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Depression is within the five most prevalent diseases in the world, affecting approximately 322 million people (Fusar-Poli L et al. 2019). Previous studies have shown that 80-90% of patients with major depressive disorder also have anxiety symptoms. Comorbidity between anxiety and depression predicts poor outcomes with a higher percentage of treatment resistance (Coplan et al. 2015). There is a need for new investigations to develop novel drugsand strategies of treatments, which has led to alternative approaches within ethnomedicine, being our goal to study the effect of Glandularia Cabrerae (GC), native plant of Argentina; on the anxiety and depression behavior in a murine model. Therefore, the present study has as a hypothesis that the extract of this plant induces antidepressant predictive effect since it shares gender with Glandularia dissecta, popularly used in  nervous system conditions . Male albino Swiss-N: NIH mice, were treated with a hydroalcoholic extract of GC (macerated 5% w/v ethanol/water 1: 1) which was lyophilized and subsequently resuspected with saline solution. A set of 8 controls treated with saline solution was used, 8 animals treated with a dose of 55 mg/kg body weight and 8 with a dose of 175 mg/kg. The treatment for 28 days was carried out orally. An open field test (OFT) was performed to study depressive behavior. Setting basal, pre-treatment and post-treatment behavior. On the 28th day a Plus Maze test (PMT) was performed to assess anxiety. The OFT results were analyzed by repeated measures ANOVA and PMT by MANOVA. The results show that there are no significant differences in the OFT, while the animals treated with both doses of the macerate exhibit a significant increase with respect to control group in the PMT, both in the %time in open arms (p = 0.00; F = 4.37; df = 18) as in the % entrance to open arms (p = 0.01 f = 4.37 df = 18). Although macerated has no antidepressant-like effect, it induces an anxiolytic effect that could contribute to the efficacy of depression treatment.La depresión se encuentra dentro de las cinco enfermedades más prevalentes del mundo, afectando aproximadamente a 322 millones de personas (Fusar-Poli L et al. 2019). Estudios previos han demostrado que el 80-90% de individuos con trastorno depresivo mayor tienen síntomas de ansiedad. La sobreposición de ansiedad y depresión tiene peores resultados con un porcentaje más alto de resistencia al tratamiento (Coplan et al. 2015).  Esto genera la necesidad de nuevas investigaciones en búsqueda de un tratamiento más eficaz, lo que ha llevado indagar enfoques alternativos dentro de la etnomedicina, siendo nuestro objetivo estudiar el efecto de Glandularia Cabrerae (GC), planta nativa de Córdoba y La Rioja, sobre la conducta de ansiedad y depresión en un modelo murino. Nosotros hipotetizamos que el extracto de esta planta induce efecto predictivo antidepresivo dado que comparte género con Glandularia dissecta, usada popularmente en afecciones nerviosas. Ratones macho albinos Swiss-N:NIH , fueron tratados con un extracto hidroalcohólico de GC  (macerado etanol/agua 1:1 al 5% p/v) el cual fue liofilizado y posteriormente resuspendido con solución fisiológica. Se empleó un set de 8 animales control tratados con solución fisiológica, 8 animales tratados con una dosis de 55 mg/kg peso corporal y 8 con una dosis de 175 mg/kg. El tratamiento durante 28 días se realizó por vía oral forzada. Los animales fueron expuestos al test de campo abierto (TCA) para estudiar la conducta de tipo depresiva, antes del inicio de tratamiento y al día 27.  El día 28 se realizó el Test de laberinto elevado en cruz (LEC) para valorar ansiedad. Los resultados de TCA fueron analizados por ANOVA de medidas repetidas y los de LEC por MANOVA. Los resultados muestran que no hay diferencias significativas en el TCA, en tanto Los animales tratados con ambas dosis del macerado exhiben un incremento significativo respecto al grupo Control en el LEC, tanto en el %Tiempo en Brazos Abiertos (p =0,00; F=4,37; df=18) como en el % Entrada a Brazos Abiertos (p = 0,01 F=4,37 df=18). El macerado no presenta efecto antidepresivo, pero induce un efecto ansiolítico que podría contribuir a la eficacia del tratamiento de la depresión.

Quantum Control at the Boundary

We present a scheme for controlling the state of a quantum system by modifying the boundary conditions. This constitutes an infinite-dimensional control problem. We provide conditions for the existence of solutions of the dynamics and prove that this system is approximately controllable

Ghrelin Modulates the fMRI BOLD Response of Homeostatic and Hedonic Brain Centers Regulating Energy Balance in the Rat

The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin’s BOLD effect in a region specific manner. In females, the estradiol milieu does not influence the BOLD response to ghrelin

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09–13.2), and in patients carrying the UGT1A1*28/*28 genotype, OR=4.43 (95% CI=1.30–15.2). Patients with UGT1A1*28/*28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70–27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01–2.45)

Evolution of Alternative Splicing Regulation: Changes in Predicted Exonic Splicing Regulators Are Not Associated with Changes in Alternative Splicing Levels in Primates

Alternative splicing is tightly regulated in a spatio-temporal and quantitative manner. This regulation is achieved by a complex interplay between spliceosomal (trans) factors that bind to different sequence (cis) elements. cis-elements reside in both introns and exons and may either enhance or silence splicing. Differential combinations of cis-elements allows for a huge diversity of overall splicing signals, together comprising a complex ‘splicing code’. Many cis-elements have been identified, and their effects on exon inclusion levels demonstrated in reporter systems. However, the impact of interspecific differences in these elements on the evolution of alternative splicing levels has not yet been investigated at genomic level. Here we study the effect of interspecific differences in predicted exonic splicing regulators (ESRs) on exon inclusion levels in human and chimpanzee. For this purpose, we compiled and studied comprehensive datasets of predicted ESRs, identified by several computational and experimental approaches, as well as microarray data for changes in alternative splicing levels between human and chimpanzee. Surprisingly, we found no association between changes in predicted ESRs and changes in alternative splicing levels. This observation holds across different ESR exon positions, exon lengths, and 5′ splice site strengths. We suggest that this lack of association is mainly due to the great importance of context for ESR functionality: many ESR-like motifs in primates may have little or no effect on splicing, and thus interspecific changes at short-time scales may primarily occur in these effectively neutral ESRs. These results underscore the difficulties of using current computational ESR prediction algorithms to identify truly functionally important motifs, and provide a cautionary tale for studies of the effect of SNPs on splicing in human disease

Hypertension in children with chronic kidney disease: pathophysiology and management

Arterial hypertension is very common in children with all stages of chronic kidney disease (CKD). While fluid overload and activation of the renin–angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension. Moreover, several drugs commonly administered in CKD, such as erythropoietin, glucocorticoids and cyclosporine A, independently raise blood pressure in a dose-dependent fashion. Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes, an active screening approach should be adapted in patients with all stages of CKD. Before one starts antihypertensive treatment, non-pharmacological options should be explored. In hemodialysis patients a low salt diet, low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria, due to their additional anti-proteinuric properties. Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin–angiotensin system blockade. Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target, but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes

The effects of Δ9-tetrahydrocannabinol on the dopamine system

Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug