Seventeen semicarbazone and thiosemicarbazone derivatives were prepared and tested in vitro against a chloroquine resistant strain of
Plasmodium falciparum (W2) to evaluate their antiplasmodial ...potential. Three thiosemicarbazones were found to be active against the parasite and non-toxic to human peripheral blood mononuclear cells (PBMC). Among these, compound
5b presented the lowest IC
50 value against
P. falciparum (7.2
μM) and was the least toxic in the PBMC proliferation assay (IC
50
=
73.5
μM). It was selected for in vivo tests on mice infected with
Plasmodium berghei (strain NK-65). The thiosemicarbazone
5b was able to reduce the parasitaemia by 61% at 20
mg/kg on day 7 after infection without any sign of toxicity to the animals. In comparison, the standard drug chloroquine at 15
mg/kg showed a reduction around 95%. These in vitro and in vivo results make
5b an interesting lead for further development.
Display omitted Semicarbazone and thiosemicarbazone derivatives were prepared and tested in vitro against a chloroquine resistant strain of
Plasmodium falciparum (W2) to evaluate their antiplasmodial potential. The thiosemicarbazone
5b was selected for in vivo tests on mice infected with
Plasmodium berghei (strain NK-65). The in vitro and in vivo results make
5b an interesting lead for further development.
Early events play a decisive role in virus multiplication. We have shown previously that activation of MAPK/ERK1/2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2) and ...protein kinase A are pivotal for vaccinia virus (VV) multiplication de Magalhães, Andrade, Silva, Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem. 276, 38353-38360. In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results also provide evidence that this pattern of kinase activation depends on virus multiplication and ongoing protein synthesis and is maintained independently of virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although involved, is not essential for prolonged ERK1/2 activation. Furthermore, our findings suggest that the VV-stimulated ERK1/2 activation also seems to require actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation. The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase) leads to phosphorylation of the ternary complex factor Elk-1 and expression of the early growth response (egr-1) gene, which kinetically paralleled the kinase activation. The recruitment of this pathway is biologically relevant, since its disruption caused a profound effect on viral thymidine kinase gene expression, viral DNA replication and VV multiplication. This pattern of sustained kinase activation after VV infection is unique. In addition, by connecting upstream signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2 cascade seems to play a decisive role not only at early stages of the infection, i.e. post-penetration, but is also crucial to define the fate of virus progeny.
Pitanga (Eugenia uniflora L.) cultivation has increased rapidly around the world, but most seedlings come from sexual propagation and thus present high genetic variability and respond differently to ...environmental conditions. This work studied the phenology and thermal requirement of pitanga genotypes in the Brazilian semiarid. Forty‐eight genotypes were evaluated in 2017 and 2018 in an experimental farm at the Federal Rural University of Semiarid, Mossoró, Brazil. The time and thermal requirement for phenological stages from fruit pruning to harvesting, and fruit production were evaluated. Highly productive and precocious genotypes were identified, and six groups were arranged based on dissimilarity.
Record of phenological stages of the pitanga (Eugenia uniflora L.) development under semiarid conditions in Mossoró, Brazil. DAP, days after fruit pruning.
Abstract
This study presents two years of characterization of a warm temperate rhodolith bed in order to analyse how certain environmental changes influence the community ecology. The biomass of ...rhodoliths and associated species were analysed during this period and
in situ
experiments were conducted to evaluate the primary production, calcification and respiration of the dominant species of rhodoliths and epiphytes. The highest total biomass of rhodoliths occurred during austral winter.
Lithothamnion crispatum
was the most abundant rhodolith species in austral summer. Epiphytic macroalgae occurred only in January 2015, with
Padina gymnospora
being the most abundant. Considering associated fauna, the biomass of Mollusca increased from February 2015 to February 2016. Population densities of key reef fish species inside and around the rhodolith beds showed significant variations in time. The densities of grouper (carnivores/piscivores) increased in time, especially from 2015 to 2016. On the other hand, grunts (macroinvertebrate feeders) had a modest decrease over time (from 2014 to 2016). Other parameters such as primary production and calcification of
L. crispatum
were higher under enhanced irradiance, yet decreased in the presence of
P. gymnospora
. Community structure and physiological responses can be explained by the interaction of abiotic and biotic factors, which are driven by environmental changes over time. Biomass changes can indicate that herbivores play a role in limiting the growth of epiphytes, and this is beneficial to the rhodoliths because it decreases competition for environmental resources with fleshy algae.
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest ...genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r
) between PSC and ulcerative colitis (UC) (r
= 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r
= 0.04) (P = 2.55 × 10
). UC and CD were genetically more similar to each other (r
= 0.56) than either was to PSC (P < 1.0 × 10
). Our study represents a substantial advance in understanding of the genetics of PSC.
1
The nuclear translocation of transcription factors may be a critical factor in the intracellular pathway involved in ischaemia/reperfusion (I/R) injury. Here, we examined whether NF‐κB and AP‐1 ...participated in the cascade of events leading to TNF‐α production, neutrophil recruitment, tissue injury and lethality following intestinal I/R.
2
The superior mesenteric artery (SMA) of mice was made ischaemic for 60 min followed by 30 min of reperfusion. The effects of NF‐κB and AP‐1 were studied by the administration of the thioredoxin inhibitor, MOL‐294 (methyl 4‐hydroxy‐4‐(8‐methyl‐1,3‐dioxo‐2‐phenyl‐2,3,5,8‐tetrahydro‐1H‐1,2,4triazolo1,2‐apyridazin‐5‐yl)but‐2‐ynoate), and the AP‐1 inhibitor, PNRI‐299 (N‐benzyl‐2‐(3‐cyanophenyl)‐1,3,7‐trioxo‐2,3,7,8‐tetrahydro‐1H‐1,2,4triazolo1,2‐apyridazine‐5‐carboxamide). After I/R, there was increase of translocation of NF‐κB, but not of AP‐1, in the intestine and lungs, as assessed by a gel shift assay.
3
Treatment with MOL‐294 inhibited the increase in vascular permeability, neutrophil accumulation, hemorrhage and proinflammatory cytokine levels, induced by intestinal I/R injury in the intestine. In the lungs, MOL‐294 partially inhibited edema formation, TNF‐α production, but did not alter neutrophil recruitment.
4
Treatment with MOL‐294 inhibited reperfusion‐associated lethality, an effect likely to be secondary to the inhibition of systemic TNF‐α levels. PNRI‐299 had no effects on the inflammatory changes or lethality induced by I/R injury.
5
Our results point to an important role for NF‐κB in triggering endogenous proinflammatory networks during intestinal I/R injury. Inhibition of NF‐κB prevents tissue injury and lethality, and this was associated with inhibition of TNF‐α production and decrease in neutrophil recruitment.
British Journal of Pharmacology (2005) 145, 246–254. doi:10.1038/sj.bjp.0706190
Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during ...development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.
Appropriation of signalling pathways facilitates poxvirus replication. Poxviruses, as do most viruses, try to modify the host cell environment to achieve favourable replication conditions. In the ...present study, we show that the early growth response 1 gene (egr-1) is one of the host cell factors intensely modulated by the orthopoxviruses VV (vaccinia virus) and CPV (cowpox virus). These viruses stimulated the generation of both egr-1 mRNA and its gene product, throughout their entire replication cycles, via the requirement of MEK mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase/ERK pathway. We showed that, upon VV infection, EGR-1 translocates into the nucleus where it binds to the EBS (egr-1-binding site) positioned at the 5' region of EGR-1-regulated genes. In spite of both viruses belonging to the same genus, several lines of evidence, however, revealed a remarkable contrast between them as far as the roles played by the MEK/ERK/EGR-1 pathway in their biological cycles are concerned. Hence (i) the knocking-down of egr-1 by siRNA (small interfering RNA) proved that this transcription factor is of critical relevance for VV biology, since a decrease of about one log cycle in virus yield was verified, along with a small virus plaque phenotype, whereas the gene silencing did not have a detrimental effect on either CPV multiplication or viral plaque size; (ii) while both pharmacological and genetic inhibition of MEK/ERK resulted in a significant decrease in VV yield, both approaches had no impact on CPV multiplication; and (iii) CPV DNA replication was unaffected by pharmacological inhibition of MEK/ERK, but phosphorylation of MEK/ERK was dependent on CPV DNA replication, contrasting with a significant VV DNA inhibition and VV DNA replication-independence to maintain ERK1/2 phosphorylation, observed under the same conditions.
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest ...comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.
Abstract
Extrusion is a thermomechanical process that can reduce the content antinutritional factors in soybean, improving the use of its nutrients by pigs. The purpose of this study was to evaluate ...extruded corn-soybean grain blends, replacing soybean meal in weanling pig diets, on pig growth performance from 21 to 63 d old. Ground corn and the corn-soybean blend (75.27% of ground corn and 24.73%) were extruded at 120°C in a single-screw extruder. One hundred and sixty crossbred weaned pigs (6.02 ± 0.63 kg) were used in a three-phase feeding program (21-35, 36-49, 50-63 days of age) and fed a basal diet (BD - extruded corn, dairy product, spray dried plasma, and soybean meal) or one of four diets in which soybean meal was replaced for deactivated (DS) or extruded (EX) corn-soybean blend, in 50 or 100%, generating diets DS50, DS100, EX50 and EX100. Diets were formulated to provide 3.40, 3.38, and 3.20 Mcal of ME/kg; 220, 215, and 190 g/kg of CP; and 14.5, 13.3, and 10.9 g/kg of digestible lysine, in phases 1, 2, and 3, respectively. A randomized block design based on initial BW was used. The data was submitted to ANOVA and means were separated using Tukey test (5%). Pigs fed diets EX50 and EX100 presented reductions (P< 0.05) in ADG (16-50%), final BW and G:F (13-33%) compared to pigs submitted to diets SBM100, DS50 or DS100 in phases 1 and 2. ADG, ADFI, and G:F of pigs were not affected (P >0.05) in phase 3, but final BW of pigs fed extruded corn-soybean blend were lower (P< 0.05) than that of pigs fed other diets. The extrusion temperature may have been insufficient to inactivate the anti-nutritional factors of soybean that probably reduced pig growth performance. The inclusion of extruded corn-soybean blend in replacement of soybean meal reduced growth performance of pigs.
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