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Elephant grass [Pennisetum purpureum Schumach. syn. Cenchrus purpureus (Schumach.) Morrone], also known as Napier grass and King grass, includes varieties Taiwán, Gigante, Merkerón, Maralfalfa, and others. The grass achieves high biomass production in tropical-subtropical, temperate, and arid areas. The high-water concentration of elephant grass suggests that ensiling could offer an alternative way to preserve the nutritional quality of the grass during storage, however, some considerations should be addressed because of the particularities of the grass. Ensiling elephant grass may produce adequate fermentation but could suffer effluent losses and subsequent losses of nutrients due to leaching. To improve fermentation and nutrient characteristics of elephant grass silages, several studies were conducted with the inclusion of additives. Lactic acid bacteria inocula have reduced pH and increased crude protein content of elephant grass silage, but aerobic stability of silages could be affected by the bacterial inoculation. There is limited information, however, on the potential of different silage inoculants to reduce growth of spoilage microorganisms during the aerobic phase of silage prepared with elephant grass. Exogenous fibrolytic enzymes also may improve elephant grass silage quality by enhancing microbial fiber-degradation with subsequent increase in lactic acid and its associated pH reduction. Another study approach to improve fermentation and nutritional quality of elephant grass silages involved the addition of different feeds at ensiling, including conventional feeds such corn, wheat, rice bran, and molasses or alternative feeds such as different dehydrated by-products obtained from the food industries of juice and jelly. In the manuscript, the presented scientific information shows the great potential of the different manipulations to improve the quality of elephant grass silages and with possible enhance of the economic profit and sustainability of livestock farming in the tropical areas.

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The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.

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Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT. Herein, we report our efforts on the exploration of novel small molecule macrocycles (MCXs) as dual PI3K/mTOR inhibitors. Macrocyclization is an attractive approach used in drug discovery, as the semi-rigid character of these structures could provide improved potency, selectivity and favorable pharmacokinetic properties. Importantly, this strategy allows access to new chemical space thus obtaining a better intellectual property position. A series of MCXs based on GSK-2126458, a known clinical PI3K/mTOR inhibitor is described. These molecules showed potent biochemical and cellular dual PI3K/mTOR inhibition, demonstrated strong antitumoral effects in human cancer cell lines, and displayed good drug-like properties. Among them, MCX 83 presented remarkable selectivity against a panel of 468 kinases, high in vitro metabolic stability, and favorable pharmacokinetic parameters without significant CYP450 and h-ERG binding inhibition. This profile qualified this compound as a suitable candidate for future in vivo PK-PD and efficacy studies in mouse cancer models.

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Acacia farnesiana pods are rich in secondary metabolites and their biological activities have been recorded as antibacterial, antioxidant and anthelmintic. Previously, an in vitro bioguided study showed the important ovicidal and larvicidal effects of an organic fraction (EtOAc-F) from a hydroalcoholic extract of A. farnesiana pods against Haemonchus contortus. The present study aimed to assess the in vivo anthelmintic effect of EtOAc-F from A. farnesiana pods on the H. contortus faecal egg elimination in female lambs and on the infective larvae (L3) population reduction in coprocultures. The EtOAc-F was obtained from a hydroalcoholic extract from A. farnesiana pods through chromatographic procedures; additionally, some secondary compounds were identified using high-performance liquid chromatography (HPLC). Twenty-one 'Katahdin' crossbred female lambs ranging from three to four months of age, with body weights 21.9 ± 0.39 kg were used. Animals were orally infected with H. contortus (L3) by a single dose of 350 L3/kg BW. Three experimental groups (n = 7) were assigned as follows: 1) Control (untreated), 2) Albendazole, as a positive control (at 7.5 mg/kg BW, unique dose) and 3) EtOAc-F (at 100 mg/kg BW, once every third day, with three applications in total). Individual faecal samples were collected once a week for 5 weeks (at days 38, 45, 52, 59 and 66) post-treatment, to measure the faecal egg counts (FEC) and to obtain the H. contortus (L3) population from faecal cultures. The highest FEC reduction caused by EtOAc-F was 67.7%; meanwhile, albendazole showed a total FEC reduction after the second week post-treatment (day 45). On the other hand, the fraction caused an important reduction in the larval population in coprocultures (54.3-68.5%). The phytochemical analysis revealed the presence of galloyl derivatives and flavonoids as major compounds. The A. farnesiana pods could serve as a natural anthelmintic for the control of H. contortus, and perhaps for controlling other parasites of veterinary importance.

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CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC50 = 8.25 nM). Co-crystal studies and the remarkable selectivity profile of compound 2 are presented. Compound 2 showed moderate reduction of phosphorylation of CDK8 substrate STAT1 in cells, in line with other reported Type II CDK8 inhibitors. We propose herein an alternative to find a potential therapeutic use for this chemical series.

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ETHNOPHARMACOLOGY RELEVANCE: Acacia farnesiana (L.) Willd is a shrub legume used as condiment, medicinal plant and bioactive herbage. This species is used in traditional medicine of several countries to relieve the symptoms of gastrointestinal diseases, diarrhoea, stomach pain and typhoid as well as astringent, antidysenteric and anthelmintic. Some studies have shown that this plant displayed anthelmintic activity against several gastrointestinal nematode parasites of livestock, and also against parasites of human beings, such as malaria. AIM OF THE STUDY: This work describes the isolation and chemical identification of the anthelmintic compounds of Acacia farnesiana pods against eggs and infective larvae of the sheep parasitic nematode Haemonchus contortus. The bio-guided chemical fractioning of A. farnesiana pods using ethyl acetate against H. contortus eggs and infective larvae allowed for the identification of naringenin 7-O-(6″-galloylglucoside) (flavonol group) as the compound responsible for the anthelmintic activity against this important parasitic nematode. MATERIALS AND METHODS: Anthelmintic activity was assessed using the egg hatching inhibition assay (EHI) and mortality tests. A complete hydroalcoholic extract (HA-E) at 12.5-50 mg/mL, an aqueous fraction (Aq-F) at 3.12-25 mg/mL and an ethyl acetate fraction (EtOAc-F) at 3.12-25 mg/mL were analysed in the first selection phase. The purification of compounds through the chromatographic separation of the organic fraction resulted in nine less complex mixtures (C1F1, C1F2, C1F3, C1F4, C2F1, C2F2, C2F3, C2F4 and C2F5) that were assessed at 0.62-5 mg/mL concentrations. In addition, thiabendazole (0.6 mg/mL) and ivermectin (5 mg/mL) were used as positive controls. Likewise, distilled water and 4% methanol were used as negative controls. The bioactive compounds of EtOAc-F were obtained and characterised through chromatographic processes like open column chromatography, thin layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC) and gass chromatography-mass detection (GC-MS). Bioactive compounds were identified by spectroscopy (1H and 13C NMR) and mass spectrometric analysis. Additionally, the H. contortus eggs and infective larvae exposed to the bioactive compounds were observed through environmental scanning electron microscopy (ESEM) and confocal laser scanning microscopy (CLSM). Data were analysed based on a completely randomised design using ANOVA through a general linear model. RESULTS: The EtOAc-F fraction showed the highest ovicidal and larvicidal activities, at close to 100% at 3.12 and 6.25 mg/mL, respectively. The treatments C1F2, C1F3 and C2F3 displayed the main ovicidal activity (80-100%) at 2.5 mg/mL. The major compounds found in these sub-fractions were identified as galloyl derivatives and flavanones, including gallic acid (1), methyl gallate (2), ethyl gallate (3), naringin (4), naringenin 7-O-(4″, 6″-digalloylglucoside) (5), naringenin 7-O-(6″-galloylglucoside) (6) and naringenin (7). Likewise, the ESEM and CLSM images showed that the assessed compounds adhered to the eggshell and the external cuticle of the larvae. CONCLUSION: These results indicate that A. farnesiana pods contain nematocidal compounds and might be promising natural anthelmintic agents against H. contortus. This leguminous plant could be used as a nutraceutical food source for the control of gastrointestinal nematodes in small ruminants.

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UNLABELLED: The purpose of this study was to adapt the 'Voice and You' Scale (VAY) (Hayward, Denney, Vaughan, & Fowler, 2008) to Spanish and explore its psychometric properties for measuring the perceived relationship with voices. A sample of 50 psychiatric patients with verbal auditory hallucinations (48 had a psychotic disorder and two a borderline personality disorder) was used. Its reliability was calculated using the Cronbach's α and test-retest, and concurrent validity by the Pearson correlation coefficient of the VAY with the Beliefs About Voices Questionnaire and the Psychotic Symptom Rating Scales. The results showed that internal consistency of the Spanish version of the VAY ranged from 0.74 to 0.84 on the various subscales, and test-retest reliability varied from 0.74 to 0.83 on three subscales (voice 'dominance', 'intrusiveness' and hearer 'dependence'), and was lower (0.68) on the hearer 'distance' subscale. Concurrent validity was acceptable as significant associations were found with the Beliefs About Voices Questionnaire and the Psychotic Symptom Rating Scales subscales. It is concluded that the Spanish version of the VAY is a reliable and valid instrument that can assist the exploration of voices within relational frameworks across research and clinical domains. KEY PRACTITIONER MESSAGE: The Spanish version of the VAY is a reliable, valid instrument for evaluating the perception a person can have about his or her relationship with the voices and how the person relates to them. Voices that are perceived as relating dominantly and intrusively, and from whom distance is sought, seem to be distressing and cause disturbance. Voices that are related to dependently are perceived as having benevolent intent and are engaged with. Benevolent or neutral voices may be considered as intrusive because of the intensity and frequency with which they are experienced.

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INTRODUCTION: The purpose of this study was to investigate the relationships among self-focused attention, mindfulness and distress caused by the voices in psychiatric patients. METHODS: Fifty-one individuals with a psychiatric diagnosis participated in this study. The Psychotic Symptom Rating Scale (PSYRATS) emotional factor was applied to measure the distress caused by the voices, the Self-Absorption Scale (SAS) was given for measuring the levels of self-focused attention, and the Mindful Attention Awareness Scale (MAAS) was used to measure mindfulness. RESULTS: The results showed that distress caused by the voices correlated positively with self-focused attention (private and public) and negatively with mindfulness. A negative correlation was also found between mindfulness and self-focused attention (private and public). Finally, multiple linear regression analysis showed that public self-focus was the only factor predicting distress caused by the voices. CONCLUSIONS: Intervention directed at diminishing public self-focused attention and increasing mindfulness could improve distress caused by the voices.

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INTRODUCCIÓN. Las infecciones del sitio quirúrgico son muy frecuentes tras cirugía colo-rectal. El objetivo de este estudio es analizar cuantitativa y cualitativamente dichas infecciones en nuestro servicio. MATERIAL Y MÉTODOS. Se realizó un estudio observacional en 23 enfermos sometidos a resecciones colo-rectales programadas a los que se administró la profilaxis antibiótica habitual de nuestro servicio, gentamicina y metronidazol (G+M). Se analizó la presencia de infecciones incisionales superficiales o profundas y los gérmenes causantes. Ante los resultados, y guiados por los cultivos, se decidió cambiar la profilaxis por amoxicilina y ácido clavulánico (AMC), y continuar el estudio en 38 enfermos. RESULTADOS. Los enfermos que recibieron como profilaxis G+M tuvieron un índice de infecciones incisionales del 48%. En el 90% de esas infecciones había Escherichia coli, y en un 80% enterococos o estreptococos. En el grupo de AMC hubo un índice de infecciones incisionales del 19%, siendo la diferencia con el grupo de G+M estadísticamente significativa (p=0,021). En los cultivos de sus heridas no había enterococos ni estreptococos. DISCUSIÓN. El índice de infecciones incisionales del grupo G+M es superior al comunicado en cirugía colo-rectal programada. El predominio de Escherichia coli en estas infecciones es habitual, no así la elevada presencia de cocos positivos, especialmente enterococos. Estos resultados exigen un cambio en nuestra profilaxis antibiótica, para cubrir estreptococos y enterococos, además de bacilos negativos y anaerobios. AMC parece la opción más lógica. Nuestros resultados corroboran esta hipótesis (AU)

BACKGROUND. Surgical site infections are very common after colorectal surgery. The objective of this study is to analyze quantitatively and qualitatively such infections in our service. METHOD. An observational study was performed in 23 patients undergoing elective colorectal resections who received the usual antibiotic prophylaxis of our service, gentamicin and metronidazole (G+M). Superficial and deep incisional infections, as well as microbes that cause them, were analyzed. Given the results, and guided by the cultures, it was decided to change the prophylaxis to amoxicillin and clavulanic acid (AMC), and continue the study in 38 patients. RESULTS. Patients who were given G+M for prophylaxis had incisional infection rate of 48%. Escherichia coli was present in 90% of these infections, enterococci or streptococci were present in 80% of these infections. In the AMC group there was an incisional infection rate of 19%. The observed difference with the G+M group is statistically significant (p = 0.021). Enterococci and streptococci were not isolated in their incisions. CONCLUSION. The rate of incisional infections in the G+M group is higher than the usually reported in elective colorectal surgery. The predominance of Escherichia coli is usual in these infections, but not the high presence of positive cocci, especially enterococci. These results call for a change in our antibiotic prophylaxis to cover streptococci and enterococci, as well as gram-negative bacilli and anaerobes. AMC seems the most logical choice. Our results support this hypothesis (AU)

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Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies. ETP-46992 showed tumor growth inhibition in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474).

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PIM kinases have become targets of interest due to their association with biochemical mechanisms affecting survival, proliferation and cytokine production. 1,2,3-Triazolo[4,5-b]pyridines were identified as PIM inhibitors applying a scaffold hopping approach. Initial exploration around this scaffold and X-ray crystallographic data are hereby described.

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Las neoplasias endocrinas múltiples constituyen síndromes con herencia autosómica dominante en los cuales hay afectación tumoral de dos o más glándulas endocrinas. Presentamos un paciente de sexo masculino, de 51 años de edad, con inapetencia sexual, cefalea, pirosis, halitosis y debilidad muscular de 3 años de evolución. Tras el diagnóstico de sospecha por su médico de atención primaria y su posterior ingreso hospitalario se le diagnosticó macroadenoma hipofisario con hiperprolactinemia, hiperparatiroidismo primario y neoplasia renal. Concluyendo, un probable MEN 1. Dada la rareza del caso y que su sospecha se realizó en el ámbito de atención primaria, consideramos oportuna su presentación (AU)

Multiple endocrine neoplasms are a series of autosomal-dominant inherited syndromes with tumour involvement in at least two endocrine glands. We report a case of a 51-year old male who had lack of sexual appetite, headache, heartburn, halitosis and muscle weakness for three years. After suspicion by his family practitioner and his admittance to the hospital he was diagnosed with a pituitary macroadenoma with hyperprolactinemia, primary hyperparathyroidism and a renal neoplasm, hence concluding a likely MEN type 1. Given the peculiarity of this case and its diagnosis in the context of primary care, we believe that this should be reported (AU)

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Melatonin was recently shown to be a component of the antioxidative defense system of organisms due to its free radical scavenging ability and to its capacity to stimulate several antioxidant enzymes. In this report, we studied the endogenous rhythm of the antioxidant enzyme superoxide dismutase (SOD) in three different tissues (cerebral cortex, liver and lung) of chick (Gallus domesticus) (three weeks, at age and sacrificed every 2 hr). During the study the chicks were under a light:dark cycle of 12:12. Total antioxidant status of the plasma was correlated with physiological blood melatonin concentrations. Superoxide dismutase activity exhibited a marked 24 hr rhythm in cerebral cortex, lung and liver, with peak activity coincident with the melatonin and total antioxidant status peaks. The exposure of chicks to constant light for 7 days eliminated the melatonin rhythm as well as the peaks in superoxide dismutase activity and the total antioxidant status. These findings suggest that the melatonin rhythm may be related to the nighttime increase in the superoxide dismutase activity and to total antioxidant capacity of the blood.

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The infection by Opecoeloides furcatus and Poracanthium furcatum (Opecoeliidae) was studied in 121 Mullus barbatus and 113 M. surmuletus collected from the Spanish south-eastern Mediterranean. The prevalence of infection was most frequent in M. surmuletus with values of 81.42% for O. furcatus and 38.05% for P. furcatum. In M. barbatus the prevalences of O. furcatus and P. furcatum were 54.54% and 14.88% respectively. Statistically significant differences were found between the infection of the two hosts with P. furcatum. No significant differences in worm burdens could be attributable to host size or to seasonal changes, although a lower infection of M. barbatus by O. furcatus occurred in the autumn. Furthermore, the electrophoretic mobility of the enzyme malic dehydrogenase (MDH) was also studied and both digeneans presented different patterns, corresponding in both cases to homozygotic genotypes.

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BACKGROUND: An epidemiological study on intestinal parasites has been carried out in Northern Morocco (province of Tangier, Tetuan and Larache). A comparative Study has been made at a provincial, city and areas (urban and rural) level. Also the SPI (simple parasitism index) and the CPI (comparative parasitism index) distribution. METHODS: The coprological method used were: direct, concentration (Fulleborn, Telemann and Kato) method and ye test technics (Ferric Hematoxylin and E. Chlorazol Black). RESULTS: The number of faecal samples were 4643, parasitism people 2637 and the total number of parasites were 4816. SPI 56.79% and CPI 1.83. Among the Protozoa, Entamoeba coli, followed by Endolimax nana, Giardia lamblia and Iodamoeba buetschlii prevailed, the other species coming a lung distance behind. Among the Helminths, Trichuris trichiura prevailed much more than the others; Ascaris lumbricoides followed and on the third place were Enterobius vermicularis and Hymenolepis nana. The percentage found for E. vermicularis was very high, since an appropriate technique of diagnosis was not used. The data have been statistically tested. CONCLUSIONS: We found a high rate of parasitism in the 3 provinces that have studied and an approximate number of two parasites per person. SPI and CPI are greater in Tetuan and Larache than in Tangier.

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Attention-deficit hyperactivity disorder (ADHD) is a type of disruptive behavior of unknown etiology with a prevalence of 2.5-5% in school-age children. The useful evaluation of the GRF-induced GH response as a marker in some mental disorders led us to study the response of GH to the exogenous administration of GRF (1-29) NH2 (150 micrograms, i.v.) in ADHD children (N = 12, age = 7.78 +/- 1.66 years) and healthy children (N = 6; age = 8.73 +/- 2.24 years) in order to evaluate the functioning of the somatotropinergic system (GRF-SS-GH-SM axis) and using this neuroendocrine test as a potential diagnostic marker and/or a therapeutic predictor in ADHD. While controls (CS) showed a maximum GH response to GRF 15 min after injection (37.15 +/- 29.56 ng/ml; basal GH = 5.49 +/- 4.71 ng/ml), ADHD children (basal GH = 2.28 +/- 1.66 ng/ml) exhibited a lower response with a plateau from 15 (21.32 +/- 10.00 ng/ml) to 60 min (26.48 +/- 23.72 ng/ml). Serum GH levels at 90 (17.23 +/- 14.45 vs. 5.99 +/- 2.82 ng/ml, p less than 0.05) and 120 min (11.89 +/- 8.63 vs. 4.12 +/- 1.66 ng/ml, p less than 0.05) were significantly higher in ADHD than in CS. According to the GRF-induced GH response elicited in ADHD, two different populations of patients can be distinguished; one group with high response of GH (AUC = 3372.21 +/- 1127.61 ng.min/ml) and another group with a hyporeactive GH (AUC = 1567.46 +/- 726.0 ng.min/ml, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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