Effects of Amphetamine on Striatal Dopamine Release, Open-Field Activity, and Play in Fischer 344 and Sprague–Dawley Rats

Previous work from our laboratories has shown that juvenile Fischer 344 (F344) rats are less playful than other strains and also appear to be compromised in dopamine (DA) functioning. To determine whether the dysfunctional play in this strain is associated with deficits in the handling and delivery of vesicular DA, the following experiments assessed the extent to which F344 rats are differentially sensitive to the effects of amphetamine. When exposed to amphetamine, striatal slices obtained from F344 rats showed a small increase in unstimulated DA release when compared with slices from Sprague–Dawley rats; they also showed a more rapid high K+-mediated release of DA. These data provide tentative support for the hypothesis that F344 rats have a higher concentration of cytoplasmic DA than Sprague–Dawley rats. When rats were tested for activity in an open field, F344 rats presented a pattern of results that was consistent with either an enhanced response to amphetamine (3 mg/kg) or a more rapid release of DA (10 mg/kg). Although there was some indication that amphetamine had a dose-dependent differential effect on play in the two strains, play in F344 rats was not enhanced to any degree by amphetamine. Although these results are not consistent with our working hypothesis that F344 rats are less playful because of a deficit in vesicular release of DA, they still suggest that this strain may be a useful model for better understanding the role of DA in social behavior during the juvenile period

Distal unfolding of ferricytochrome C induced by the F82K mutation

It is well known that axial coordination of heme iron in mitochondrial cytochrome c has redox-dependent stability. The Met80 heme iron axial ligand in the ferric form of the protein is relatively labile and can be easily replaced by alternative amino acid side chains under non-native conditions induced by alkaline pH, high temperature, or denaturing agents. Here, we showed a redox-dependent destabilization induced in human cytochrome c by substituting Phe82\u2014conserved amino acid and a key actor in cytochrome c intermolecular interactions\u2014with a Lys residue. Introducing a positive charge at position 82 did not significantly affect the structure of ferrous cytochrome c but caused localized unfolding of the distal site in the ferric state. As revealed by1 H NMR fingerprint, the ferric form of the F82K variant had axial coordination resembling the renowned alkaline species, where the detachment of the native Met80 ligand favored the formation of multiple conformations involving distal Lys residues binding to iron, but with more limited overall structural destabilization

A potential role of il-6/il-6r in the development and management of colon cancer

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second greatest cause of cancer deaths. About 75% of all CRCs are sporadic cancers and arise following somatic mutations, while about 10% are hereditary cancers caused by germline mutations in specific genes. Several factors, such as growth factors, cytokines, and genetic or epigenetic alterations in specific oncogenes or tumor-suppressor genes, play a role during the adenoma–carcinoma sequence. Recent studies have reported an increase in interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels in the sera of patients affected by colon cancer that correlate with the tumor size, suggesting a potential role for IL-6 in colon cancer progression. IL-6 is a pleiotropic cytokine showing both pro-and anti-inflammatory roles. Two different types of IL-6 signaling are known. Classic IL-6 signaling involves the binding of IL-6 to its membrane receptor on the surfaces of target cells; alternatively, IL-6 binds to sIL-6R in a process called IL-6 trans-signaling. The activation of IL-6 transsignaling by metalloproteinases has been described during colon cancer progression and metastasis, involving a shift from membrane-bound interleukin-6 receptor (IL-6R) expression on the tumor cell surface toward the release of soluble IL-6R. In this review, we aim to shed light on the role of IL-6 signaling pathway alterations in sporadic colorectal cancer and the development of familial polyposis syndrome. Furthermore, we evaluate the possible roles of IL-6 and IL-6R as biomarkers useful in disease follow-up and as potential targets for therapy, such as monoclonal antibodies against IL-6 or IL-6R, or a food-based approach against IL-6

Serum or Plasma (and Which Plasma), That Is the Question

Blood derivatives are the biofluids of choice formetabolomic clinical studies since blood can be collected with lowinvasiveness and is rich in biological information. However, the choiceof the blood collection tubes has an undeniable impact on the plasmaand serum metabolic content. Here, we compared the metabolomicand lipoprotein profiles of blood samples collected at the same timeand place from six healthy volunteers but using different collectiontubes (each enrolled volunteer provided multiple blood samples at adistance of a few weeks/months): citrate plasma, EDTA plasma, andserum tubes. All samples were analyzed via nuclear magnetic resonancespectroscopy. Several metabolites showed statistically significantalterations among the three blood matrices, and also metabolites'correlations were shown to be affected. The effects of blood collectiontubes on the lipoproteins'profiles are relevant too, but less marked. Overcoming the issue associated with different blood collectiontubes is pivotal to scale metabolomics and lipoprotein analysis at the level of epidemiological studies based on samples frommulticenter cohorts. We propose a statistical solution, based on regression, that is shown to be efficient in reducing the alterationsinduced by the different collection tubes for both the metabolomic and lipoprotein profile

Iron Binding in the Ferroxidase Site of Human Mitochondrial Ferritin

Ferritins are nanocage proteins that store iron ions in their central cavity as hydrated ferric oxide biominerals. In mammals, further the L (light) and H (heavy) chains constituting cytoplasmic maxi-ferritins, an additional type of ferritin has been identified, the mitochondrial ferritin (MTF). Human MTF (hMTF) is a functional homopolymeric H-like ferritin performing the ferroxidase activity in its ferroxidase site (FS), in which Fe(II) is oxidized to Fe(III) in the presence of dioxygen. To better investigate its ferroxidase properties, here we performed time-lapse X-ray crystallography analysis of hMTF, providing structural evidence of how iron ions interact with hMTF and of their binding to the FS. Transient iron binding sites, populating the pathway along the cage from the iron entry channel to the catalytic center, were also identified. Furthermore, our kinetic data at variable iron loads indicate that the catalytic iron oxidation reaction occurs via a diferric peroxo intermediate followed by the formation of ferric-oxo species, with significant differences with respect to human H-type ferritin

Acute Dacryocystitis with Empyema of the Lacrimal Sac: Is Immediate Endoscopic Dacryocystorhinostomy Justified?

Objectives. To evaluate the efficacy of endoscopic dacryocystorhinostomy (Endo-DCR) in the treatment of acute dacryocystitis with lacrimal sac empyema (ADLSE). Design. Case series with chart review. Setting. Academic tertiary center. Patients. The study included 26 consecutive patients who underwent Endo-DCR for ADLSE between August 2005 and December 2013. Main Outcome Measures. The success of the procedure was defined as complete complaint relief and DCR patency. Data on the time from referral to surgery, postoperative complications, and revision surgery are also reported. Results. The present patient series included 4 males (15.4%) and 22 females (84.6%) (mean age, 66 years). The mean time between referral and surgery was 0.88 days and the mean follow-up time was 29 months. All patients showed immediate relief from symptoms, with no ADLSE recurrences. Complete success was achieved in 25 (96.2%) cases; the only failure was in a patient who had previously undergone radioiodine treatment. In this case, revision Endo-DCR was not successful. The only perioperative complication (3.8%) was epistaxis in a patient who required revision surgery under general anesthesia. The definitive success rate was 96.2% after primary and revision surgery. Conclusions. Endo-DCR enables rapid resolution of ADLSE with a very high success rate. Immediate surgery may reduce the risk of skin fistulization and/or orbital complications. DCR shrinkage and lacrimal obstruction are unlikely with Endo-DCR since the procedure is performed on an enlarged sac. The main advantage of Endo-DCR, compared with external DCR, is the absence of a skin incision in an inflamed and infected field

Pathway Switching Explains the Sharp Response Characteristic of Hypoxia Response Network

Hypoxia induces the expression of genes that alter metabolism through the hypoxia-inducible factor (HIF). A theoretical model based on differential equations of the hypoxia response network has been previously proposed in which a sharp response to changes in oxygen concentration was observed but not quantitatively explained. That model consisted of reactions involving 23 molecular species among which the concentrations of HIF and oxygen were linked through a complex set of reactions. In this paper, we analyze this previous model using a combination of mathematical tools to draw out the key components of the network and explain quantitatively how they contribute to the sharp oxygen response. We find that the switch-like behavior is due to pathway-switching wherein HIF degrades rapidly under normoxia in one pathway, while the other pathway accumulates HIF to trigger downstream genes under hypoxia. The analytic technique is potentially useful in studying larger biomedical networks

Adsorption of the prototypical organic corrosion inhibitor benzotriazole on the Cu(100) surface

The interaction of benzotriazole (BTAH) with Cu(100) has been studied as a function of BTAH exposure in a joint experimental and theoretical effort. Scanning tunnelling microscopy (STM), X-ray photoelectron spectroscopy (XPS), high resolution electron energy loss spectroscopy (HREELS) and density functional theory (DFT) calculations have been combined to elucidate the structural and chemical characteristics of this system. BTAH is found to deprotonate upon adsorption on the copper surface and to adopt an orientation that depends on the molecular coverage. Benzotriazolate (BTA) species initially lie with their planes parallel to the substrate but, at a higher molecular coverage, a transition occurs to an upright adsorption geometry. Upon increasing the BTAH exposure, different phases of vertically aligned BTAs are observed with increasing molecular densities until a final, self-limiting monolayer is developed. Both theory and experiment agree in identifying CuBTA and Cu(BTA)2 metal-organic complexes as the fundamental building blocks of this monolayer. This work shows several similarities with the results of previous studies on the interaction of benzotriazole with other low Miller index copper surfaces, thereby ideally completing and concluding them. The overall emerging picture constitutes an important starting point for understanding the mechanism for protection of copper from corrosion