, sudanophilic area, fibrosis and macrophage infiltration were evaluated. The rabbits voluntarily consumed 9293.13 ml and 9930 ml of milk with low and high tFA/SFA ratio, respectively, without difference between groups (p 0.404). Rabbits in high trans group registered higher serum levels of total cholesterol than the control group (6.08 vs. 5.58 g/l, p 0.049). The ALT were significantly (p <0.0001) higher in the high trans group than the control group. The liver lipids recorded a significant (p 0.0437) increase in the high trans group (10.62%) when it was compared to the control (8.68%).The high trans group recorded a greater extension of the sudanophilic area (37.05 ± 7.53% vs. 26.42 ± 12.55%, p 0.0338), a greater frequency of fibrosis (8 vs. 3 livers, p 0.0247) and more infiltration of macrophages in hepatic parenchyma (94.20 vs. 48 macrophages, p 0.0190) than the control group. In conclusion, milk with high tFA/SFA ratio contributed to increase total cholesterol levels and to increase the hepatotoxic effect of cholesterol, when was compared with milk with a low ratio of tFA/SFA. These effects are possibly related to the tFA content of this milk.Fil: Lertora, Walter Javier. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; ArgentinaFil: Villordo, Gabriela Ines. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; ArgentinaFil: Mussart, Norma Beatriz. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Patiño, Exequiel Maria. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; ArgentinaFil: Montenegro, M. A.. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; ArgentinaFil: Cabrera, Ailen Emilse. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; ArgentinaFil: Sánchez Negrette, M.. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; Argentin

The dynamic use of EGFR mutation analysis in cell-free DNA as a follow-up biomarker during different treatment lines in non-small-cell lung cancer patients

Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9 5-13) to the best response (median = 0, IQR = 0-0, p < 0 01), followed by a significant increase at progression (median = 11, IQR = 11-15, p < 0 01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received