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nts in FASD could be the consequence, in part, of pregnancies in which the mother was also iron inadequate.Oncostatin-M (OSM) is a patho-physiologically important pleiotropic, multifunctional cytokine. OSM mRNA sequence analysis revealed that its 3'UTR contains three highly conserved GC-rich cis-elements (GCREs) whose role in mRNA stability is unidentified. In the present study, the functional role of the proximal GC-rich region of osm 3'-UTR (GCRE-1) in post-transcriptional regulation of osm expression in U937 cells was assessed by transfecting construct containing GCRE-1 at 3'-end of a fairly stable reporter gene followed by analysis of the expression of the reporter. GCRE-1 showed mRNA destabilizing activity; however, upon PMA treatment the reporter message containing GCRE-1 was stabilized. This stabilization is owing to a time-dependent progressive binding of trans-factors (at least five proteins) to GCRE-1 post-PMA treatment. Nucleolin was identified as one of the proteins in the RNP complex of GCRE-1 with PMA-treated U937 cytosolic extracts by oligo-dT affinity chromatography of poly-adenylated GCRE-1. Immuno-blot revealed time-dependent enhancement of nucleolin in the cytoplasm which in turn directly binds GCRE-1. RNA co-immunoprecipitation confirmed the GCRE-1-nucleolin interaction in vivo. To elucidate the functional role of nucleolin in stabilization of osm mRNA, nucleolin was overexpressed in U937 cells and found to stabilize the intrinsic osm mRNA, where co-transfection with the reporter containing GCRE-1 confirms the role of GCRE-1 in stabilization of the reporter mRNA. Thus, in conclusion, the results asserted that PMA treatment in U937 cells leads to cytoplasmic translocation of nucleolin that directly binds GCRE-1, one of the major GC-rich instability elements, thereby stabilizing the osm mRNA.Dapoxetine, a selective serotonin reuptake inhibitor, is considered an antidepressant drug and has been developed for the treatment of premature ejaculation. Hence the objective was to assess whether dapoxetine administration to male rats adversely affect sexual behavior and pregnancy outcomes after mating with untreated female rats. Proven fertile male rats were gavaged with 0, 2.0, 4.0 and 8.0 mg dapoxetine per kg body weight (bw) per day (DC, DI, DII and DIII groups, respectively) for 70 days prior to mating with untreated female rats. Weight gain, organ weights and feed consumption were decreased significantly in the DII and DIII groups. A significant decline in the number of spermatozoa in the DII and DIII groups is attributed to a significant decrease in testosterone, luteinizing hormone and follicle-stimulating hormone. Levels of prolactin were significantly increased in the DII and DIII groups. Rats treated with a high dose of dapoxetine (8.0 mg kg(-1)) showed a significant inhibition in sperm motility and increment in sperm abnormalities. There was a pronounced decrease in fertility index in females mated with males treated chronically with 4.0 and 8.0 mg per kg bw dapoxetine. In addition, the treatment markedly increased the number of fetal resorptions in female rats impregnated by males in the DII and DIII groups reflecting their infertility. The number of implantation sites and the number of viable fetuses were also notably decreased in female rats impregnated by males given 4.0 or 8.0 mg kg(-1) dapoxetine. These findings suggest that the long-term dapoxetine at high dosages causes failure of the fertilization or successful impregnation of the females mated with dapoxetine-treated male rats, which were clearly able to copulate. A detrimental effect of dapoxetine on fertility parameters was also revealed.Bacteriolytic enzymes often possess a C-terminal binding domain that recognizes specific motifs on the bacterial surface and a catalytic domain that cleaves covalent linkages within the cell wall peptidoglycan. PlyPH, one such lytic enzyme of bacteriophage origin, has been reported to be highly effective against Bacillus anthracis, and can kill up to 99.99% of the viable bacteria. The bactericidal activity of this enzyme, however, appears to be strongly dependent on the age of the bacterial culture. Although highly bactericidal against cells in the early exponential phase, the enzyme is substantially less effective against stationary phase cells, thus limiting its application in real-world settings. We hypothesized that the binding domain of PlyPH may differ in affinity to cells in different Bacillus growth stages and may be primarily responsible for the age-restricted activity. We therefore employed an in silico approach to identify phage lysins differing in their specificity for the bacterial cell wall. Specifically we focused our attention on Plyβ, an enzyme with improved cell wall-binding ability and age-independent bactericidal activity. Although PlyPH and Plyβ have dissimilar binding domains, their catalytic domains are highly homologous. We characterized the biocatalytic mechanism of Plyβ by identifying the specific bonds cleaved within the cell wall peptidoglycan. Our results provide an example of the diversity of phage endolysins and the opportunity for these biocatalysts to be used for broad-based protection from bacterial pathogens.Quantitative sensory testing (QST), a set of noninvasive methods used to assess sensory and pain perception, has been used for three decades. The precision of the instruments and the uninvasiveness encouraged many QST-based trials. The developments made have benefited multiple disciplines. QST relies on analysis of an individual's response to external stimuli, reflecting the integrity of the PNS and the sensory pathway. The sensory pathway cannot be assessed in isolation from the affective and cognitive characteristics of patients or testers. Many variables potentially affect the reliability and reproducibility of QST, which after all, is designed for the testing of individuals by other individuals. Several decades of QST research have yielded exciting contributions, but the future of QST cannot be fully known.

Although an International Workshop has suggested that cardiovascular assessment in asymptomatic primary hyperparathyroidism (PHPT) patients is not necessary, improvements in risk factors of subclinical atherosclerosis have been shown following parathyroidectomy. The objectives of this study were to determine whether parathyroidectomy in asymptomatic PHPT patients causes any change in carotid intima-media thickness (CIMT), arterial stiffness [pulse wave velocity (PWV)] and soluble CD40 ligand (sCD40L) levels.

Prospective study evaluating female patients diagnosed with asymptomatic PHPT in a single centre over a 6-month period.

A total of 48 subjects were included 17 hypercalcaemic (HC, mean age 51 ± 8 years, Ca 2·73 ± 0·17 mmol/l) and 16 normocalcaemic (NC, mean age 58 ± 7 years, Ca 2·30 ± 0·10 mmol/l) PHPT patients, and 15 healthy controls (mean age 52 ± 4 years, Ca 2·27 ± 0·07 mmol/l).

Biochemical tests, CIMT, PWV and sCD40L levels were compared at baseline and 6 months after parathyroidectomy (PTx).

At baseline, CIMT and PWV values in the HC and NC patients were higher than in the control group. While there was a significant reduction in CIMT (601 ± 91 μm vs 541 ± 65 μm, P = 0·006) and PWV (9·6 ± 1·8 vs 8·4 ± 1·5 m/s, P = 0·000) in the hypercalcaemic group at the end of the 6th month after PTx, no change was observed in normocalcaemic group (P = 0·686 and P = 0·196 respectively). No differences were observed in sCD40L levels between patient and control groups or between baseline and 6 months in patients undergoing parathyroidectomy.

Parathyroidectomy leads to an improvement in the structural and functional impairment associated with atherosclerosis in the vascular wall in asymptomatic hypercalcaemic PHPT patients.

Parathyroidectomy leads to an improvement in the structural and functional impairment associated with atherosclerosis in the vascular wall in asymptomatic hypercalcaemic PHPT patients.

Recent advances in novel targeted therapies have created the need for molecular characterization of cancer to allow accurate personalized treatments. In this study, our aim was to investigate the incidence of activating mutations of oncogenes BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma.

We analyzed a cohort of 57 oral mucosal melanoma samples, including 27 frozen samples and 30 formalin-fixed paraffin-embedded samples. The tumors were screened for hotspot mutations of BRAF (exon 15), NRAS (exons 2 and 3), KIT (exons 9, 11, 13, and 17), and GNAQ/GNA11 (exon 5) by high-resolution melting and direct sequencing.

In oral mucosal melanoma, 7.0% of tumors harbored KIT mutations and 3.5% harbored BRAF mutations, while classic BRAF V600E mutation was not detected. We found no mutations of NRAS or GNAQ/GNA11 in oral mucosal melanoma.

We demonstrated that driver mutations are rare in mutational hotspots of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma. The majority of patients will not benefit from KIT and BRAF inhibitors.

We demonstrated that driver mutations are rare in mutational hotspots of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma. The majority of patients will not benefit from KIT and BRAF inhibitors.Although activity has been reported in vivo, free nucleic acid-based drugs are rapidly degraded and cleared following systemic administration. To address these challenges and improve the potency and bioavailability of genetic drugs, significant efforts have been made to develop effective delivery systems of which lipid nanoparticles (LNP) represent the most advanced technology currently available. In this review, we will describe and discuss the improvements to the pharmacokinetic and pharmacodynamic properties of nucleic acid-based drugs mediated by LNP delivery. It is envisioned that the significant improvements in potency and safety, largely driven by the development of LNP encapsulated siRNA drugs, will be translatable to other types of genetic drugs and enable the rapid development of potent molecular tools and drugs.Fatal enterovirus type-71 (EV71) cases are associated with central nervous system infection characterized by inflammatory cell infiltration and activation, cytokine overproduction, and neuronal cell death. Although EV71 antigen has been detected in neurons and glia, the molecular mechanisms underlying EV71-associated neuroinflammation and neuronal cell death are not fully understood. Using cultured rodent neural cell models, we found that EV71 infection preferentially caused cell death in neurons but not brain-resident immune cells astrocytes and microglia. Neurons, astrocytes, and microglia responded to EV71 infection by releasing distinct profiles of cytokines, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, regulated on activation normal T cell expressed and secreted (RANTES), and glutamate. EV71 infection-induced neuronal cell death correlated well with the elevated production of NO, TNF-α, IL-1β, and glutamate as well as activation of microglia. Exogenous addition studies further demonstrated the neurotoxic potential of NO, TNF-α, IL-1β, and glutamate. EV71 infection-induced cytokine expression was accompanied by activation of protein tyrosine phosphorylation, mitogen-activated protein kinases (MAPKs), and NF-κB. Intriguingly, EV71 susceptibility was accompanied by infection-elevated neuronal human scavenger receptor class B member 2 expression in cultured neural cells with age-dependent manner. Biochemical and pharmacological studies revealed that after EV71 infection, microglia and accompanied cytokines play an active role in triggering bystander damage to neurons involving the tyrosine kinase/MAPKs/NF-κB signaling cascade. These data suggest that bystander damage caused by activated glia particularly the microglia could be an alternative mechanism of EV71-associated neuronal cell death. However, its clinical importance and implication require further investigation.