Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy

The RNA binding protein Human antigen R (HuR) interacts with specific AU-rich domains in target mRNAs and is highly expressed in many cell types, including cardiomyocytes. However, the role of HuR in cardiac physiology is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic cardiac myocytes. Specifically, HuR cytoplasmic translocation is significantly increased in NRVMs (neonatal rat ventricular myocytes) following treatment with phenylephrine or angiotensin II, agonists of two independent Gαq-coupled GPCRs known to induce hypertrophy. This Gq-mediated HuR activation is dependent on p38 MAP kinase, but not canonical Gq-PKC signaling. Furthermore, we show that HuR activation is necessary for Gq-mediated hypertrophic growth of NRVMs as siRNA-mediated knockdown of HuR inhibits hypertrophy as measured by cell size and expression of ANF (atrial natriuretic factor). Additionally, HuR overexpression is sufficient to induce hypertrophic cell growth. To decipher the downstream mechanisms by which HuR translocation promotes cardiomyocyte hypertrophy, we assessed the role of HuR in the transcriptional activity of NFAT (nuclear factor of activated T cells), the activation of which is a hallmark of cardiac hypertrophy. Using an NFAT-luciferase reporter assay, we show an acute inhibition of NFAT transcriptional activity following pharmacological inhibition of HuR. In conclusion, our results identify HuR as a novel mediator of cardiac hypertrophy downstream of the Gq-p38 MAPK pathway, and suggest modulation of NFAT activity as a potential mechanism

Heavy metals and radioactivity reduction from acid mine drainage lime neutralized sludge

Abstract: The worldwide known treatment processes of acid mine drainage result into the formation of hydrous ferric oxides that is amorphous, poorly crystalline and into the generation of hazardous voluminous sludge posing threat to the environment. Applicable treatment technologies to treat hazardous solid material and produce useful products are limited and in most cases nonexistence. A chemical treatment process utilizing different reagents was developed to treat hazardous acid mine drainage (AMD) sludge with the objectives to conduct radioactivity assessment of the sludge generated from lime treatment process and determine the reagent that provides the best results. Leaching with 0.5 M citric acid, 0.4 M oxalic acid, 0.5 M sodium carbonate and 0.5 M sodium bicarbonate was investigated. The leaching time applied was 24 hours at 25 oC. The characterization of the raw AMD revealed that the AMD sludge from lime treatment process is radioactive. The sludge was laden with radioactive elements namely, 238U, 214Pb, 226Ra, 232Th, 40K and 214Bi. 0.5 M citric acid provided the best results and the hazardous contaminants were significantly reduced. The constituents in the sludge after treatment revealed that there is a great potential for the sludge to be used for other applications such as building and construction

Synthesis and receptor profiling of Stemona alkaloid analogues reveal a potent class of sigma ligands

Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry was subsequently adapted to afford a series of analogue sets bearing simplified, diverse Stemona-inspired skeleta. Over 100 of these analogues were subjected to general G protein-coupled receptor profiling along with the known antitussive compound, neostenine; this led to the identification of hit compounds targeting several receptor types. The particularly rich hit subset for sigma receptors was expanded with two focused library sets, which resulted in the discovery of a fully synthetic, potent chemotype of sigma ligands. This collaborative effort combined the development of synthetic methods with extensive, flexible screening resources and exemplifies the role of natural products in bioactivity mining

Molecular Landscape of the Ribosome Pre-initiation Complex during mRNA Scanning: Structural Role for eIF3c and Its Control by eIF5

Citation: Obayashi, E., Luna, R. E., Nagata, T., Martin-Marcos, P., Hiraishi, H., Singh, C. R., . . . Asano, K. (2017). Molecular Landscape of the Ribosome Pre-initiation Complex during mRNA Scanning: Structural Role for eIF3c and Its Control by eIF5. Cell Reports, 18(11), 2651-2663. doi:10.1016/j.celrep.2017.02.052During eukaryotic translation initiation, eIF3 binds the solvent-accessible side of the 40S ribosome and recruits the gate-keeper protein eIF1 and eIF5 to the decoding center. This is largely mediated by the N-terminal domain (NTD) of eIF3c, which can be divided into three parts: 3c0, 3c1, and 3c2. The N-terminal part, 3c0, binds eIF5 strongly but only weakly to the ribosome-binding surface of eIF1, whereas 3c1 and 3c2 form a stoichiometric complex with eIF1. 3c1 contacts eIF1 through Arg-53 and Leu-96, while 3c2 faces 40S protein uS15/S13, to anchor eIF1 to the scanning pre-initiation complex (PIC). We propose that the 3c0:eIF1 interaction diminishes eIF1 binding to the 40S, whereas 3c0:eIF5 interaction stabilizes the scanning PIC by precluding this inhibitory interaction. Upon start codon recognition, interactions involving eIF5, and ultimately 3c0:eIF1 association, facilitate eIF1 release. Our results reveal intricate molecular interactions within the PIC, programmed for rapid scanning-arrest at the start codon

Predictor variables and screening protocol for depressive and anxiety disorders in cancer outpatients

Background Cancer patients are at increased risk of persistent depressive and anxiety symptoms and disorders compared to the general population. However, these issues are not always identified, which may worsen the prognosis and increase morbidity and mortality. Therefore, the objectives of this study are to identify predictor variables (demographic and clinical) for the development of mood and anxiety disorders in cancer outpatients and to propose a probabilistic screening protocol considering these variables and certain standardized screening instruments. Methods A total of 1,385 adults, of both genders, receiving outpatient cancer care were evaluated using a questionnaire and screening instruments. Thereafter, 400 of these subjects responded to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-IV) by telephone to confirm or rule out the presence of a Current Major Depressive Episode (CMDE) or Anxiety Disorder (AD). Results Of the patients surveyed, 64% met the criteria for CMDE and 41% for AD. Female gender was found to be a risk factor for both disorders, and the presence of previous psychiatric history and marital status (divorced and widowed) were risk factors for anxiety disorders. When scoring above the recommended cutoff score, the screening instruments also indicated a risk of the studied disorders. Based on these findings, a screening protocol and nomograms were created for the quantification, combination and probabilistic estimate of risk, with accuracy indicators >0.68. Conclusion The prevalence rates for the disorders under study are extremely high in cancer patients. The use of the proposed protocol and nomogram can facilitate rapid and wide screening, thus refining triage and supporting the establishment of criteria for referral to mental health professionals, so that patients can be properly diagnosed and treated.info:eu-repo/semantics/publishedVersio

Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Background: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.This work was sponsored by grants from Acción Estratégica en Salud (PI13/00297 and PI11/00581), the Neurosciences and Aging Foundation, the Francisco Soria Melguizo Foundation, Octopharma, and Parkinson Madrid (PI2012/0032).S

Evaluating the association between artificial light-at-night exposure and breast and prostate cancer risk in Spain (MCC-Spain Study)

Background: Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers. Objectives: We evaluated the association of exposure to ALAN during sleeping time with breast and prostate cancer in a population based multicase–control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night. Methods: We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008–2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012–2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject. Results: Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer [adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47 ; 95% CI: 1.00, 2.17] and prostate cancer (OR=2.05 ; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in “quite illuminated” bedrooms had a higher risk of prostate cancer (OR=2.79 ; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77 ; 95% CI: 0.39, 1.51). Conclusion: Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP183

Efficient synthesis of gamma-lactams by a tandem reductive amination/lactamization sequence

A three-component method for the synthesis of highly substituted gamma-lactams from readily available maleimides, aldehydes, and amines is described. A new reductive amination/intramolecular lactamization sequence provides a straightforward route to the lactam products in a single manipulation. The general utility of this method is demonstrated by the parallel synthesis of a gamma-lactam library

Effect of differnet management system on rutting behavior and behavioral repertoire of housed Maghrebi male camels (Camelus dromedarius)

Camel management has been changing in recent years from an extensive to a semi-intensive or intensive system, particularly for breeding bulls and dairy dromedary camels. Captivity may affect animal welfare, and low libido is the major complaint for housed breeding bulls. Since welfare status could also affect reproductive performance, the aim of this study was to evaluate different management practices on behavior, particularly on sexual behavior, and to identify some behavioral needs of male dromedary camels reared for semen collection. The effects of the following management systems on their behavior were compared: i) traditional: housing in a single stall for 24 hours (H24), ii) housing in a single stall for 23 hours with one hour free in the paddock (H23) and iii) housing in a single stall for 22 hours and 30 min with 1 h paddock time and 30 min exposure to a female camel herd (ExF). During the trial, blood cortisol concentrations were assessed and camels were filmed daily for thirty minutes in the mornings and during a female passage in the evenings. Videos were analyzed in order to fill out a focal sampling ethogram and to score sexual behavior. As a result, there were no differences between the H24 and H23 systems, whereas ExF had a significant positive impact on their sexual behavior score and behavioral repertoire, further reducing cortisol levels. Overall, it seems that male dromedary camel welfare status improves when their behavioral needs for social interaction and movement are satisfied